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Branched chain α-keto acid dehydrogenase kinase (BCKDK) is a key enzyme involved in the metabolism of branched-chain amino acids (BCAAs). Its potential as a therapeutic target and prognostic factor for a variety of cancers has been widely reported. In this study, we investigated the expression of BCKDK in clinical glioma samples and found that BCKDK was significantly overexpressed in glioblastoma (GBM) and was associated with its poor prognosis. We further found that BCKDK is phosphorylated by tyrosine protein kinase Fyn at Y151, which increases its catalytic activity and stability, and demonstrate through in vivo and in vitro experiments that BCKDK phosphorylation promotes GBM cell proliferation. In addition, we found that the levels of the metabolite N-acetyl-L-alanine (NAAL) in GBM cells with high BCKDK were higher than those in the silencing group, and silencing or inhibition of BCKDK promotes the expression of ACY1, an enzyme that catalyzes the hydrolysis of NAAL into acetic acid and alanine. Exogenous addition of NAAL can activate the ERK signaling pathway and promote the proliferation of GBM cells. Taken together, we identified a novel mechanism of BCKDK activation and found NAAL is a novel oncogenic metabolite. Our study confirms the importance of the Fyn-BCKDK-ACY1-NAAL signalling axis in the development of GBM and suggests that p-BCKDK (Y151) and NAAL can serve as potential predictors of GBM progression and prognosis.
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Fermentation has been identified as an effective strategy to alter the chemical makeup of tobacco, thereby enhancing its quality. The deliberate introduction of microorganisms can hasten the fermentation process. In this research, microbial consortia harvested from the tobacco surface were utilized to enhance the tobacco quality. This enhancement also elevated several sensory attributes of HnB cigarettes, such as aroma richness, moisture, strength, and reduced irritation, achieving a sensory quality rating of 84.5. This marks a notable improvement compared to the 82 rating of the original, unfermented cigarettes. Untargeted metabolomics analysis revealed a decrease in total polyphenols and unsaturated fatty acids, while the levels of polyacids, alcohols, ketones, furans, and other compounds increased in the fermented tobacco. Additionally, KEGG pathway enrichment analysis indicated that the enhancement in tobacco quality through microbial consortia fermentation is linked to various biological pathways, with pathways related to fatty acid and amino acid degradation playing pivotal roles. The findings of this study will serve as a reference for the commercial production of HnB cigarettes, and the elucidated mechanism offers a theoretical basis for exploring microbial fermentation as a means to improve tobacco quality.
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This review, part of a special issue on drug-drug interactions (DDIs) spearheaded by the International Society for the Study of Xenobiotics (ISSX) New Investigators, explores the critical role of drug transporters in absorption, disposition, and clearance in the context of DDIs. Over the past two decades, significant advances have been made in understanding the clinical relevance of these transporters. Current knowledge on key uptake and efflux transporters that affect drug disposition and development is summarized. Regulatory guidelines from the FDA, EMA, and PMDA that inform the evaluation of potential transporter-mediated DDIs are discussed in detail. Methodologies for preclinical and clinical testing to assess potential DDIs are reviewed, with an emphasis on the utility of physiologically based pharmacokinetic (PBPK) modeling. This includes the application of relative abundance and expression factors to predict human pharmacokinetics (PK) using preclinical data, integrating the latest regulatory guidelines. Considerations for assessing transporter-mediated DDIs in special populations, including pediatric, hepatic, and renal impairment groups, are provided. Additionally, the impact of transporters at the blood-brain barrier (BBB) on the disposition of CNS-related drugs is explored. Enhancing the understanding of drug transporters and their role in drug disposition and toxicity can improve efficacy and reduce adverse effects. Continued research is essential to bridge remaining gaps in knowledge, particularly in comparison with cytochrome P450 (CYP) enzymes.
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Osteoarthritis is a highly prevalent progressive joint disease that still requires an optimal therapeutic approach. Intermittent fasting is an attractive dieting strategy for improving health. Here this study shows that intermittent fasting potently relieves medial meniscus (DMM)- or natural aging-induced osteoarthritic phenotypes. Osteocytes, the most abundant bone cells, secrete excess neuropeptide Y (NPY) during osteoarthritis, and this alteration can be altered by intermittent fasting. Both NPY and the NPY-abundant culture medium of osteocytes (OCY-CM) from osteoarthritic mice possess pro-inflammatory, pro-osteoclastic, and pro-neurite outgrowth effects, while OCY-CM from the intermittent fasting-treated osteoarthritic mice fails to induce significant stimulatory effects on inflammation, osteoclast formation, and neurite outgrowth. Depletion of osteocyte NPY significantly attenuates DMM-induced osteoarthritis and abolishes the benefits of intermittent fasting on osteoarthritis. This study suggests that osteocyte NPY is a key contributing factor in the pathogenesis of osteoarthritis and intermittent fasting represents a promising nonpharmacological antiosteoarthritis method by targeting osteocyte NPY.
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OBJECTIVES: This study pursued two main purposes. The first aim was to expound on the microscopic factors of radiation-related caries (RRC). Further, it aimed to compare the remineralization effect of different remineralizing agents on demineralized teeth after radiotherapy. METHODS: The enamel and dentin samples of bovine teeth were irradiated with different doses of radiation. After analysis of scanning electron microscope (SEM), X-Ray diffraction (XRD), and energy dispersive spectrometer (EDS), the samples irradiated with 50 Gy radiation were selected and divided into the demineralization group, the double distilled water (DDW) group, the Sodium fluoride (NaF) group, the Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) group, the NaF + CPP-ACP group, and the Titanium tetrafluoride (TiF4) group. After demineralization, remineralizing agents treatment, and remineralization, the samples were evaluated using SEM, atomic force microscope (AFM), EDS, and transverse microradiography (TMR). RESULTS: A radiation dose of 30 Gy was sufficient to cause damage to the dentinal tubules, but 70 Gy radiation had little effect on the microstructure of enamel. Additionally, the NaF + CPP-ACP group and the TiF4 group significantly promoted deposit formation, decreased surface roughness, and reduced mineral loss and lesion depth of demineralized enamel and dentin samples after radiation. CONCLUSIONS: Radiation causes more significant damage to dentin compared to enamel. NaF + CPP-ACP and TiF4 had a promising ability to promote remineralization of irradiated dental hard tissues. ADVANCES IN KNOWLEDGE: This in vitro study contributes to determining a safer radiation dose range for teeth and identifying the most effective remineralization approach for RRC.
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Caseínas , Esmalte Dental , Dentina , Microscopía Electrónica de Rastreo , Fluoruro de Sodio , Remineralización Dental , Animales , Bovinos , Remineralización Dental/métodos , Caseínas/uso terapéutico , Dentina/efectos de la radiación , Dentina/efectos de los fármacos , Fluoruro de Sodio/uso terapéutico , Esmalte Dental/efectos de la radiación , Esmalte Dental/efectos de los fármacos , Difracción de Rayos X , Titanio , Cariostáticos/uso terapéutico , Microrradiografía , Microscopía de Fuerza Atómica , Fluoruros/uso terapéutico , Espectrometría por Rayos X , Caries Dental/etiología , Desmineralización Dental/etiología , Técnicas In VitroRESUMEN
The brown planthopper (Nilaparvata lugens Stål, BPH) is the most destructive pest of rice (Oryza sativa L.). Utilizing resistant rice cultivars that harbor resistance gene/s is an effective strategy for integrated pest management. Due to the co-evolution of BPH and rice, a single resistance gene may fail because of changes in the virulent BPH population. Thus, it is urgent to explore and map novel BPH resistance genes in rice germplasm. Previously, an indica landrace from India, Paedai kalibungga (PK), demonstrated high resistance to BPH in both in Wuhan and Fuzhou, China. To map BPH resistance genes from PK, a BC1F2:3 population derived from crosses of PK and a susceptible parent, Zhenshan 97 (ZS97), was developed and evaluated for BPH resistance. A novel BPH resistance locus, BPH39, was mapped on the short arm of rice chromosome 6 using next-generation sequencing-based bulked segregant analysis (BSA-seq). BPH39 was validated using flanking markers within the locus. Furthermore, near-isogenic lines carrying BPH39 (NIL-BPH39) were developed in the ZS97 background. NIL-BPH39 exhibited the physiological mechanisms of antibiosis and preference toward BPH. BPH39 was finally delimited to an interval of 84 Kb ranging from 1.07 to 1.15 Mb. Six candidate genes were identified in this region. Two of them (LOC_Os06g02930 and LOC_Os06g03030) encode proteins with a similar short consensus repeat (SCR) domain, which displayed many variations leading to amino acid substitutions and showed higher expression levels in NIL-BPH39. Thus, these two genes are considered reliable candidate genes for BPH39. Additionally, transcriptome sequencing, DEGs analysis, and gene RT-qPCR verification preliminary revealed that BPH39 may be involved in the jasmonic acid (JA) signaling pathway, thus mediating the molecular mechanism of BPH resistance. This work will facilitate map-based cloning and marker-assisted selection for the locus in breeding programs targeting BPH resistance. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01485-6.
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Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-ß (TGF-ß)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
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Cardiomegalia , Fibrosis , Sirtuina 3 , Animales , Humanos , Masculino , Ratones , Ratas , Cardiomegalia/genética , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Cardiomegalia/inducido químicamente , Cardiomegalia/metabolismo , Fibrosis/genética , Homeostasis/efectos de los fármacos , Isoproterenol , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/patología , Mitocondrias/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Miocardio/patología , Miocardio/metabolismo , Sirtuina 3/efectos de los fármacos , Sirtuina 3/metabolismoRESUMEN
With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.
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Lipogénesis , Hígado , Ratones Endogámicos C57BL , Nanopartículas , Enfermedad del Hígado Graso no Alcohólico , Especies Reactivas de Oxígeno , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ratones , Nanopartículas/química , Lipogénesis/efectos de los fármacos , Masculino , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Receptores Notch/metabolismo , Receptores Notch/antagonistas & inhibidores , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Bilirrubina , Polietilenglicoles/química , Modelos Animales de Enfermedad , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , DibenzazepinasRESUMEN
OBJECTIVE: The pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS-D) is related to damage to the intestinal mucosal barrier function. Based on the Mast cell (MC)/Tryptase/Protease-activated receptor-2 (PAR-2)/Myosin light chain kinase (MLCK) pathway, this study explored the effect of electroacupuncture (EA) on IBS-D rats and its possible mechanism of protecting the intestinal mucosal barrier. METHODS: The IBS-D rat model was established by mother-offspring separation, acetic acid enema, and chronic restraint stress. The efficacy of EA on IBS-D rats was evaluated by observing the rate of loose stool (LSP) and the minimum volume threshold of abdominal withdrawal reflex (AWR) in rats. Mast cells and the ultrastructure of intestinal mucosa were observed by H&E staining, toluidine blue staining, and transmission electron microscopy. The expression levels of Tryptase, PAR-2, MLCK, zonula occludens-1 (ZO-1), and Occludin in rats were detected by ELISA, qRT-PCR, and western blot. RESULTS: After 7 days of intervention, compared to the IBS-D group, the loose stool rates of rats in IBS-D + EA group and IBS-D + ketotifen group were decreased (P < 0.01), the minimum volume thresholds of AWR were improved (P < 0.01), the inflammation of colon tissue decreased, the number of MCs were decreased (P < 0.01), the expression of Tryptase, PAR-2, and MLCK were lowered (P < 0.01, P < 0.05), and the expression of ZO-1 and Occludin were enhanced (P < 0.01, P < 0.05). Compared to the EA group, there was no significant difference in each index between the ketotifen groups (P > 0.05). CONCLUSION: EA has a good therapeutic effect on IBS-D rats. Regulating the MCs/Tryptase/PAR-2/MLCK pathway may be a mechanism to protect the intestinal mucosal barrier.
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Objective: To explore the relationships among motivation, professional identity, and innovative ability of nursing intern students. Background: Professional identity and innovative ability are important for nursing students' core competitiveness and care quality. During the internship, nursing students integrate theoretical knowledge and practice, and have a rapid growth. Motivation is positively associated with professional identity and innovative ability. However, there are limited studies examining the professional identity, motivation, and innovative ability of nursing intern students. Design: A descriptive cross-sectional online study. Methods: Students in the nursing schools in southwest and central of China were included in this study and conducted from June to July 2022. A total of 474 nursing intern students were recruited from 16 nursing schools. Research data were collected with "Participants' Demographics Form", "the Professional Identity Questionnaire for Nursing Students", "the Revised Life Goals Questionnaire", and "the Revised Multidimensional Innovative Questionnaire". Independent-sample t-tests, one-way analysis of variance, correlation coefficients, and structural equation modeling were used in data analysis. This study adhered to the STROBE guidelines. Results: A significantly positive correlation was determined among the professional identity (67.55 ± 8.42), motivation (53.38 ± 5.54), and innovative ability (47.99 ± 5.46) of nursing students (r > 0.4, P < 0.001). Motivation had a mediating effect on professional identity and innovative ability (P = 0.003), accounting for 10.9% (0.075/0.689) of the total effect. Conclusions: There was a positive correlation among professional identity, motivation, and innovative ability. Developing motivation and professional identity can enhance nursing intern students' ability to innovate.
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OBJECTIVES: Systemic lupus erythematosus (SLE) is a highly heterogeneous disease, and B cell abnormalities play a central role in the pathogenesis of SLE. Long non-coding RNAs (lncRNAs) have also been implicated in the pathogenesis of SLE. The expression of lncRNAs is finely regulated and cell-type dependent, so we aimed to identify B cell-expressing lncRNAs as biomarkers for SLE, and to explore their ability to reflect the status of SLE critical pathway and disease activity. METHODS: Weighted gene coexpression network analysis (WGCNA) was used to cluster B cell-expressing genes of patients with SLE into different gene modules and relate them to clinical features. Based on the results of WGCNA, candidate lncRNA levels were further explored in public bulk and single-cell RNA-sequencing data. In another independent cohort, the levels of the candidate were detected by RT-qPCR and the correlation with disease activity was analysed. RESULTS: WGCNA analysis revealed one gene module significantly correlated with clinical features, which was enriched in type I interferon (IFN) pathway. Among non-coding genes in this module, lncRNA RP11-273G15.2 was differentially expressed in all five subsets of B cells from patients with SLE compared with healthy controls and other autoimmune diseases. RT-qPCR validated that RP11-273G15.2 was highly expressed in SLE B cells and positively correlated with IFN scores (r=0.7329, p<0.0001) and disease activity (r=0.4710, p=0.0005). CONCLUSION: RP11-273G15.2 could act as a diagnostic and disease activity monitoring biomarker for SLE, which might have the potential to guide clinical management.
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Interferón Tipo I , Lupus Eritematoso Sistémico , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Redes Reguladoras de Genes , Interferón Tipo I/genética , BiomarcadoresRESUMEN
Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression.
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Proliferación Celular , Glioblastoma , Transaminasas , Ubiquitinación , Animales , Humanos , Ratones , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/genética , Células HEK293 , Ratones Desnudos , Fosforilación , Proteolisis , Temozolomida/farmacología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Transaminasas/metabolismoRESUMEN
INTRODUCTION: This study aimed to perform a bibliometric analysis examining contributing countries and collaborative networks, authors and collaborative relationships, the performance of the institutions, and cocited journals and references in 3 major orthodontic journals (American Journal of Orthodontics and Dentofacial Orthopedics, European Journal of Orthodontics, and Angle Orthodontist) over two 10-year periods (2002-2011 and 2012-2021). METHODS: In this study, 4432 publications in the first decade and 4012 publications in the second decade were quantitatively analyzed and visualized using visualization software such as VOSviewer (Leiden University, Leiden, Netherlands), CiteSpace (Drexel University, Philadelphia, Pa), and Scimago Graphica (SCImago Lab, Spain). RESULTS: Institutions in the United States had the highest number of publications through the 2 decades, whereas Brazil, South Korea, and China achieved significant improvements in performance in the second decade compared with the first. Closer collaborative networks among scholars were revealed in the second decade. The cocitation analysis of the journals showed that highly cited journals included more professional orthodontic journals in the second decade than in the first decade. CONCLUSIONS: Bibliometric analysis of publications in 3 major orthodontic journals over two 10-year periods revealed a trend of diversification in countries and institutions participating in publishing, international collaborations, and collaboration networks among authors in the field of orthodontics during the 2 decades.
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Bibliometría , Ortodoncia , Publicaciones Periódicas como Asunto , Ortodoncia/estadística & datos numéricos , Publicaciones Periódicas como Asunto/estadística & datos numéricos , Humanos , Edición/estadística & datos numéricos , Factores de TiempoRESUMEN
BACKGROUND: This study explored the denaturation of 11S globulin, a protein known for its diverse functional properties in soy protein applications, at pH 3.0 and pH 10.0, followed by a gradual return to pH 7.0 to facilitate renaturation. It investigated the structural and functional changes during renaturation induced by a change in pH, revealing the stabilization mechanism of 11S globulin. RESULTS: The findings revealed that during pH adjustment to neutral, the denatured soybean 11S globulin - resulting from alkaline (pH 10.0) or acidic (pH 3.0) treatments - experienced a refolding of its extended tertiary structure to varying extents. The particle size and the proportions of α-helix and ß-sheet in the secondary structure aligned progressively with those of the natural-state protein. However, for the alkali-denatured 11S, the ß-sheet content decreased upon adjustment to neutral, whereas an increase was observed for the acid-denatured 11S. In terms of functional properties, after alkaline denaturation, the foaming capacity (FC) and emulsifying activity index (EAI) of 11S increased by 1.4 and 1.2 times, respectively, in comparison with its native state. The solubility, foamability, and emulsifiability of the alkali-denatured 11S gradually diminished during renaturation but remained superior to those of the native state. Conversely, these properties showed an initial decline, followed by an increase during renaturation triggered by pH neutralization. CONCLUSIONS: This research contributes to the enhancement of protein functionality, offering a theoretical foundation for the development of functional soy protein products and expanding their potential applications. © 2024 Society of Chemical Industry.
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Globulinas , Glycine max , Desnaturalización Proteica , Proteínas de Soja , Concentración de Iones de Hidrógeno , Globulinas/química , Glycine max/química , Proteínas de Soja/química , Solubilidad , Estructura Secundaria de ProteínaRESUMEN
Research on functional changes in the brain of inflammatory bowel disease (IBD) patients is emerging around the world, which brings new perspectives to medical research. In this paper, the methods of canonical correlation analysis (CCA), kernel canonical correlation analysis (KCCA), and sparsity preserving canonical correlation analysis (SPCCA) were applied to the fusion of simultaneous EEG-fMRI data from 25 IBD patients and 15 healthy individuals. The CCA, KCCA and SPCCA fusion methods were used for data processing to compare the results obtained by the three methods. The results clearly show that there is a significant difference in the activation intensity between IBD and healthy control (HC), not only in the frontal lobe (p < 0.01) and temporal lobe (p < 0.01) regions, but also in the posterior cingulate gyrus (p < 0.01), gyrus rectus (p < 0.01), and amygdala (p < 0.01) regions, which are usually neglected. The mean difference in the SPCCA activation intensity was 60.1. However, the mean difference in activation intensity was only 36.9 and 49.8 by using CCA and KCCA. In addition, the correlation of the relevant components selected during the SPCCA calculation was high, with correlation components of up to 0.955; alternatively, the correlations obtained from CCA and KCCA calculations were only 0.917 and 0.926, respectively. It can be seen that SPCCA is indeed superior to CCA and KCCA in processing high-dimensional multimodal data. This work reveals the process of analyzing the brain activation state in IBD disease, provides a further perspective for the study of brain function, and opens up a new avenue for studying the SPCCA method and the change in the intensity of brain activation in IBD disease.
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Análisis de Correlación Canónica , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Electroencefalografía , Mapeo Encefálico/métodosRESUMEN
OBJECTIVES: To observe the effects of moxibustion on colonic mast cell degranulation and inflammatory factor expression in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), and explore the potential mechanism of moxibustion in treating IBS-D. METHODS: Forty-five rat pups born from 5 healthy SPF-grade pregnant SD rats, with 8 rats were randomly selected as the normal group. The remaining 37 rats were intervened with maternal separation, acetic acid enema, and chronic restraint stress to establish the IBS-D model. The successfully modeled 32 rats were then randomly assigned to a model group, a ketotifen group, a moxibustion group, and a moxibustion-medication group, with 8 rats in each group. The rats in the ketotifen group were intervened with intragastric administration of ketotifen solution (10 mL/kg); the rats in the moxibustion group were intervened with suspended moxibustion on bilateral "Tianshu" (ST 25) and "Shangjuxu" (ST 37); the rats in the moxibustion-medication group were intervened with suspended moxibustion combined with intragastric administration of ketotifen solution. All interventions were administered once daily for 7 consecutive days. The diarrhea rate and minimum volume threshold of abdominal withdrawal reflex (AWR) were calculated before and after modeling, as well as after intervention. After intervention, colonic tissue morphology was observed using HE staining; colonic mucosal ultrastructure was examined by scanning electron microscopy; colonic mast cell ultrastructure was observed using transmission electron microscopy; mast cell degranulation was assessed by toluidine blue staining; serum and colonic levels of histamine, interleukin (IL)-1ß, IL-6, IL-1α, trypsin-like enzyme, and protease-activated receptor 2 (PAR-2) were measured by ELISA; the Western blot and real-time quantitative PCR were employed to evaluate the protein and mRNA expression of colonic IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2; the immunofluorescence was used to detect the positive expression of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colonic tissue. RESULTS: Compared to the normal group, the rats in the model group exhibited extensive infiltration of inflammatory cells in colonic tissue, severe damage to the colonic mucosa, disordered arrangement of villi, reduced electron density, and a significant decrease in granule quantity within mast cells. The diarrhea rate and mast cell degranulation rate were increased (P<0.01), AWR minimum volume threshold was decreased (P<0.01); the serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 were elevated (P<0.01); the positive expression of histamine, as well as protein, mRNA and positive expression of IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colon were all elevated (P<0.01). Compared to the model group, the rats in the ketotifen group, the moxibustion group, and the moxibustion-medication group exhibited significantly reduced infiltration of inflammatory cells in colonic tissue, relatively intact colonic mucosa, orderly arranged villi, increased electron density, and an augmented number of mast cell granules; the diarrhea rate and mast cell degranulation rate were decreased (P<0.01), and AWR minimum volume threshold was increased (P<0.01); the serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 were reduced (P<0.01); the positive expression of histamine, as well as protein, mRNA and positive expression of IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colon were all decreased (P<0.01). Compared to the ketotifen group, the moxibustion group showed decreased serum levels of histamine, IL-6, and trypsin-like enzyme (P<0.01, P<0.05), as well as reduced colonic levels of IL-1ß and IL-6 (P<0.01, P<0.05); the protein expression of colonic IL-1ß, IL-1α, and PAR-2 was reduced (P<0.05), and the positive expression of colonic IL-1ß and trypsin-like enzyme was reduced (P<0.01, P<0.05). Compared to both the ketotifen group and the moxibustion group, the moxibustion-medication group exhibited decreased diarrhea rate and mast cell degranulation rate (P<0.01), an increased AWR minimum volume threshold (P<0.01), reduced serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 (P<0.01), decreased protein expression of colonic IL-1ß, trypsin-like enzyme, and PAR-2 (P<0.01, P<0.05), reduced mRNA and positive expression of colonic IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 (P<0.01, P<0.05), and decreased positive expression of colonic histamine (P<0.01). CONCLUSIONS: Moxibustion on "Tianshu" (ST 25) and "Shangjuxu" (ST 37) might inhibit low-grade inflammatory reactions in the colon of IBS-D model rats. The mechanism may be related to the inhibition of histamine and trypsin-like enzyme secreted by mast cell, thereby reducing the expression of related inflammatory factors.
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Síndrome del Colon Irritable , Moxibustión , Ratas , Animales , Síndrome del Colon Irritable/genética , Síndrome del Colon Irritable/terapia , Ratas Sprague-Dawley , Mastocitos/metabolismo , Tripsina , Degranulación de la Célula , Histamina , Interleucina-6 , Cetotifen , Privación Materna , Diarrea/etiología , Diarrea/terapia , ARN MensajeroRESUMEN
Chronic inflammation at diabetic wound sites results in the uncontrolled accumulation of pro-inflammatory factors and reactive oxygen species (ROS), which impedes cell proliferation and delays wound healing. To promote the healing of diabetic wounds, chitosan/gelatin hydrogels containing ceria nanoparticles (CNPs) of various sizes were created in the current study. CNPs' efficacy in removing O 2 ⢠- , â¢OH, and H2O2 was demonstrated, and the scavenging ability of CNPs of varying sizes was compared. The in vitro experiments demonstrated that hydrogels containing CNPs could effectively protect cells from ROS-induced damage and facilitate mouse fibroblast migration. Furthermore, during the treatment of diabetic wounds in vivo, hydrogels containing CNPs exhibited anti-inflammatory activity and could reduce the expression of the pro-inflammatory factors TNF-α (above 30%), IL-6 (above 90%), and IL-1ß (above 80%), and effectively promote wound closure (above 80%) by inducing re-epithelialization, collagen deposition, and angiogenesis. In addition, the biological properties and therapeutic effects of hydrogels containing CNPs of various sizes were compared and discussed. The finding revealed that hydrogels with 4 nm CNPs exhibited more significant biological properties and had implications for diabetic wound treatment.
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Cerio , Quitosano , Gelatina , Hidrogeles , Cicatrización de Heridas , Animales , Quitosano/química , Hidrogeles/química , Hidrogeles/farmacología , Gelatina/química , Cicatrización de Heridas/efectos de los fármacos , Ratones , Cerio/química , Cerio/farmacología , Nanopartículas/química , Diabetes Mellitus Experimental , Masculino , Especies Reactivas de Oxígeno/metabolismo , Movimiento Celular/efectos de los fármacosRESUMEN
Understanding the characteristics of bacteriophages is crucial for the optimization of phage therapy. In this study, the biological and genomic characteristics of coliphage LHE83 were determined and its synergistic effects with different types of antibiotics against E. coli E82 were investigated. Phage LHE83 displayed a contractile tail morphology and had a titer of 3.02 × 109 pfu/mL at an optimal MOI of 0.01. Meanwhile, phage LHE83 exhibited good physical and chemical factors tolerance. The 1-step growth analysis revealed a latent period of approx. 10 min with a burst size of 87 pfu/infected cell. Phage LHE83 belongs to the genus Dhakavirus. Its genome consists of 170,464 bp with a 40% GC content, and a total of 268 Open Reading Frames (ORF) were predicted with no detected virulent or resistant genes. ORF 213 was predicted to encode the receptor binding protein (RBP) and confirmed by the antibody-blocking assay. Furthermore, a phage-resistant strain E. coli E82R was generated by co-culturing phage LHE83 with E. coli E82. Genomic analysis revealed that OmpA served as the receptor for phage LHE83, which was further confirmed by phage adsorption assay using E. coli BL21ΔOmpA, E. coli BL21ΔOmpA: OmpA and E. coli BL21:OmpA strains. Additionally, a synergistic effect was observed between phage LHE83 and spectinomycin against the drug-resistant strain E. coli E82. These results provide a theoretical basis for understanding the interactions between phages, antibiotics, and host bacteria, which can assist in the clinical application of phages and antibiotics against drug-resistant bacteria.
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Antibacterianos , Proteínas de la Membrana Bacteriana Externa , Colifagos , Escherichia coli , Espectinomicina , Escherichia coli/virología , Escherichia coli/efectos de los fármacos , Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Colifagos/fisiología , Colifagos/genética , Espectinomicina/farmacologíaRESUMEN
Presently, the combination of graph convolutional networks (GCN) with resting-state functional magnetic resonance imaging (rs-fMRI) data is a promising approach for early diagnosis of autism spectrum disorder (ASD). However, the prevalent approach involves exclusively full-brain functional connectivity data for disease classification using GCN, while overlooking the prior information related to the functional connectivity of brain subnetworks associated with ASD. Therefore, in this study, the multiple functional connectivity-based graph convolutional network (MFC-GCN) framework is proposed, using not only full brain functional connectivity data but also the established functional connectivity data from networks of key brain subnetworks associated with ASD, and the GCN is adopted to acquire complementary feature information for the final classification task. Given the heterogeneity within the Autism Brain Imaging Data Exchange (ABIDE) dataset, a novel External Attention Network Readout (EANReadout) is introduced. This design enables the exploration of potential subject associations, effectively addressing the dataset's heterogeneity. Experiments were conducted on the ABIDE dataset using the proposed framework, involving 714 subjects, and the average accuracy of the framework was 70.31%. The experimental results show that the proposed EANReadout outperforms the best traditional readout layer and improves the average accuracy of the framework by 4.32%.
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Trastorno del Espectro Autista , Encéfalo , Imagen por Resonancia Magnética , Redes Neurales de la Computación , Humanos , Trastorno del Espectro Autista/diagnóstico por imagen , Trastorno del Espectro Autista/fisiopatología , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Masculino , Femenino , Adolescente , Niño , Adulto Joven , Adulto , Mapeo Encefálico/métodos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
Objective: The aim of this study was to explore the resting-state functional connectivity (rsFC) of amygdala subregions in healthy controls (HCs) and in patients with Crohn's disease (CD) both with and without anxiety or depression. Materials and Methods: A total of 33 patients with CD and with anxiety or depression (CDad group), 31 patients with CD but without anxiety or depression (CDnad group), and 29 age-, sex-, and education level-matched HCs underwent functional magnetic resonance imaging. rsFC analysis was used to analyze the FC between the amygdala subregions and other areas of the brain. Results: Compared with the HC group, the CDad group demonstrated decreased rsFC between the right laterobasal subregion and the left hippocampus (P < .001) and right middle frontal gyrus (P < .001) and between the left superficial subregion and the left insula (P < .001). Compared with the HC group, the CDnad group demonstrated decreased rsFC between the left centromedial subregion and the left insula (P < .001). Compared with the CDnad group, the CDad group demonstrated decreased rsFC between the left centromedial subregion and the right precuneus (P < .001) and postcentral gyrus (P < .001), between the right laterobasal subregion and the left hippocampus (P < .001), and between the left superficial subregion and the right middle frontal gyrus (P < .001). Conclusions: There are significant FC changes in the amygdala subregions in patients with CD. These changes may be related to the disease itself or to the symptoms of anxiety and depression.