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1.
Artigo em Inglês | MEDLINE | ID: mdl-38623977

RESUMO

Polygonum multiflorum Thunb. (PMT) has shown promise in exerting cerebrovascular protective effects, and its potential for treating ischemic stroke (IS) has garnered attention. However, the lack of clarity regarding its chemical constituents and mechanisms has significantly hindered its clinical application. In this study, we employed network pharmacology and molecular docking techniques for the first time to elucidate the potential compounds and targets of PMT in treating IS. The databases CTD, DrugBank, DisGeNET, GeneCards, OMIM, TTD, PGKB, NCBI, TCMIP, CNKI, PubMed, ZINC, STITCH, BATMAN, ETCM and Swiss provided information on targets related to IS and components of PMT, along with their associated targets. We constructed "compound-target" and protein-protein interaction (PPI) networks sourced from the STRING database using the Cytoscape software. Gene Ontology (GO) enrichment analysis and KEGG pathway analysis were conducted using the DAVID database. Molecular docking between core targets and active compounds was conducted using Autodock4 software. Experiments were performed in an oxygen-glucose deprivation and reperfusion (OGD/R) model to validate the anti-IS activity of compounds isolated from PMT preliminarily. Network pharmacological analysis revealed 16 core compounds, including resveratrol, polydatin, TSG, ω- hydroxyemodin, emodin anthrone, tricin, moupinamide, and others, along with 11 high-degree targets, such as PTGS1, PTGS2, ADORA1, ADORA2, CA1, EGFR, ESR1, ESR2, SRC, MMP3 and MMP9. GO and KEGG enrichment analyses revealed the involvement of HIF-1, Akt signaling pathway and energy metabolism-related signaling pathways. Molecular docking results emphasized eight key compounds and confirmed their interactions with corresponding targets. In vitro OGD/R model experiments identified TSG and tricin as the primary active substances within PMT for its anti-stroke activity. This study contributes new insights into the potential development of PMT for stroke prevention and treatment.

2.
J Hum Genet ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565611

RESUMO

Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.

3.
Front Oncol ; 14: 1308317, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38549935

RESUMO

Objective: To evaluate the value of a machine learning model using enhanced CT radiomics features in the prediction of lymphovascular invasion (LVI) of esophageal squamous cell carcinoma (ESCC) before treatment. Methods: We reviewed and analyzed the enhanced CT images of 258 ESCC patients from June 2017 to December 2019. We randomly assigned the patients in a ratio of 7:3 to a training set (182 cases) and a validation (76 cases) set. Clinical risk factors and CT image characteristics were recorded, and multifactor logistic regression was used to screen independent risk factors of LVI of ESCC patients. We extracted the CT radiomics features using the FAE software and screened radiomics features using maximum relevance and minimum redundancy (MRMR) and least absolute shrinkage and selection operator (LASSO) algorithms, and finally, the radiomics labels of each patient were established. Five machine learning algorithms, namely, support vector machine (SVM), K-nearest neighbor (KNN), logistic regression (LR), Gauss naive Bayes (GNB), and multilayer perceptron (MLP), were used to construct the model of radiomics labels, and its clinical features were screened. The predictive efficacy of the machine learning model for LVI of ESCC was evaluated using the receiver operating characteristic (ROC) curve. Results: Tumor thickness [OR = 1.189, 95% confidence interval (CI) 1.060-1.351, P = 0.005], tumor-to-normal wall enhancement ratio (TNR) (OR = 2.966, 95% CI 1.174-7.894, P = 0.024), and clinical N stage (OR = 5.828, 95% CI 1.752-20.811, P = 0.005) were determined as independent risk factors of LVI. We extracted 1,316 features from preoperative enhanced CT images and selected 14 radiomics features using MRMR and LASSO to construct the radiomics labels. In the test set, SVM, KNN, LR, and GNB showed high predictive performance, while the MLP model had poor performance. In the training set, the area under the curve (AUC) values were 0.945 and 0.905 in the KNN and SVM models, but these decreased to 0.866 and 0.867 in the validation set, indicating significant overfitting. The GNB and LR models had AUC values of 0.905 and 0.911 in the training set and 0.900 and 0.893 in the validation set, with stable performance and good fitting and predictive ability. The MLP model had AUC values of 0.658 and 0.674 in the training and validation sets, indicating poor performance. A multiscale combined model constructed using multivariate logistic regression has an AUC of 0.911 (0.870-0.951) and 0.893 (0.840-0.962), accuracy of 84.4% and 79.7%, sensitivity of 90.8% and 87.1%, and specificity of 80.5% and 79.0% in the training and validation sets, respectively. Conclusion: Machine learning models can preoperatively predict the condition of LVI effectively in patients with ESCC based on enhanced CT radiomics features. The GNB and LR models exhibit good stability and may bring a new way for the non-invasive prediction of LVI condition in ESCC patients before treatment.

4.
Curr Opin Microbiol ; 79: 102456, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38554450

RESUMO

Mucosal immunity is posed to constantly interact with commensal microbes and invading pathogens. As a fundamental cell biological pathway affecting immune response, autophagy regulates the interaction between mucosal immunity and microbes through multiple mechanisms, including direct elimination of microbes, control of inflammation, antigen presentation and lymphocyte homeostasis, and secretion of immune mediators. Some of these physiologically important functions do not involve canonical degradative autophagy but rely on certain autophagy genes and their 'autophagy gene-specific functions.' Here, we review the relationship between autophagy and important mucosal pathogens, including influenza virus, Mycobacterium tuberculosis, Salmonella enterica, Citrobacter rodentium, norovirus, and herpes simplex virus, with a particular focus on distinguishing the canonical versus gene-specific mechanisms of autophagy genes.

5.
Clin Transl Sci ; 17(3): e13750, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38451110

RESUMO

This study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects (FE) of SC0062, a highly active endothelin-A (ETA ) receptor antagonist, in healthy subjects. The primary objectives of this first-in-human phase I study, comprised of single-ascending-dose, multiple-ascending-dose, and FE parts, were to characterize the safety and tolerability of SC0062, and FE. The secondary objectives were to determine the PK behavior of SC0062 and its major active metabolite M18, whereas exploratory objectives focused on PD effects, principally effects on endothelin-1 (ET-1) and total bile acids (TBA). Single doses of 10 to 100 mg and multiple daily doses of 20 and 50 mg for 6 days were well tolerated. SC0062 was rapidly absorbed and plasma exposure of SC0062 and M18 increased disproportionately with dose, achieving steady state by day 3, with accumulation ratios of 1.22 and 1.89 on day 6 for SC0062 and M18, respectively. The geometric mean (geometric standard deviation) terminal elimination half-life (t1/2 ) values of SC0062 and M18 were 7.25 (1.70) h and 13.73 (1.32) h, respectively. Plasma ET-1 concentrations were dose-proportional, whereas plasma TBA concentrations behaved erratically. Following a single 50 mg dose of SC0062 after a high-fat meal, Cmax values for SC0062 and M18 increased by 41% and 32%, respectively, and median Tmax values for SC0062 were 3 h longer than fasting values; exposure was unaffected. These favorable safety, PK, and PD results provide a foundation for further studies of SC0062 in pulmonary arterial hypertension, chronic kidney disease, and other relevant indications.


Assuntos
Povo Asiático , Humanos , Ácidos e Sais Biliares , China , Jejum , Voluntários Saudáveis
6.
J Vasc Interv Radiol ; 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38490364

RESUMO

PURPOSE: To assess the safety and effectiveness of using modified radiation lobectomy (mRL) to treat primary hepatic tumors located in the right hepatic lobe (segments V-VIII) and determine future liver remnant (FLR) hypertrophy. METHODS: A retrospective review was performed at a single institution to include 19 consecutive patients (7 Female, 12 Male) who underwent single-session mRL for right sided primary hepatic tumors: 15 received segmentectomy plus lobectomy (segmental dose >190 Gy and lobar dose >80 Gy); 4 were treated with the double-segmental approach (dominant segments >190 Gy and non-dominant segments > 80 Gy). Treated tumors included 13 hepatocellular carcinoma (HCC), 4 cholangiocarcinoma (CCA), and 2 mixed-type HCC-CCA with a median dominant tumor size of 5.3 cm (Interquartile range [IQR]: 3.7-7.3cm). FLR of the left hepatic lobe was measured at baseline, T1 (4-8 weeks), T2 (2-4 months), T3 (4-6 months), and T4 (9-12 months). RESULTS: Objective tumor response and tumor control were achieved in 17/19 (89.5%) and 18/19 (94.7%) patients, respectively. FLR hypertrophy was observed at T1 (median 47.8%, p=0.0245), T2 (median 48.4%, p=0.0120), T3 (median 50.4%, p=0.0147), and T4 (median 59.1%, p=0.00023). Non-cirrhotic patients demonstrated greater hypertrophy by 6-month (median 55.8% vs 47.2%, p=0.0310). One patient developed a grade 3 adverse event (ascites requiring paracentesis) at 1-month follow-up. Grade 2 or above serum toxicities are associated with worse baseline Child-Pugh Score, serum albumin, and total bilirubin (p<0.05). Among 7 patients who underwent neoadjuvant mRL, two underwent resection and one received liver transplant. CONCLUSION: mRL appears safe and effective for treatment of right-sided primary hepatic tumors with the benefit of promoting FLR hypertrophy.

7.
Front Neurol ; 15: 1364108, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481940

RESUMO

Objectives: To investigate the risk factors of pulmonary infection in patients with severe myelitis and construct a prediction model. Methods: The clinical data of 177 patients with severe myelitis at admission from the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2022 were retrospectively analyzed. The predicting factors associated with pulmonary infection were screened by multivariate logistic regression analysis, and the nomogram model was constructed, and the predictive efficiency of the model was evaluated, which was verified by calibration curve, Hosmer-Lemeshow goodness-of-fit test and decision curve analysis. Results: Of the 177 patients with severe myelitis, 38 (21.5%) had pulmonary infection. Multivariate logistic regression analysis showed that neutrophil percentage to albumin ratio (NPAR) (OR = 6.865, 95%CI:1.746-26.993, p = 0.006) and high cervical cord lesion (OR = 2.788, 95%CI:1.229-6.323, p = 0.014) were independent risk factors for pulmonary infection, and the combined nomogram could easily predict the occurrence of pulmonary infection, with a C-index of 0.766 (95% CI: 0.678-0.854). The calibration curve, Hosmer-Lemeshow goodness-of-fit test (χ2 = 9.539, p = 0.299) and decision curve analysis showed that the model had good consistency and clinical applicability. Conclusion: The nomogram model constructed based on NPAR combined with high cervical cord lesion at admission has good clinical application value in predicting pulmonary infection in patients with severe myelitis, which is conducive to clinicians' evaluation of patients.

8.
Anal Methods ; 16(12): 1756-1762, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38440844

RESUMO

Single-chain variable fragments (scFvs) are valuable in the development of immunoassays for pesticide detection. In this study, scFvs specific to thiamethoxam (Thi) were successfully isolated from a library generated by chicken immunization through heterologous coating selection. These scFvs were subsequently expressed with fusion with an Avi tag and alkaline phosphatase. After combination and optimization, a scFv-biotin based enzyme linked immunosorbent assay (ELISA) was developed for the detection of Thi, demonstrating an impressive half-maximum signal inhibition concentration (IC50) of 30 ng mL-1 and a limit of detection (LOD) of 1.8 ng mL-1. The immunoassay exhibited minimal cross-reactivity with other neonicotinoid insecticides, except for 7.5% for imidacloprid and 6.7% for imidaclothiz. The accuracy of the assay was confirmed by testing spiked samples of apple, pear, cabbage, and cucumber, which resulted in average recoveries ranging between 82% and 119%, closely aligning with the results obtained through high-performance liquid chromatography. Therefore, the chicken scFv-biotin based assay showed promise as a high-throughput screening tool for Thi in agricultural samples.


Assuntos
Inseticidas , Anticorpos de Cadeia Única , Animais , Tiametoxam , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/química , Galinhas , Biotina , Inseticidas/análise
9.
Sci Immunol ; 9(93): eadi7038, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38517952

RESUMO

The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8+ T cells by adoptively transferring JEDI (just EGFP death inducing) CD8+ T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8+ T cell-mediated killing-unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells-despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8+ T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8+ T cells neither cleared nor prevented MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8+ T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.


Assuntos
Linfócitos T CD8-Positivos , Norovirus , Camundongos , Humanos , Animais , 60419 , Norovirus/fisiologia , Privilégio Imunológico , Intestinos
10.
Curr Opin Biotechnol ; 86: 103072, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38330874

RESUMO

Yeast is widely studied in producing biofuels and biochemicals using renewable biomass. Among various yeasts, Saccharomyces cerevisiae has been particularly recognized as an important yeast cell factory. However, economic bioproduction using S. cerevisiae is challenged by harsh environments during fermentation, among which inhibitory chemicals in the culture media or toxic products are common experiences. Understanding the stress-responsive mechanisms is conducive to developing robust yeast strains. Here, we review recent progress in mechanisms underlying yeast stress response, including regulation of cell wall integrity, membrane transport, antioxidative system, and gene transcription. We highlight epigenetic regulation of stress response and summarize manipulation of yeast stress tolerance for improved bioproduction. Prospects in the application of machine learning to improve production efficiency are also discussed.


Assuntos
Epigênese Genética , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Etanol/metabolismo , Fermentação , Biocombustíveis
11.
Vet Microbiol ; 291: 110013, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38364468

RESUMO

Potassium diformate (KDF) is a kind of formate, which possesses the advantages of antimicrobial activity, growth promotion and preventing diarrhea in weaned piglets. However, the researches of KDF in animal production mostly focused on apparent indexes such as growth performance and the mechanisms of KDF on intestinal health have not been reported. Thus, porcine small intestinal epithelial cells (IPEC-J2) infected with Enterohemorrhagic Escherichia coli (EHEC) was used to investigate the role of KDF on alleviating intestinal inflammation in this study. The 0.125 mg/mL KDF treated IPEC-J2 cells for 6 h and IPEC-J2 cells challenged with 5 × 107 CFU/mL EHEC for 4 h were confirmed as the optimum concentration and time for the following experiment. The subsequent experiment was divided into four groups: control group (CON), EHEC group, KDF group, KDF+EHEC group. The results showed that KDF increased the cell viability and the gene expression levels of SGLT3 and TGF-ß, while decreased the content of IL-1ß compared with the CON group. The cell viability and the gene expressions of SGLT1, SGLT3, GLUT2, Claudin-1, Occludin and TGF-ß, and the protein expression of ZO-1 in EHEC group were lower than those in CON group, whereas the gene expressions of IL-1ß, TNF, IL-8 and TLR4, and the level of phosphorylation NF-кB protein were increased. Pretreatment with KDF reduced the content of IgM and IL-1ß, the gene expressions of IL-1ß, TNF, IL-8 and TLR4 and the level of phosphorylation NF-кB protein, and increased the gene expression of TGF-ß and the protein expression of Occludin in IPEC-J2 cells infected EHEC. In conclusion, 0.125 mg/mL KDF on IPEC-J2 cells for 6 h had the beneficial effects on ameliorating the intestinal inflammation because of reduced pro-inflammatory cytokines and enhanced anti-inflammatory cytokines through regulating NF-кB signaling pathway under the EHEC challenge.


Assuntos
Escherichia coli Êntero-Hemorrágica , Doenças dos Suínos , Animais , Suínos , Ocludina/genética , Ocludina/metabolismo , Escherichia coli Êntero-Hemorrágica/metabolismo , Interleucina-8/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/veterinária , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Mucosa Intestinal , Doenças dos Suínos/tratamento farmacológico , Doenças dos Suínos/metabolismo
12.
J Proteome Res ; 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38396335

RESUMO

Acetic acid is a prevalent inhibitor in lignocellulosic hydrolysate, which represses microbial growth and bioproduction. Histone modification and chromatin remodeling have been revealed to be critical for regulating eukaryotic metabolism. However, related studies in chronic acetic acid stress responses remain unclear. Our previous studies revealed that overexpression of the histone H4 methyltransferase Set5p enhanced acetic acid stress tolerance of the budding yeast Saccharomyces cerevisiae. In this study, we examined the role of Set5p in acetic acid stress by analyzing global protein expression. Significant activation of intracellular protein expression under the stress was discovered, and the functions of the differential proteins were mainly involved in chromatin modification, signal transduction, and carbohydrate metabolism. Notably, a substantial increase of Set5p expression was observed in response to acetic acid stress. Functional studies demonstrated that the restriction of the telomere capping protein Rtc3p, as well as Ies3p and Taf14p, which are related to chromatin regulation, was critical for yeast stress response. This study enriches the understanding of the epigenetic regulatory mechanisms underlying yeast stress response mediated by histone-modifying enzymes. The results also benefit the development of robust yeast strains for lignocellulosic bioconversion.

13.
Anal Methods ; 16(10): 1546-1553, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38404205

RESUMO

The compound 3-phenoxybenzoic acid (3-PBA) is frequently utilized as a biomarker to detect exposure to various pyrethroids. In this study, a bivalent nanobody (Nb2) specifically targeting 3-PBA was biotinylated and immobilized onto streptavidin (SA)-modified bacterial magnetic nanoparticles (BMPs), resulting in the formation of BMP-SA-Biotin-Nb2 complexes. These complexes demonstrated remarkable stability when exposed to strongly acidic solutions (4 M HCl), methanol (80%), and high ionic strength (1.37 M NaCl). An immunoassay was subsequently developed utilizing BMP-SA-Biotin-Nb2 as the capture agent and 3-PBA-horseradish peroxidase as the detection probe. The immunoassay exhibited an IC50 value (half-maximum signal inhibition concentration) of 1.11 ng mL-1 for 3-PBA. To evaluate the accuracy of the assay, spiked sheep and cow urine samples (ranging from 3.0 to 240 ng mL-1) were analyzed. The quantitative recoveries ranged from 82.5% to 113.1%, which agreed well with the findings obtained using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Overall, the BMP-SA-Biotin-Nb2-based immunoassay holds great promise for rapid monitoring of 3-PBA following acid dissociation.


Assuntos
Benzoatos , Biotina , Magnetossomos , Feminino , Bovinos , Animais , Ovinos , Estreptavidina/química , Biotina/química , Ensaio de Imunoadsorção Enzimática/métodos , Cromatografia Líquida , Espectrometria de Massas em Tandem
14.
Nat Microbiol ; 9(3): 684-697, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38413834

RESUMO

Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro cultured macrophages, loss of autophagy in macrophages in vivo does not result in susceptibility to a standard low-dose Mtb infection until late during infection, leaving open questions regarding the protective role of autophagy during Mtb infection. Here we report that loss of autophagy in lung macrophages and dendritic cells results in acute susceptibility of mice to high-dose Mtb infection, a model mimicking active tuberculosis. Rather than observing a role for autophagy in controlling Mtb replication in macrophages, we find that autophagy suppresses macrophage responses to Mtb that otherwise result in accumulation of myeloid-derived suppressor cells and subsequent defects in T cell responses. Our finding that the pathogen-plus-susceptibility gene interaction is dependent on dose has important implications both for understanding how Mtb infections in humans lead to a spectrum of outcomes and for the potential use of autophagy modulators in clinical medicine.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Animais , Camundongos , Linfócitos T , Macrófagos/microbiologia , Mycobacterium tuberculosis/fisiologia , Autofagia
15.
Org Biomol Chem ; 22(9): 1770-1774, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38324332

RESUMO

A facile and efficient method for constructing 2,3-diacyl trisubstituted furans via a silver-mediated radical process of ß-keto sulfones is developed. The reaction mechanism has been carefully investigated, revealing that the transformation proceeds through a radical pathway, leading to moderate to good yields of desired products.

16.
J Lipid Res ; 65(3): 100515, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38309417

RESUMO

LDL-C lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin-induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin-mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small-molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin-mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post-transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Pró-Proteína Convertase 9 , Camundongos , Animais , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , LDL-Colesterol , Anticorpos Monoclonais/farmacologia , Colesterol
17.
Front Immunol ; 15: 1336239, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38322258

RESUMO

CpG oligodeoxynucleotides (CpG ODNs) boost the humoral and cellular immune responses to antigens through interaction with Toll-like receptor 9 (TLR9). These CpG ODNs have been extensively utilized in human vaccines. In our study, we evaluated five B-type CpG ODNs that have stimulatory effects on pigs by measuring the proliferation of porcine peripheral blood mononuclear cells (PBMCs) and assessing interferon gamma (IFN-γ) secretion. Furthermore, this study examined the immunoenhancing effects of the MF59 and CpG ODNs compound adjuvant in mouse and piglet models of porcine epidemic diarrhea virus (PEDV) subunit vaccine administration. The in vitro screening revealed that the CpG ODN named CpG5 significantly stimulated the proliferation of porcine PBMCs and elevated IFN-γ secretion levels. In the mouse vaccination model, CpG5 compound adjuvant significantly bolstered the humoral and cellular immune responses to the PEDV subunit vaccines, leading to Th1 immune responses characterized by increased IFN-γ and IgG2a levels. In piglets, the neutralizing antibody titer was significantly enhanced with CpG5 compound adjuvant, alongside a considerable increase in CD8+ T lymphocytes proportion. The combination of MF59 adjuvant and CpG5 exhibits a synergistic effect, resulting in an earlier, more intense, and long-lasting immune response in subunit vaccines for PEDV. This combination holds significant promise as a robust candidate for the development of vaccine adjuvant.


Assuntos
Polissorbatos , Vírus da Diarreia Epidêmica Suína , Esqualeno , Animais , Suínos , Camundongos , Humanos , Leucócitos Mononucleares , Adjuvantes Imunológicos , Imunidade , Vacinas de Subunidades , Adjuvantes Farmacêuticos , Oligodesoxirribonucleotídeos
18.
Chemistry ; 30(15): e202303820, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38183354

RESUMO

As promising alternatives to liquid electrolytes, polymer electrolytes attract much research interest recently, but their widespread use is limited by the low ionic conductivity. In this study, we use electrostatic spinning to introduce particles of an ionic conductor into polyacrylonitrile (PAN) fibers to prepare a porous membrane as the host of gel polymer electrolytes (GPEs). The relevant in-situ produced GPE performs a high ionic conductivity of 6.0×10-3  S cm-1 , and a high lithium transfer number (tLi + ) of 0.85 at 30 °C, respectively. A symmetrical Li cell with this GPE can cycle stably for 550 h at a current density of 0.5 mA cm-2 . While the capacity retention of the NCM|GPE|Li cell is 79.84 % after 500 cycles at 2 C. Even with an increased cut-off voltage of 4.5 V, the 1st coulomb efficiency reaches 91.58 % with a specific discharge capacity of 213.4 mAh g-1 . This study provides a viable route for the practical application of high energy density lithium metal batteries.

19.
Fungal Genet Biol ; 170: 103864, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38199492

RESUMO

Methyl jasmonate (MeJA)-regulated postharvest quality retention of Agaricus bisporus fruiting bodies is associated with arginine catabolism. However, the mechanism of MeJA-regulated arginine catabolism in edible mushrooms is still unclear. This study aimed to investigate the regulatory modes of MeJA on the expression of arginine catabolism-related genes and proteins in intact and different tissues of A. bisporus mushrooms during storage. Results showed that exogenous MeJA treatment activated endogenous JA biosynthesis in A. bisporus mushrooms, and differentially and tissue-specifically regulated the expression of arginine catabolism-related genes (AbARG, AbODC, AbSPE-SDH, AbSPDS, AbSAMDC, and AbASL) and proteins (AbARG, AbSPE-SDH, AbASL, and AbASS). MeJA caused no significant change in AbASS expression but resulted in a dramatic increase in AbASS protein level. Neither the expression of the AbSAMS gene nor the AbSAMS protein was conspicuously altered upon MeJA treatment. Additionally, MeJA reduced the contents of arginine and ornithine and induced the accumulation of free putrescine and spermidine, which was closely correlated with MeJA-regulated arginine catabolism-related genes and proteins. Hence, the results suggested that the differential and tissue-specific regulation of arginine catabolism-related genes and proteins by MeJA contributed to their selective involvement in the postharvest continuing development and quality retention of button mushrooms.


Assuntos
Agaricus , Agaricus/genética , Acetatos/farmacologia , Ciclopentanos/farmacologia , Oxilipinas/farmacologia
20.
Anal Methods ; 16(6): 837-845, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38230997

RESUMO

In this study, we developed a simple and sensitive colorimetric sensing method for the detection of UO22+, which was built to release MB from the molybdenum disulfide with a phosphate group (MoS2-PO4) gated mesoporous silica nanoparticles functionalized phosphate group (MSN-PO4) with UO22+ chelating. In the presence of UO22+, MoS2-PO4 can be effectively adsorbed onto the surface of MSN-PO4 based on the coordination chemistry for strong affinity between the P-O bond and UO22+. The adsorbed MoS2-PO4 was then utilized as an ideal gate material to control the release of signal molecules (MB) entrapped within the pores of MSN-PO4, resulting in a detectable decrease in the absorption peak at 663 nm. This colorimetric sensing demonstrated the advantages of simplicity and easy manipulation and exhibited a linear response to the concentration of UO22+ within the range of 0.02-0.2 µM. The detection limit of UO22+ was determined to be 0.85 nM, which was lower than the limit (130 nmol L-1) set by the US Environmental Protection Agency. Furthermore, the proposed colorimetric sensing method has been utilized to determine UO22+ in samples of Xiangjiang River and tap water, and a high recovery rate was achieved. This method shows promising potential in preventing and controlling environmental pollution.

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