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1.
Front Immunol ; 15: 1424933, 2024.
Article in English | MEDLINE | ID: mdl-39086485

ABSTRACT

Introduction: Immunotherapies targeting T cells in solid cancers are revolutionizing clinical treatment. Novel immunotherapies have had extremely limited benefit for acute myeloid leukemia (AML). Here, we characterized the immune microenvironment of t(8;21) AML patients to determine how immune cell infiltration status influenced prognosis. Methods: Through multi-omics studies of primary and longitudinal t(8;21) AML samples, we characterized the heterogeneous immune cell infiltration in the tumor microenvironment and their immune checkpoint gene expression. Further external cohorts were also included in this research. Results: CD8+ T cells were enriched and HAVCR2 and TIGIT were upregulated in the CD34+CD117dim%-High group; these features are known to be associated with immune exhaustion. Data integration analysis of single-cell dynamics revealed that a subset of T cells (cluster_2) (highly expressing GZMB, NKG7, PRF1 and GNLY) evolved and expanded markedly in the drug-resistant stage after relapse. External cohort analysis confirmed that the cluster_2 T-cell signature could be utilized to stratify patients by overall survival outcome. Discussion: In conclusion, we discovered a distinct T-cell signature by scRNA-seq that was correlated with disease progression and drug resistance. Our research provides a novel system for classifying patients based on their immune microenvironment.


Subject(s)
Chromosomes, Human, Pair 8 , Leukemia, Myeloid, Acute , Single-Cell Analysis , Tumor Microenvironment , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Single-Cell Analysis/methods , Prognosis , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Chromosomes, Human, Pair 8/genetics , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Male , Female , Translocation, Genetic , Chromosomes, Human, Pair 21/genetics , CD8-Positive T-Lymphocytes/immunology , Adult , Middle Aged , Biomarkers, Tumor/genetics
2.
Front Endocrinol (Lausanne) ; 15: 1396041, 2024.
Article in English | MEDLINE | ID: mdl-39086896

ABSTRACT

Background: Clinical studies have indicated a comorbidity between sepsis and kidney diseases. Individuals with specific mutations that predispose them to kidney conditions are also at an elevated risk for developing sepsis, and vice versa. This suggests a potential shared genetic etiology that has not been fully elucidated. Methods: Summary statistics data on exposure and outcomes were obtained from genome-wide association meta-analysis studies. We utilized these data to assess genetic correlations, employing a pleiotropy analysis method under the composite null hypothesis to identify pleiotropic loci. After mapping the loci to their corresponding genes, we conducted pathway analysis using Generalized Gene-Set Analysis of GWAS Data (MAGMA). Additionally, we utilized MAGMA gene-test and eQTL information (whole blood tissue) for further determination of gene involvement. Further investigation involved stratified LD score regression, using diverse immune cell data, to study the enrichment of SNP heritability in kidney-related diseases and sepsis. Furthermore, we employed Mendelian Randomization (MR) analysis to investigate the causality between kidney diseases and sepsis. Results: In our genetic correlation analysis, we identified significant correlations among BUN, creatinine, UACR, serum urate, kidney stones, and sepsis. The PLACO analysis method identified 24 pleiotropic loci, pinpointing a total of 28 nearby genes. MAGMA gene-set enrichment analysis revealed a total of 50 pathways, and tissue-specific analysis indicated significant enrichment of five pairs of pleiotropic results in kidney tissue. MAGMA gene test and eQTL information (whole blood tissue) identified 33 and 76 pleiotropic genes, respectively. Notably, genes PPP2R3A for BUN, VAMP8 for UACR, DOCK7 for creatinine, and HIBADH for kidney stones were identified as shared risk genes by all three methods. In a series of immune cell-type-specific enrichment analyses of pleiotropy, we identified a total of 37 immune cells. However, MR analysis did not reveal any causal relationships among them. Conclusions: This study lays the groundwork for shared etiological factors between kidney and sepsis. The confirmed pleiotropic loci, shared pathogenic genes, and enriched pathways and immune cells have enhanced our understanding of the multifaceted relationships among these diseases. This provides insights for early disease intervention and effective treatment, paving the way for further research in this field.


Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Kidney Diseases , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Sepsis , Humans , Sepsis/genetics , Sepsis/epidemiology , Kidney Diseases/genetics , Genetic Pleiotropy
3.
FASEB J ; 38(15): e23847, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39096137

ABSTRACT

Intestinal failure-associated liver disease (IFALD) is a serious complication of long-term parenteral nutrition in patients with short bowel syndrome (SBS), and is the main cause of death in SBS patients. Prevention of IFALD is one of the major challenges in the treatment of SBS. Impairment of intestinal barrier function is a key factor in triggering IFALD, therefore promoting intestinal repair is particularly important. Intestinal repair mainly relies on the function of intestinal stem cells (ISC), which require robust mitochondrial fatty acid oxidation (FAO) for self-renewal. Herein, we report that aberrant LGR5+ ISC function in IFALD may be attributed to impaired farnesoid X receptor (FXR) signaling, a transcriptional factor activated by steroids and bile acids. In both surgical biopsies and patient-derived organoids (PDOs), SBS patients with IFALD represented lower population of LGR5+ cells and decreased FXR expression. Moreover, treatment with T-ßMCA in PDOs (an antagonist for FXR) dose-dependently reduced the population of LGR5+ cells and the proliferation rate of enterocytes, concomitant with decreased key genes involved in FAO including CPT1a. Interestingly, however, treatment with Tropifexor in PDOs (an agonist for FXR) only enhanced FAO capacity, without improvement in ISC function and enterocyte proliferation. In conclusion, these findings suggested that impaired FXR may accelerate the depletion of LGR5 + ISC population through disrupted FAO processes, which may serve as a new potential target of preventive interventions against IFALD for SBS patients.


Subject(s)
Liver Diseases , Receptors, Cytoplasmic and Nuclear , Short Bowel Syndrome , Signal Transduction , Stem Cells , Humans , Short Bowel Syndrome/metabolism , Short Bowel Syndrome/pathology , Receptors, Cytoplasmic and Nuclear/metabolism , Stem Cells/metabolism , Male , Liver Diseases/metabolism , Liver Diseases/pathology , Liver Diseases/etiology , Female , Child , Intestinal Failure/metabolism , Child, Preschool , Infant , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Receptors, G-Protein-Coupled/metabolism , Cell Proliferation , Intestines/pathology , Enterocytes/metabolism
4.
Int J Biol Macromol ; 277(Pt 2): 134367, 2024 Jul 31.
Article in English | MEDLINE | ID: mdl-39089562

ABSTRACT

The protein aggregation induced by UHT treatment shortens the shelf life of UHT milk. However, the mechanism of ß-Lg induced casein micelle aggregation remains unclear. Herein, the dynamic interaction between ß-Lg and casein micelles during UHT processing was investigated by experimental techniques and molecular dynamics simulations. Results showed that ß-Lg decreased the stability of casein micelles, increased their size and zeta potential. Raman and FTIR spectra analysis suggested that hydrogen and disulfide bonds facilitated their interaction. Cryo-TEM showed that the formation of the casein micelle/ß-Lg complex involved rigid binding, flexible linking, and severe cross-linking aggregation during UHT processing. SAXS and MST demonstrated ß-Lg bound to κ-casein on micelle surfaces with a dissociation constant (Kd) of 3.84 ± 1.14 µm. Molecular docking and dynamic simulations identified the interacting amino acid residues and clarified that electrostatic and van der Waals forces drove the interaction. UHT treatment increased hydrogen bonds and decreased total binding energy. The non-covalent binding promoted the formation of disulfide bonds between ß-Lg and casein micelles under heat treatment. Ultimately, it was concluded that non-covalent interaction and disulfide bonding resulted in casein micelle/ß-Lg aggregates. These findings provided scientific insights into protein aggregation in UHT milk.

5.
Article in English | MEDLINE | ID: mdl-39094603

ABSTRACT

OBJECTIVE: Auto-segmentation in mouse micro-CT enhances the efficiency and consistency of preclinical experiments but often struggles with low-native-contrast and morphologically complex organs, such as the spleen, resulting in poor segmentation performance. While CT contrast agents can improve organ conspicuity, their use complicates experimental protocols and reduces feasibility. We developed a 3D Cycle Generative Adversarial Network (CycleGAN) incorporating anatomy-constrained U-Net models to leverage contrast-enhanced CT (CECT) insights to improve unenhanced native CT (NACT) segmentation. Approach: We employed a standard CycleGAN with an anatomical loss function to synthesize virtual CECT images from unpaired NACT scans at two different resolutions. Prior to training, two U-Nets were trained to automatically segment six major organs in NACT and CECT datasets, respectively. These pretrained 3D U-Nets were integrated during the CycleGAN training, segmenting synthetic images, and comparing them against ground truth annotations. The compound loss within the CycleGAN maintained anatomical fidelity. Full image processing was achieved for low-resolution datasets, while high-resolution datasets employed a patch-based method due to GPU memory constraints. Automated segmentation was applied to original NACT and synthetic CECT scans to evaluate CycleGAN performance using the Dice Similarity Coefficient (DSC) and the 95th percentile Hausdorff Distance (HD95p). Main Results: High-resolution scans showed improved auto-segmentation, with an average DSC increase from 0.728 to 0.773 and a reduced HD95p from 1.19 mm to 0.94 mm. Low-resolution scans benefited more from synthetic contrast, showing a DSC increase from 0.586 to 0.682 and an HD95p reduction from 3.46 mm to 1.24 mm. Significance: Implementing CycleGAN to synthesize CECT scans substantially improved the visibility of the mouse spleen, leading to more precise auto-segmentation. This approach shows the potential in preclinical imaging studies where contrast agent use is impractical. .

6.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(7): 782-788, 2024 Jul 15.
Article in Chinese | MEDLINE | ID: mdl-39014957

ABSTRACT

Ivabradine, as a specific If current inhibitor, has been widely used in the treatment of chronic heart failure in adults due to its ability to reduce heart rate without affecting myocardial contractility and blood pressure. It has also shown good effects in various types of tachyarrhythmias. However, the application of ivabradine in pediatric cardiovascular diseases still faces many limitations. This article reviews the current research progress on the use of ivabradine in treating pediatric cardiovascular diseases both domestically and internationally, aiming to provide guidance for pediatric cardiologists. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 782-788.


Subject(s)
Benzazepines , Cardiovascular Diseases , Ivabradine , Ivabradine/therapeutic use , Ivabradine/pharmacology , Humans , Child , Cardiovascular Diseases/drug therapy , Benzazepines/therapeutic use , Benzazepines/pharmacology
7.
Phytochem Anal ; 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39016051

ABSTRACT

INTRODUCTION: Corydalis DC., the largest genus of Papaveraceae, comprises numerous species known for their abundant alkaloid content and historical use in clinical medicine. Recently, a new species of genus Corydalis named Corydalis huangshanensis Lu Q. Huang & H. S. Peng was discovered in the Huangshan Mountains of Anhui Province, China. OBJECTIVE: To compare the chemical characteristics of C. huangshanensis and other 13 Corydalis species, aiming to elucidate the potential medicinal value of this new species. MATERIALS AND METHODS: The chemical constituents of C. huangshanensis and other 13 medicinal plants of genus Corydalis were analyzed using ultra-high-performance liquid chromatography Q-Exactive Plus hybrid quadrupole-Orbitrap mass spectrometer (Q-Orbitrap) mass technology. The differences in the alkaloids in the 14 species were distinguished by chemometrics. RESULTS: The mass spectrometry fragmentation information and relative content of 72 alkaloids were obtained. Orthogonal partial least squares discriminant analysis (OPLS-DA) and cluster heat mapping analysis showed that these 14 species were divided into two groups. The clustering relationship between C. huangshanensis and C. decumbens (Thunb.) Pers. was similar, exhibiting similar chemical compositions and characteristics. These results indicate the potential pharmacological effects of C. huangshanensis. CONCLUSION: This study enhances our understanding of the chemical classification of Corydalis and provides a basis for speculations on the medicinal value of C. huangshanensis.

8.
Sci Adv ; 10(30): eadn8401, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39047096

ABSTRACT

The transformation of organoboron compounds plays an important role in synthetic chemistry, and recent advancements in boron-migration reactions have garnered considerable attention. Here, we report an unprecedented 1,2-boron migrative acylation upon photocatalysis-facilitated N-heterocyclic carbene catalysis. The design of a redox-active boronic ester substrate, serving as an excellent ß-boron radical precursor, is the linchpin to the success of this chemistry. With the established protocol, a wide spectrum of ß-boryl ketones has been rapidly synthesized, which could further undergo various C─B bond transformations to give multifunctionalized products. The robustness of this catalytic strategy is underscored by its successful application in late-stage modification of drug-derived molecules and natural products. Preliminary mechanistic investigations, including several control experiments, photochemistry measurements, and computational studies, shed light on the catalytic radical reaction mechanism.

9.
Drug Resist Updat ; 76: 101116, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38968684

ABSTRACT

Drug resistance and tumor recurrence remain clinical challenges in the treatment of urothelial carcinoma (UC). However, the underlying mechanism is not fully understood. Here, we performed single-cell RNA sequencing and identified a subset of urothelial cells with epithelial-mesenchymal transition (EMT) features (EMT-UC), which is significantly correlated with chemotherapy resistance and cancer recurrence. To validate the clinical significance of EMT-UC, we constructed EMT-UC like cells by introducing overexpression of two markers, Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and Desmin (DES), and examined their histological distribution characteristics and malignant phenotypes. EMT-UC like cells were mainly enriched in UC tissues from patients with adverse prognosis and exhibited significantly elevated EMT, migration and gemcitabine tolerance in vitro. However, EMT-UC was not specifically identified from tumorous tissues, certain proportion of them were also identified in adjacent normal tissues. Tumorous EMT-UC highly expressed genes involved in malignant behaviors and exhibited adverse prognosis. Additionally, tumorous EMT-UC was associated with remodeled tumor microenvironment (TME), which exhibited high angiogenic and immunosuppressive potentials compared with the normal counterparts. Furthermore, a specific interaction of COL4A1 and ITGB1 was identified to be highly enriched in tumorous EMT-UC, and in the endothelial component. Targeting the interaction of COL4A1 and ITGB1 with specific antibodies significantly suppressed tumorous angiogenesis and alleviated gemcitabine resistance of UC. Overall, our findings demonstrated that the driven force of chemotherapy resistance and recurrence of UC was EMT-UC mediated COL4A1-ITGB1 interaction, providing a potential target for future UC treatment.

10.
Front Plant Sci ; 15: 1405253, 2024.
Article in English | MEDLINE | ID: mdl-39081519

ABSTRACT

The unresolved phylogenetic framework within the Selaginellaceae subfamily Gymnogynoideae (ca. 130 species) has hindered our comprehension of the diversification and evolution of Selaginellaceae, one of the most important lineages in land plant evolution. Here, based on plastid and nuclear data extracted from genomic sequencing of more than 90% species of all genera except two in Gymnogynoideae, a phylogenomic study focusing on the contentious relationships among the genera in Gymnogynoideae was conducted. Our major results included the following: (1) Only single-copy region (named NR) and only one ribosomal operon was firstly found in Afroselaginella among vascular plants, the plastome structure of Gymnogynoideae is diverse among the six genera, and the direct repeats (DR) type is inferred as the ancestral state in the subfamily; (2) The first strong evidence was found to support Afroselaginella as a sister to Megaloselaginella. Alternative placements of Ericetorum and Gymnogynum were detected, and their relationships were investigated by analyzing the variation of phylogenetic signals; and (3) The most likely genus-level relationships in Gymnogynoideae might be: ((Bryodesma, Lepidoselaginella), (((Megaloselaginella, Afroselaginella), Ericetorum), Gymnogynum)), which was supported by maximum likelihood phylogeny based on plastid datasets, maximum likelihood, and Bayesian inference based on SCG dataset and concatenated nuclear and plastid datasets and the highest proportion of phylogenetic signals of plastid genes.

11.
Front Genet ; 15: 1417266, 2024.
Article in English | MEDLINE | ID: mdl-39045329

ABSTRACT

Melon (Cucumis melo L.) is one of the most extensively grown horticulture crops of the world. Based on the morphological characters, melon was formerly divided into two subspecies, Cucumis melo ssp. melo and C. melo ssp. agrestis. However, the present methods are still inadequate to distinguish between them. The phylogenetic analysis based on chloroplast genome sequences could provide essential evidence for the classification of melon varieties. We sequenced the chloroplast genomes of nine different melon varieties by the Illumina Hiseq and performed bioinformatic analyses including repeat element analysis, genome comparison and phylogenetic analysis. The results showed that the melon chloroplast genome has a typical quadripartite structure that was conserved across the analyzed sequences. Its length ranges between 155, 558 and 156, 569 bp, with a total GC content varying from 36.7% to 37%. We found 127-132 genes in melon chloroplast genomes, including 85-87 protein-coding regions, 34-37 tRNA and 6-8 rRNA genes. The molecular structure, gene order, content, codon usage, long repeats, and simple sequence repeats (SSRs) were mostly conserved among the nine sequenced genomes. Phylogenetic analysis showed that the chloroplast genome could clearly distinguish between C. melo ssp. melo and C. melo ssp. agrestis. This study not only provides valuable knowledge on melon chloroplasts, but also offers a theoretical basis and technical support for the genetic breeding of melons.

12.
Biochem Pharmacol ; 227: 116446, 2024 Jul 20.
Article in English | MEDLINE | ID: mdl-39038552

ABSTRACT

Cerebral ischemia/reperfusion (CIRI) is a leading cause of death worldwide. A small GTPase known as ADP-ribosylation factor-like protein 13B (ARL13B) is essential in several illnesses. The role of ARL13B in CIRI remains unknown, though. A middle cerebral artery occlusion/reperfusion (MCAO/R) in rats as well as an oxygen-glucose deprivation/reoxygenation (OGD/R) models in PC12 cells were constructed. The neuroprotective effects of ARL13B against MCAO/R were evaluated using neurological scores, TTC staining, rotarod testing, H&E staining, and Nissl staining. To detect the expression of proteins associated with the SHH pathway and apoptosis, western blotting and immunofluorescence were employed. Apoptosis was detected using TUNEL assays and flow cytometry. There was increased expression of ARL13B in cerebral ischemia/reperfusion models. However, ARL13B knockdown aggravated CIRI nerve injury by inhibiting the sonic hedgehog (SHH) pathway. In addition, the use of SHH pathway agonist (SAG) can increased ARL13B expression, reverse the effects of ARL13B knockdown exacerbating CIRI nerve injury. ARL13B alleviated cerebral infarction and pathological injury and played a protective role against MCAO/R. Furthermore, ARL13B significantly increased the expression of SHH pathway-related proteins and the anti-apoptotic protein BCL-2, while decreased the expression of pro-apoptotic protein BAX, thus reducing apoptosis. The results from the OGD/R model in PC12 cells were consistent with those obtained in vivo. Surprisingly, we demonstrated that ARL13B regulates the cell cycle to protect against CIRI nerve injury. Our findings indicate that ARL13B protects against CIRI by reducing apoptosis through SHH-dependent pathway activation, and suggest that ARL13B plays a crucial role in CIRI pathogenesis.

13.
Acad Radiol ; 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38902111

ABSTRACT

RATIONALE AND OBJECTIVES: It is critical to predict early recurrence (ER) after percutaneous thermal ablation (PTA) for hepatocellular carcinoma (HCC). We aimed to develop and validate a delta-radiomics nomogram based on multi-phase contrast-enhanced magnetic resonance imaging (MRI) to preoperatively predict ER of HCC after PTA. MATERIALS AND METHODS: We retrospectively enrolled 164 patients with HCC and divided them into training, temporal validation, and other-scanner validation cohorts (n = 110, 29, and 25, respectively). The volumes of interest of the intratumoral and/or peritumoral regions were delineated on preoperative multi-phase MR images. Original radiomics features were extracted from each phase, and delta-radiomics features were calculated. Logistic regression was used to train the corresponding radiomics models. The clinical and radiological characteristics were evaluated and combined to establish a clinical-radiological model. A fusion model comprising the best radiomics scores and clinical-radiological risk factors was constructed and presented as a nomogram. The performance of each model was evaluated and recurrence-free survival (RFS) was assessed. RESULTS: Child-Pugh grade B, high-risk tumor location, and an incomplete/absent tumor capsule were independent predictors of ER. The optimal radiomics model comprised 12 delta-radiomics features with areas under the curve (AUCs) of 0.834, 0.795, and 0.769 in the training, temporal validation, and other-scanner validation cohorts, respectively. The nomogram showed the best predictive performance with AUCs as 0.893, 0.854, and 0.827 in the three datasets. There was a statistically significant difference in RFS between the risk groups calculated using the delta-radiomics model and nomogram. CONCLUSIONS: The nomogram combined with the delta-radiomic score and clinical-radiological risk factors could non-invasively predict ER of HCC after PTA.

14.
ArXiv ; 2024 May 29.
Article in English | MEDLINE | ID: mdl-38855547

ABSTRACT

Image-guided mouse irradiation is essential to understand interventions involving radiation prior to human studies. Our objective is to employ Swin UNEt Transformers (Swin UNETR) to segment native micro-CT and contrast-enhanced micro-CT scans and benchmark the results against 3D no-new-Net (nnU-Net). Swin UNETR reformulates mouse organ segmentation as a sequence-to-sequence prediction task, using a hierarchical Swin Transformer encoder to extract features at 5 resolution levels, and connects to a Fully Convolutional Neural Network (FCNN)-based decoder via skip connections. The models were trained and evaluated on open datasets, with data separation based on individual mice. Further evaluation on an external mouse dataset acquired on a different micro-CT with lower kVp and higher imaging noise was also employed to assess model robustness and generalizability. Results indicate that Swin UNETR consistently outperforms nnU-Net and AIMOS in terms of average dice similarity coefficient (DSC) and Hausdorff distance (HD95p), except in two mice of intestine contouring. This superior performance is especially evident in the external dataset, confirming the model's robustness to variations in imaging conditions, including noise and quality, thereby positioning Swin UNETR as a highly generalizable and efficient tool for automated contouring in pre-clinical workflows.

15.
Article in English | MEDLINE | ID: mdl-38850333

ABSTRACT

AIM: To explore the molecular mechanism underlying the protective effect of hypothermic perfusion on the corneal endothelium during phacoemulsification. METHODS: Phacoemulsification was performed on New Zealand white rabbits. Perfusate at different temperatures was used during the operation, and the aqueous humor was collected for proteomic sequencing after the operation. Corneal endothelial cell injury was simulated by a corneal endothelial cell oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. Flow cytometry and evaluation of fluorescent LC3B puncta were used to detect apoptosis and autophagy, and western blotting was used to detect protein expression. RESULTS: A total of 381 differentially expressed proteins were identified between the two groups. In vitro, 4 ℃ hypothermia significantly reduced apoptosis and promoted autophagy. Apoptosis increased after autophagy was inhibited by 3-Methyladenine (3-MA). Furthermore, adiponectin (ADIPOQ) knockdown inhibited phospho-AMPK and blocked the protective effect of hypothermia on corneal endothelial cells. CONCLUSIONS: We investigated the differential expression of proteins between the hypothermia group and normothermia group by proteomics. Moreover, hypothermia-induced ADIPOQ can reduce apoptosis by promoting AMPK-mediated autophagy.

16.
Food Chem ; 456: 140012, 2024 Oct 30.
Article in English | MEDLINE | ID: mdl-38876066

ABSTRACT

Age gelation is undesirable for direct UHT (dUHT) milk, which is closely related to protein hydrolysis. However, little information is available for the role of serum peptides during the age gelation. In this study, the composition and protein morphology of serum phase were characterized by RP-HPLC, ICP-MS and TEM. The results showed significant increases in soluble proteins, free amino acids, calcium, and phosphorus from casein micelles, indicating protein hydrolysis and peptide release into the serum phase. 23,466 peptides derived from caseins and other proteins were identified in serum phase by peptidomics. The serum peptide profiles of age gelation milk changed dramatically. Peptide fingerprinting revealed that plasmin and cathepsin contributed to the protein hydrolysis during age gelation, with a significant increase in their activity observed. 23 characteristic peptides were ultimately selected as potential indicators for age gelation. These findings provide new insights into the age gelation of UHT milk.


Subject(s)
Milk , Peptides , Animals , Milk/chemistry , Peptides/chemistry , Cattle , Gels/chemistry , Proteomics , Caseins/chemistry , Milk Proteins/chemistry , Hydrolysis
17.
Int J Oral Sci ; 16(1): 46, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38886342

ABSTRACT

Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2A receptor (A2AR) on trigeminal ganglia. Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A2AR. Therefore, we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.


Subject(s)
Calcitonin Gene-Related Peptide , Carcinoma, Squamous Cell , Disease Progression , Mouth Neoplasms , Receptor, Adenosine A2A , Animals , Humans , Mice , Adenosine A2 Receptor Antagonists/pharmacology , Calcitonin Gene-Related Peptide/metabolism , Carcinoma, Squamous Cell/metabolism , Cell Line, Tumor , Mouth Neoplasms/metabolism , Pyrimidines/pharmacology , Receptor, Adenosine A2A/metabolism , Triazoles , Trigeminal Nerve/metabolism
18.
Article in English | MEDLINE | ID: mdl-38852915

ABSTRACT

To reveal the protective effect on the nephrotoxicity of Quercus salicina Blume(QS), a traditional medicine for the treatment of urolithiasis, the 50 % ethanol extract from the branches and leaves of QS was chemically studied by systematic solvent extraction and HPLC chromatography. Two phenolic acids and three flavonoids were identified by nuclear magnetic resonance spectroscopy, namely Ferulic acid (1), p-Hydroxycinnamic acid (2), Hesperidin (3), Formononetin (4), and Quercetin (5). At the same time, the gentamicin-induced nephrotoxicity of zebrafish was used as a model for the first time. The antioxidant activity of these derivatives with good antioxidant activity screened from free radical scavenging experiments in vitro (DPPH and ABTS) was evaluated in vivo, including protein levels (LPO, NO, GSH, and SOD), kidney injury factor (KIM-1), zebrafish kidney pathology and real-time PCR. The results showed that metabolites 1, 3, and 5 had strong antioxidant activity, and oxidative stress in renal tissue was significantly reduced; KIM-1, TNF-α, and IL-6 mRNA expression in a dose-dependent manner, which preliminarily revealed the protective effect of the secondary metabolites of QS on nephrotoxicity, and preliminarily discussed the structure-activity relationship. This study provides an experimental basis for further exploring the mechanism of QS in the kidney.


Subject(s)
Antioxidants , Gentamicins , Kidney Diseases , Kidney , Oxidative Stress , Plant Extracts , Quercus , Zebrafish , Animals , Gentamicins/toxicity , Plant Extracts/pharmacology , Plant Extracts/chemistry , Quercus/chemistry , Antioxidants/pharmacology , Antioxidants/metabolism , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Kidney Diseases/chemically induced , Kidney Diseases/prevention & control , Kidney Diseases/metabolism , Kidney Diseases/pathology , Oxidative Stress/drug effects , Secondary Metabolism , Disease Models, Animal
19.
Inorg Chem ; 63(23): 10817-10822, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38781577

ABSTRACT

A K-Eu bimetallic ammonium metal-nitrate three-dimensional (3D) framework incorporating R-N-methyl-3-hydroxyquinuclidine, (RM3HQ)2KEu(NO3)6 (RM3HQ = R-N-methyl-3-hydroxyquinuclidine, 1), was characterized and reported. Distinguishing from the former hybrid rare-earth double perovskites, 1 adopts a mixed corner- and face-sharing K+/Eu3+-centered polyhedral connectivity to form a 3D inorganic framework, showing a rare (6, 6)-connected ion topology with a 66 framework. Notably, 1 exhibits clear phase transition, and the switchable thermodynamic behavior is confirmed by variable-temperature dielectric measurements and second-harmonic generation response. Moreover, 1 also shows photoluminescence properties. The activator Eu3+ plays a crucial role in this process, leading to a significant narrow emission at 592 nm with a photoluminescence quantum yield (PLQY) of 20.76%. The fluorescence lifetime (FLT) of 1 is 4.32 ms. This finding enriches the bimetallic hybrid system for potential electronic and/or luminescence applications.

20.
Environ Pollut ; 355: 124177, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-38763295

ABSTRACT

The electrolytic manganese industry produces a large amount of electrolytic manganese residue (EMR). Soluble Mn, NH4+-N, and other pollutants may be released from the open-air stacked EMR and transported to the environment along with rainfall or surface runoff. Aqueous EMR solution (AES) generally contains various elements required for plant growth, and phytoremediation can be applied to remove these pollutants from AES. Since the contents of Fe and Co vary greatly in AES depending on the ore sources as well as the pre-treatment processes, the presence of bioavailable Fe and Co at different levels may affect plant growth, the rhizosphere microbes, and pollutant removal. The present study investigated the in-situ removal of Mn(II) and NH4+-N from AES solution using free floating aquatic plant Pistia stratiotes, focusing especially on the effects of Fe/Co presence and rhizospheric microbe synergistic involvement on contaminant removal. The results showed that 69.08% of Mn and 94.99% of NH4+-N were removed by P. stratiotes in 24 d. Both the presence of Fe(II) and Co(II) facilitated the Mn(II) immobilization and increased Mn(II) removal by 19-31% due to the enhanced peroxidase activity and the increased Mn accumulating in roots The complete removal of Mn from AES was found in the presence of Fe(II) at 2 mg L-1 or Co(II) at 0.5 mg L-1 and more than 51% accumulated Mn in the roots was stored in the vacuole and cytoplasm. BioMnOx was found on the surface of the roots, revealing that rhizofiltration, rhizospheric plaque/biofilm formation, and Mn biogeochemical cycle exert synergic effects on Mn(II) immobilization. The findings of the present study demonstrate the feasibility of using P. stratiotes in the treatment of aqueous EMR solutions and the presence of an appropriate amount of bio-available Fe and Co can promote the removal of Mn(II) and NH4+-N.


Subject(s)
Araceae , Biodegradation, Environmental , Iron , Manganese , Rhizosphere , Manganese/metabolism , Araceae/metabolism , Iron/metabolism , Water Pollutants, Chemical/metabolism , Ammonium Compounds/metabolism
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