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1.
Appl Microbiol Biotechnol ; 108(1): 355, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38822832

ABSTRACT

Getah virus (GETV) is a re-emerging mosquito-borne alphavirus that is highly pathogenic, mainly to pigs and horses. There are no vaccines or treatments available for GETV in swine in China. Therefore, the development of a simple, rapid, specific, and sensitive serological assay for GETV antibodies is essential for the prevention and control of GETV. Current antibody monitoring methods are time-consuming, expensive, and dependent on specialized instrumentation, and these features are not conducive to rapid detection in clinical samples. To address these problem, we developed immunochromatographic test strips (ICTS) using eukaryotically expressed soluble recombinant p62-E1 protein of GETV as a labelled antigen, which has good detection sensitivity and no cross-reactivity with other common porcine virus-positive sera. The ICTS is highly compatible with IFA and ELISA and can be stored for 1 month at 37 °C and for at least 3 months at room temperature. Hence, p62-E1-based ICTS is a rapid, accurate, and convenient method for rapid on-site detection of GETV antibodies. KEY POINTS: • We established a rapid antibody detection method that can monitor GETV infection • We developed colloidal gold test strips with high sensitivity and specificity • The development of colloidal gold test strips will aid in the field serologic detection of GETV.


Subject(s)
Alphavirus , Antibodies, Viral , Gold Colloid , Sensitivity and Specificity , Animals , Gold Colloid/chemistry , Antibodies, Viral/blood , Antibodies, Viral/immunology , Alphavirus/immunology , Swine , Chromatography, Affinity/methods , Alphavirus Infections/diagnosis , Alphavirus Infections/immunology , Swine Diseases/diagnosis , Swine Diseases/virology , Reagent Strips , China , Enzyme-Linked Immunosorbent Assay/methods
2.
ISA Trans ; 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38879427

ABSTRACT

This paper proposes an observer-based hierarchical distributed model predictive control (MPC) strategy for ensuring speed consistency in multi-linear motor traction systems. First, a communication topology is considered to ensure information exchange. Secondly, the control architecture of each agent is divided into upper layers and lower layers. The upper layer utilizes a distributed MPC method to track the leader's speed. The lower layer uses a decentralized MPC method to track the command signals sent by its upper layer controller. In addition, to eliminate the negative impact of disturbance, a nonlinear disturbance observer is designed. We then prove the asymptotic stability of the entire system by properly designing the Lyapunov equation. Finally, the feasibility of the proposed strategy is verified based on several simulations.

3.
J Gene Med ; 26(6): e3693, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38860366

ABSTRACT

BACKGROUND: Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC. METHODS: An HCC model was established in male Sprague-Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of Il17a was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses. RESULTS: The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing Fap in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs. CONCLUSIONS: The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.


Subject(s)
Carcinoma, Hepatocellular , Hepatic Stellate Cells , Interleukin-17 , Liver Neoplasms , Animals , Humans , Male , Rats , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Disease Models, Animal , Endopeptidases/metabolism , Endopeptidases/genetics , Gene Expression Regulation, Neoplastic , Hepatic Stellate Cells/metabolism , Interleukin-17/metabolism , Interleukin-17/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Membrane Proteins/metabolism , Membrane Proteins/genetics , Rats, Sprague-Dawley , Tumor Microenvironment
4.
bioRxiv ; 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38746359

ABSTRACT

Ferroptosis is a cell death mechanism that has attracted significant attention as a potential basis for the development of new cancer therapies. Validation of ferroptosis biology in species commonly used in translation and pre-clinical development is a necessary foundation for enabling the advancement of such ferroptosis modulating drugs. Here, we demonstrate that canine cancer cells exhibit sensitivity to a wide range of ferroptosis-inducing perturbations in a manner indistinguishable from human cancer cells, and recapitulate characteristic patterns of ferroptotic response across tumor types seen in the human setting. The foundation provided herein establishes the dog as a relevant efficacy and toxicology model for ferroptosis and creates new opportunities to leverage the canine comparative oncology paradigm to accelerate the development of ferroptosis-inducing drugs for human cancer patients.

5.
IEEE Trans Cybern ; PP2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38557610

ABSTRACT

In this article, a novel approach of prescribed performance synchronization control is developed for heterogeneous nonlinear multiagent systems (MASs) subject to unknown actuator faults. Considering that not all followers are able to access the information of the leader, a distributed auxiliary perception system is proposed to estimate the state information of the leader to guarantee that the estimation errors converge to zero within fixed time. Then, based on the estimated states, a prescribed performance fault-tolerant control (FTC) approach is proposed, which achieves the user-defined performance specifications even in the presence of system faults. Moreover, as accurate system dynamic models are perhaps hard to acquire in practical engineering, a data-based method is proposed by using the reinforcement learning (RL) algorithm to design the fault-tolerant controller, which only needs the off-policy online data and is independent of the model dynamics of followers. The stability and synchronization with the prescribed behavior are guaranteed through the Lyapunov stability theorem. Finally, simulation results are presented to illustrate the effectiveness of the developed controller.

6.
J Med Chem ; 67(4): 2986-3003, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38347756

ABSTRACT

Although ß2-agonists are crucial for treatment of chronic respiratory diseases, optimizing ß2-agonistic activity and selectivity remains essential for achieving favorable therapeutic outcomes. A structure-based molecular design workflow was employed to discover a novel class of ß2 agonists featuring a 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold, which potently stimulated ß2 adrenoceptors (ß2-ARs). Screening for the ß2-agonistic activity and selectivity led to the identification of compound A19 (EC50 = 3.7 pM), which functioned as a partial ß2-agonist in HEK-293 cells containing endogenous ß2-ARs. Compound A19 exhibited significant relaxant effects, rapid onset time (Ot50 = 2.14 min), and long duration of action (>12 h) on isolated guinea pig tracheal strips, as well as advantageous pharmacokinetic characteristics in vivo, rendering A19 suitable for inhalation administration. Moreover, A19 suppressed the upregulation of inflammatory cytokines and leukocytes and improved lung function in a rat model of COPD, thereby indicating that A19 is a potential ß2 agonist candidate for further study.


Subject(s)
Adrenergic beta-2 Receptor Agonists , Receptors, Adrenergic, beta-2 , Humans , Rats , Animals , Guinea Pigs , HEK293 Cells , Adrenergic beta-2 Receptor Agonists/pharmacology
7.
Zhongguo Zhong Yao Za Zhi ; 48(13): 3589-3601, 2023 Jul.
Article in Chinese | MEDLINE | ID: mdl-37474992

ABSTRACT

This study aimed to explore the anti-glioma effect of natural compound pterostilbene(PTE) through regulating pyroptosis and apoptosis pathways, and to analyze the possible anti-glioma pathways and targets of PTE by network pharmacology and molecular docking. In this study, the action targets of PTE and the glioma targets were obtained by network pharmacology to construct a target network and a protein-protein interaction(PPI) network to predict the possible action targets of PTE against glioma. Molecular docking was performed on the core targets by AutoDock and the action pathways of PTE against glioma were predicted by enrichment analysis. In addition, the effect of PTE on the viability of U87MG and GL261 glioma cells was detected by CCK-8 assay. Clone formation assay and cell scratching assay were used to explore the effect of different concentrations of PTE on the proliferation and migration, respectively of glioma cells. Hoechst staining was used to observe PTE-induced apoptosis in glioma cells. The changes in mitochondrial membrane potential were detected by JC-1 staining. The pyroptosis-inducing effect of PTE on glioma cells was observed by inverted microscopy and lactate dehydrogenase(LDH) assay. Hoechst 33342/PI dual staining assay was performed to detect the integrity of glioma cell membranes. The expressions of pyroptosis and apoptosis-related proteins in glioma cells after PTE induction were determined by Western blot. In this study, 37 anti-glioma targets of PTE were obtained, and enrichment analysis suggested that PTE exerted anti-glioma effects through various signaling pathways including cancer pathway, proteoglycan in cancer, PI3K/AKT pathway, and apoptosis regulatory pathway. Molecular docking revealed that PTE had good binding activity with the main targets. Compared with the control group, PTE significantly reduced the viability as well as the proliferation, migration and adhesion abilities of U87MG and GL261 cells; it induced the apoptosis of the two glioma cells and the decrease of mitochondrial membrane potential in U87MG cells, and the effects increased with the increase of drug concentration. Compared with the conditions in the control group, glioma cells in the PTE group had increased pyroptosis-specific appearance and gradually increased LDH release; the number of PI positive cells was significantly elevated with the increase of PTE concentration as revealed by Hoechst 33342/PI staining; the expression levels of apoptosis-related factors cleaved PARP1 and B-cell lymphoma-2(Bcl-2) associated X(BAX) in the PTE group were markedly up-regulated, while the expression level of Bcl-2 was markedly down-regulated; the activation levels of pyroptosis-related proteins cleaved caspase-3 and gasdermin E-N(GSDME-N) had a remarkable rise in the PTE group, while no significant changes were found in the activation levels of gasdermin D-N(GSDMD-N) and cleaved caspase-1. In summary, PTE plays an anti-glioma role by inhibiting cell viability, proliferation, and migration and activating the caspase-3/GSDME-mediated pyroptosis pathway and mitochondrial apoptosis pathway.


Subject(s)
Network Pharmacology , Pyroptosis , Caspase 3/metabolism , Gasdermins , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Apoptosis , Proto-Oncogene Proteins c-bcl-2/metabolism
8.
World J Clin Cases ; 11(11): 2482-2488, 2023 Apr 16.
Article in English | MEDLINE | ID: mdl-37123316

ABSTRACT

BACKGROUND: Reports on perioperative anesthesia management in pediatric patients with difficult airways are scarce. In addition to relatively more difficulties in the technique of endotracheal intubation, the time for manipulation is restricted compared to adults. Securing the airways safely and avoiding the occurrence of hypoxemia in these patients are of significance. CASE SUMMARY: A 9-year-old boy with spastic cerebral palsy, severe malnutrition, thoracic scoliosis, thoracic and airway malformation, laryngomalacia, pneumonia, and epilepsy faced the risk of anesthesia during palliative surgery. After a thorough preoperative evaluation, a detailed scheme for anesthesia and a series of intubation tools were prepared by a team of anesthesiologists. Awake fiberoptic intubation is the widely accepted strategy for patients with anticipated difficult airways. Given the age and medical condition of the patient, we kept him sedated with spontaneous breathing during endotracheal intubation. The endotracheal intubation was completed on the second attempt after the failure of the first effort. Fortunately, the surgery was successful without postoperative complications. CONCLUSION: Dealing with difficult airways in the pediatric population, proper sedation allows time to intubate without interrupting spontaneous breathing. The appropriate endotracheal intubation method based on the patient's unique characteristics is the key factor in successful management of these rare cases.

9.
Sci Rep ; 13(1): 7657, 2023 05 11.
Article in English | MEDLINE | ID: mdl-37169808

ABSTRACT

Analysis of the changes of microorganisms during Chinese Feng-flavor Daqu fermentation, and the specific contribution of different environmental factors to Daqu microorganisms. High throughput sequencing technology and SourceTracker software were used to analyze the microbial diversity of Feng-flavor Daqu before and after fermentation. 85 fungal and 105 bacterial were detected in the newly pressed Feng-flavor Daqu, while 33 fungal and 50 bacterial in the mature Daqu, and 202 fungal and 555 bacterial in the environmental samples. After fermentation, the microbial community structure of Daqu changed and decreased significantly. 94.7% of fungi come from raw materials and 1.8% from outdoor ground, 60.95% of bacteria come from indoor ground, 20.44% from raw materials, and 8.98% from tools. By comparing the changes of microorganisms in Daqu before and after fermentation, the microorganisms in mature Daqu may mainly come from not only the enhanced strains but also the environment.The source of main microorganisms in Feng-flavor Daqu and the influence of environmental factors on the quality of Daqu were clarified, which provided a basis for improving the quality of Feng-flavor Daqu.


Subject(s)
Alcoholic Beverages , Microbiota , Alcoholic Beverages/microbiology , Bacteria/genetics , Fermentation
10.
Cell Death Dis ; 14(4): 269, 2023 04 14.
Article in English | MEDLINE | ID: mdl-37059730

ABSTRACT

Hypoxia contributes to the initiation and progression of glioblastoma by regulating a cohort of genes called hypoxia-regulated genes (HRGs) which form a complex molecular interacting network (HRG-MINW). Transcription factors (TFs) often play central roles for MINW. The key TFs for hypoxia induced reactions were explored using proteomic analysis to identify a set of hypoxia-regulated proteins (HRPs) in GBM cells. Next, systematic TF analysis identified CEBPD as a top TF that regulates the greatest number of HRPs and HRGs. Clinical sample and public database analysis revealed that CEBPD is significantly up-regulated in GBM, high levels of CEBPD predict poor prognosis. In addition, CEBPD is highly expressed in hypoxic condition both in GBM tissue and cell lines. For molecular mechanisms, HIF1α and HIF2α can activate the CEBPD promotor. In vitro and in vivo experiments demonstrated that CEBPD knockdown impaired the invasion and growth capacity of GBM cells, especially in hypoxia condition. Next, proteomic analysis identified that CEBPD target proteins are mainly involved in the EGFR/PI3K pathway and extracellular matrix (ECM) functions. WB assays revealed that CEBPD significantly positively regulated EGFR/PI3K pathway. Chromatin immunoprecipitation (ChIP) qPCR/Seq analysis and Luciferase reporter assay demonstrated that CEBPD binds and activates the promotor of a key ECM protein FN1 (fibronectin). In addition, the interactions of FN1 and its integrin receptors are necessary for CEBPD-induced EGFR/PI3K activation by promoting EGFR phosphorylation. Furthermore, GBM sample analysis in the database corroborated that CEBPD is positively correlated with the pathway activities of EGFR/PI3K and HIF1α, especially in highly hypoxic samples. At last, HRPs are also enriched in ECM proteins, indicating that ECM activities are important components of hypoxia induced responses in GBM. In conclusion, CEPBD plays important regulatory roles in the GBM HRG-MINW as a key TF, which activates the EGFR/PI3K pathway through ECM, especially FN1, mediated EGFR phosphorylation.


Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/genetics , Glioblastoma/metabolism , Signal Transduction , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Transcription Factors , Proteomics , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Cell Line, Tumor , Hypoxia/genetics , Hypoxia/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Extracellular Matrix/metabolism , CCAAT-Enhancer-Binding Protein-delta/metabolism
11.
Front Oncol ; 13: 1095357, 2023.
Article in English | MEDLINE | ID: mdl-36969010

ABSTRACT

Background: The differences in short- and long-term outcome between laparoscopic liver resection (LLR) and open liver resection (OLR) for BCLC stage A large hepatocellular carcinoma (HCC) in difficult segments (I, IVa, VII, VIII) remain unclear. This PSM two-centre study aimed to compare perioperative and long-term survival outcomes of LLR with OLR for this HCC. Methods: HCC patients with BCLC stage A who underwent OLR or LLR in two medical centres were enrolled in the study. PSM analysis was performed to match patients between the LLR cohort and OLR cohort. Survival was analysed based on the Kaplan-Meier method. Independent risk factors were identified by Cox regression. Results: After PSM, 35 patients remained in the LLR cohort, and 84 remained in the OLR cohort. Patients in the LLR cohort had more intraoperative blood loss (p=0.036) and shorter hospital stays after surgery (p<0.001). The LLR cohort and OLR cohort had no difference in intraoperative blood transfusion, surgical margin or postoperative short-term outcomes. The OS and RFS were not significantly different between the two cohorts. The OS and RFS of these two cohorts were not different in the subgroup analysis. Surgical margin was identified as an independent risk factor for tumour recurrence. Conclusion: For BCLC stage A large HCC patients with lesions in difficult segments, LLR was feasible and had shorter hospital stay than OLR. In addition, a surgical margin ≥1 cm could significantly decrease the recurrence probability for large HCC located in different segments without compromising short-term outcomes.

12.
IEEE Trans Med Imaging ; 42(2): 481-492, 2023 02.
Article in English | MEDLINE | ID: mdl-36227826

ABSTRACT

Automatic segmentation and differentiation of retinal arteriole and venule (AV), defined as small blood vessels directly before and after the capillary plexus, are of great importance for the diagnosis of various eye diseases and systemic diseases, such as diabetic retinopathy, hypertension, and cardiovascular diseases. Optical coherence tomography angiography (OCTA) is a recent imaging modality that provides capillary-level blood flow information. However, OCTA does not have the colorimetric and geometric differences between AV as the fundus photography does. Various methods have been proposed to differentiate AV in OCTA, which typically needs the guidance of other imaging modalities. In this study, we propose a cascaded neural network to automatically segment and differentiate AV solely based on OCTA. A convolutional neural network (CNN) module is first applied to generate an initial segmentation, followed by a graph neural network (GNN) to improve the connectivity of the initial segmentation. Various CNN and GNN architectures are employed and compared. The proposed method is evaluated on multi-center clinical datasets, including 3 ×3 mm2 and 6 ×6 mm2 OCTA. The proposed method holds the potential to enrich OCTA image information for the diagnosis of various diseases.


Subject(s)
Angiography , Retinal Vessels , Tomography, Optical Coherence , Venules , Humans , Neural Networks, Computer , Deep Learning , Retinal Vessels/diagnostic imaging , Venules/diagnostic imaging
13.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-981490

ABSTRACT

This study aimed to explore the anti-glioma effect of natural compound pterostilbene(PTE) through regulating pyroptosis and apoptosis pathways, and to analyze the possible anti-glioma pathways and targets of PTE by network pharmacology and molecular docking. In this study, the action targets of PTE and the glioma targets were obtained by network pharmacology to construct a target network and a protein-protein interaction(PPI) network to predict the possible action targets of PTE against glioma. Molecular docking was performed on the core targets by AutoDock and the action pathways of PTE against glioma were predicted by enrichment analysis. In addition, the effect of PTE on the viability of U87MG and GL261 glioma cells was detected by CCK-8 assay. Clone formation assay and cell scratching assay were used to explore the effect of different concentrations of PTE on the proliferation and migration, respectively of glioma cells. Hoechst staining was used to observe PTE-induced apoptosis in glioma cells. The changes in mitochondrial membrane potential were detected by JC-1 staining. The pyroptosis-inducing effect of PTE on glioma cells was observed by inverted microscopy and lactate dehydrogenase(LDH) assay. Hoechst 33342/PI dual staining assay was performed to detect the integrity of glioma cell membranes. The expressions of pyroptosis and apoptosis-related proteins in glioma cells after PTE induction were determined by Western blot. In this study, 37 anti-glioma targets of PTE were obtained, and enrichment analysis suggested that PTE exerted anti-glioma effects through various signaling pathways including cancer pathway, proteoglycan in cancer, PI3K/AKT pathway, and apoptosis regulatory pathway. Molecular docking revealed that PTE had good binding activity with the main targets. Compared with the control group, PTE significantly reduced the viability as well as the proliferation, migration and adhesion abilities of U87MG and GL261 cells; it induced the apoptosis of the two glioma cells and the decrease of mitochondrial membrane potential in U87MG cells, and the effects increased with the increase of drug concentration. Compared with the conditions in the control group, glioma cells in the PTE group had increased pyroptosis-specific appearance and gradually increased LDH release; the number of PI positive cells was significantly elevated with the increase of PTE concentration as revealed by Hoechst 33342/PI staining; the expression levels of apoptosis-related factors cleaved PARP1 and B-cell lymphoma-2(Bcl-2) associated X(BAX) in the PTE group were markedly up-regulated, while the expression level of Bcl-2 was markedly down-regulated; the activation levels of pyroptosis-related proteins cleaved caspase-3 and gasdermin E-N(GSDME-N) had a remarkable rise in the PTE group, while no significant changes were found in the activation levels of gasdermin D-N(GSDMD-N) and cleaved caspase-1. In summary, PTE plays an anti-glioma role by inhibiting cell viability, proliferation, and migration and activating the caspase-3/GSDME-mediated pyroptosis pathway and mitochondrial apoptosis pathway.


Subject(s)
Pyroptosis , Caspase 3/metabolism , Network Pharmacology , Gasdermins , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Apoptosis , Proto-Oncogene Proteins c-bcl-2/metabolism
14.
Mol Metab ; 66: 101611, 2022 12.
Article in English | MEDLINE | ID: mdl-36220546

ABSTRACT

OBJECTIVE: Branched chain amino acid (BCAA) catabolic defects are implicated to be causal determinates of multiple diseases. This work aimed to better understand how enhancing BCAA catabolism affected metabolic homeostasis as well as the mechanisms underlying these improvements. METHODS: The rate limiting step of BCAA catabolism is the irreversible decarboxylation by the branched chain ketoacid dehydrogenase (BCKDH) enzyme complex, which is post-translationally controlled through phosphorylation by BCKDH kinase (BDK). This study utilized BT2, a small molecule allosteric inhibitor of BDK, in multiple mouse models of metabolic dysfunction and NAFLD including the high fat diet (HFD) model with acute and chronic treatment paradigms, the choline deficient and methionine minimal high fat diet (CDAHFD) model, and the low-density lipoprotein receptor null mouse model (Ldlr-/-). shRNA was additionally used to knock down BDK in liver to elucidate liver-specific effects of BDK inhibition in HFD-fed mice. RESULTS: A rapid improvement in insulin sensitivity was observed in HFD-fed and lean mice after BT2 treatment. Resistance to steatosis was assessed in HFD-fed mice, CDAHFD-fed mice, and Ldlr-/- mice. In all cases, BT2 treatment reduced steatosis and/or inflammation. Fasting and refeeding demonstrated a lack of response to feeding-induced changes in plasma metabolites including insulin and beta-hydroxybutyrate and hepatic gene changes in BT2-treated mice. Mechanistically, BT2 treatment acutely altered the expression of genes involved in fatty acid oxidation and lipogenesis in liver, and upstream regulator analysis suggested that BT2 treatment activated PPARα. However, BT2 did not directly activate PPARα in vitro. Conversely, shRNA-AAV-mediated knockdown of BDK specifically in liver in vivo did not demonstrate any effects on glycemia, steatosis, or PPARα-mediated gene expression in mice. CONCLUSIONS: These data suggest that BT2 treatment acutely improves metabolism and liver steatosis in multiple mouse models. While many molecular changes occur in liver in BT2-treated mice, these changes were not observed in mice with AAV-mediated shRNA knockdown of BDK. All together, these data suggest that systemic BDK inhibition is required to improve metabolism and steatosis by prolonging a fasting signature in a paracrine manner. Therefore, BCAA may act as a "fed signal" to promote nutrient storage and reduced systemic BCAA levels as shown in this study via BDK inhibition may act as a "fasting signal" to prolong the catabolic state.


Subject(s)
Fatty Liver , PPAR alpha , Animals , Mice , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/metabolism , Amino Acids, Branched-Chain/metabolism , Fasting , Mice, Knockout , RNA, Small Interfering
15.
ACS Appl Mater Interfaces ; 14(38): 43362-43371, 2022 Sep 28.
Article in English | MEDLINE | ID: mdl-36112767

ABSTRACT

Owing to narrow band gap and low toxicity, tin-lead (Sn-Pb) hybrid perovskites have shown great potential in photovoltaic applications, and the highest power conversion efficiency (PCE) of Sn-Pb perovskite solar cells (PSCs) has recently reached 23.6%. However, it is still challenging to prepare Sn-Pb films in open-air condition due to the Sn2+ oxidation of the precursor solution under this condition. In this work, we report the stabilizing of the Sn-Pb perovskite precursor solution by using ionic liquid methylammonium acetate (MAAc) as the solvent, which enables the fabrication of Sn-Pb films in air. MAAc is found to coordinate with the Sn-Pb precursor via abundant hydrogen bonding, which stabilizes the colloids and protects the Sn2+ stability in the precursor solution in air. Therefore, the durability of the Sn-Pb precursor solution based on the MAAc solvent is greatly improved, which enables the fabrication of efficient PSCs and achieves a champion PCE of ∼16% with robust device stability. Moreover, due to the chemical interactions of MAAc with Sn-Pb perovskites, the Pb leakage is also suppressed in the MAAc-based Sn-Pb PSCs. This work demonstrates a feasible strategy for reliable fabrication of Sn-Pb PSCs, which could also be applied in many other optoelectronic devices.

16.
Front Pharmacol ; 13: 990505, 2022.
Article in English | MEDLINE | ID: mdl-36059964

ABSTRACT

Nanoparticles based on single-component synthetic polymers, such as poly (lactic acid-co-glycolic acid) (PLGA), have been extensively studied for antitumor drug delivery and adjuvant therapy due to their ability to encapsulate and release drugs, as well as passively target tumors. Amphiphilic block co-polymers, such as polyethylene glycol (PEG)-PLGA, have also been used to prepare multifunctional nanodrug delivery systems with prolonged circulation time and greater bioavailability that can encapsulate a wider variety of drugs, including small molecules, gene-targeting drugs, traditional Chinese medicine (TCM) and multi-target enzyme inhibitors, enhancing their antitumor effect and safety. In addition, the surface of PEG-PLGA nanoparticles has been modified with various ligands to achieve active targeting and selective accumulation of antitumor drugs in tumor cells. Modification with two ligands has also been applied with good antitumor effects, while the use of imaging agents and pH-responsive or magnetic materials has paved the way for the application of such nanoparticles in clinical diagnosis. In this work, we provide an overview of the synthesis and application of PEG-PLGA nanoparticles in cancer treatment and we discuss the recent advances in ligand modification for active tumor targeting.

17.
Front Microbiol ; 13: 943707, 2022.
Article in English | MEDLINE | ID: mdl-35992698

ABSTRACT

The highly virulent and antigenic variant of Pseudorabies virus (PRV) that emerged from classical Bartha-K61-vaccinated pig herds has caused substantial economic losses to the swine industry in China since 2011. A safe and more effective vaccine is most desirable. In this study, a gE/TK gene-deficient PRV, namely, HD/c, was constructed based on a PRV type II DX strain isolated from a commercial vaccine-immunized farm and the HD/c-based inactivated vaccine was formulated and evaluated for its safety, immunogenicity, and protective efficacy in mice and piglets. The resulting PRV HD/c strain has a similar growth curve to the parental DX strain. After vaccination, the inactivated HD/c vaccine did not cause any visible gross pathological or histopathological changes in the tissues of mice and piglets and provided rapid and potent protection against the challenge of the classical and variant PRVs at day 21 post-vaccination in mice. A single immunization of 108.5TCID50 inactivated PRV HD/c strain-elicited robust immunity with high titer of neutralizing antibody and provided complete protection from the lethal challenge of PRV DX strain in piglets. These results indicated that the inactivated PRV HD/c vaccine with the deletion of gE/TK genes was a safe and effective PRV vaccine candidate for the control of PRV.

18.
Microbiol Spectr ; 10(3): e0024222, 2022 06 29.
Article in English | MEDLINE | ID: mdl-35647875

ABSTRACT

Paramyxoviridae is a rapidly growing family of viruses, whose potential for cross-species transmission makes it difficult to predict the harm of newly emerging viruses to humans and animals. To better understand their diversity, evolutionary history, and co-evolution with their hosts, we analyzed a collection of porcine parainfluenza virus (PPIV) genomes to reconstruct the species classification basis and evolutionary history of the Respirovirus genus. We sequenced 17 complete genomes of porcine respirovirus 1 (also known as porcine parainfluenza virus 1; PPIV-1), thereby nearly tripling the number of currently available PPIV-1 genomes. We found that PPIV-1 was widely prevalent in China with two divergent lineages, PPIV-1a and PPIV-1b. We further provided evidence that a new species, porcine parainfluenza virus 2 (PPIV-2), had recently emerged in China. Our results pointed to a need for revising the current species demarcation criteria of the Respirovirus genus. In addition, we used PPIV-1 as an example to explore recombination and diversity of the Respirovirus genus. Interestingly, we only detected heterosubtypic recombination events between PPIV-1a and PPIV-1b with no intrasubtypic recombination events. The recombination hotspots highlighted a diverse geography-dependent genome structure of paramyxovirus infecting swine in China. Furthermore, we found no evidence of co-evolution between respirovirus and its host, indicating frequent cross-species transmission. In summary, our analyses showed that swine can be infected with a broad range of respiroviruses and recombination may serve as an important evolutionary mechanism for the Respirovirus genus' greater diversity in genome structure than previously anticipated. IMPORTANCE Livestock have emerged as critically underrecognized sources of paramyxovirus diversity, including pigs serving as the source of Nipah virus (NiV) and swine parainfluenza virus type 3, and goats and bovines harboring highly divergent viral lineages. Here, we identified a new species of Respirovirus genus named PPIV-2 in swine and proposed to revise the species demarcation criteria of the Respirovirus genus. We found heterosubtypic recombination events and high genetic diversity in PPIV-1. Further, we showed that genetic recombination may have occurred in the Respirovirus genus which may be associated with host range expansion. The continued expansion of Respirovirus genus diversity in livestock with relatively high human contact rates requires enhanced surveillance and ongoing evaluation of emerging cross-species transmission threats.


Subject(s)
Paramyxoviridae Infections , Swine Diseases , Animals , Cattle , Genetic Variation , Paramyxoviridae Infections/epidemiology , Paramyxoviridae Infections/veterinary , Phylogeny , Respirovirus , Swine , Swine Diseases/epidemiology
19.
Chem Res Toxicol ; 35(6): 1059-1069, 2022 06 20.
Article in English | MEDLINE | ID: mdl-35575346

ABSTRACT

As a selective ß1-receptor antagonist, metoprolol tartrate (MTA) is commonly used to treat cardiovascular diseases such as hypertension and angina pectoris. There have been cases of liver injury induced by MTA, but the mechanism of hepatotoxicity induced by MTA is not clear. The purposes of this study were to identify the reactive metabolites of MTA, to determine the pathway for the metabolic activation of MTA, and to define a possible correlation between the metabolic activation and cytotoxicity of MTA. Three oxidative metabolites (M1-M3), a glutathione (GSH) conjugate (M4), and an N-acetyl cysteine (NAC) conjugate (M5) were detected in rat liver microsomal incubations containing MTA and GSH or NAC. M4 was also detected in cultured rat primary hepatocytes and bile of rats given MTA, and M5 was detected in the urine of MTA-treated rats. A quinone methide intermediate may be produced from the metabolic activation process in vitro and in vivo. The metabolite was reactive to glutathione and N-acetyl cysteine. MTA induced marked cytotoxicity in cultured rat primary hepatocytes. Pretreatment of aminobenzotriazole, a nonselective P450 enzyme inhibitor, attenuated the susceptibility of hepatocytes to MTA cytotoxicity.


Subject(s)
Metoprolol , Microsomes, Liver , Animals , Rats , Acetylcysteine/metabolism , Acetylcysteine/pharmacology , Glutathione/metabolism , Metoprolol/metabolism , Metoprolol/pharmacology , Microsomes, Liver/metabolism
20.
FEBS Open Bio ; 12(7): 1406-1418, 2022 07.
Article in English | MEDLINE | ID: mdl-35560988

ABSTRACT

As a model system, Escherichia coli has been used to study various life processes. A dramatic paradigm shift has occurred in recent years, with the study of single proteins moving toward the study of dynamically interacting proteins, especially protein-protein interaction (PPI) networks. However, despite the importance of PPI networks, little is known about the intrinsic nature of the network structure, especially high-dimensional topological properties. By introducing general hypergeometric distribution, we reconstruct a statistically reliable combined PPI network of E. coli (E. coli-PPI-Network) from several datasets. Unlike traditional graph analysis, algebraic topology was introduced to analyze the topological structures of the E. coli-PPI-Network, including high-dimensional cavities and cycles. Random networks with the same node and edge number (RandomNet) or scale-free networks with the same degree distribution (RandomNet-SameDD) were produced as controls. We discovered that the E. coli-PPI-Network had special algebraic typological structures, exhibiting more high-dimensional cavities and cycles, compared to RandomNets or, importantly, RandomNet-SameDD. Based on these results, we defined degree of involved q-dimensional cycles of proteins (q-DCprotein ) in the network, a novel concept that relies on the integral structure of the network and is different from traditional node degree or hubs. Finally, top proteins ranked by their 1-DCprotein were identified (such as gmhB, rpoA, rplB, rpsF and yfgB). In conclusion, by introducing mathematical and computer technologies, we discovered novel algebraic topological properties of the E. coli-PPI-Network, which has special high-dimensional cavities and cycles, and thereby revealed certain intrinsic rules of information flow underlining bacteria biology.


Subject(s)
Protein Interaction Mapping , Protein Interaction Maps , Escherichia coli/genetics , Escherichia coli/metabolism , Models, Biological , Protein Interaction Mapping/methods , Proteins/metabolism
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