Structure-Activity Relationships and Changes in the Inhibition of Xanthine Oxidase by Polyphenols: A Review.

Hyperuricemia (HUA), or elevated uric acid in the blood, has become more prevalent in recent years. Polyphenols, which are known to have good inhibitory activity on xanthine oxidoreductase (XOR), are effective in uric acid reduction. In this review, we address the structure-activity relationship of flavonoids that inhibit XOR activity from two perspectives: the key residues of XOR and the structural properties of flavonoids. Flavonoids' inhibitory effect is enhanced by their hydroxyl, methoxy, and planar structures, whereas glycosylation dramatically reduces their activity. The flavonoid structure-activity relationship informed subsequent discussions of the changes that occur in polyphenols' XOR inhibitory activity during their extraction, processing, gastrointestinal digestion, absorption, and interactions. Furthermore, gastrointestinal digestion and heat treatment during processing can boost the inhibition of XOR. Polyphenols with comparable structures may have a synergistic effect, and their synergy with allopurinol thus provides a promising future research direction.

Identification and immunological characterization of genes associated with ferroptosis in Alzheimer's disease and experimental demonstration.

The incidence of Alzheimer's disease (AD) is rising globally, yet its treatment and prediction of this condition remain challenging due to the complex pathophysiological mechanisms associated with it. Consequently, the objective of the present study was to analyze and characterize the molecular mechanisms underlying ferroptosis­related genes (FEGs) in the pathogenesis of AD, as well as to construct a prognostic model. The findings will provide new insights for the future diagnosis and treatment of AD. First, the AD dataset GSE33000 from the Gene Expression Omnibus database and the FEGs from FerrDB were obtained. Next, unsupervised cluster analysis was used to obtain the FEGs that were most relevant to AD. Subsequently, enrichment analyses were performed on the FEGs to explore biological functions. Subsequently, the role of these genes in the immune microenvironment was elucidated through CIBERSORT. Then, the optimal machine learning was selected by comparing the performance of different machine learning models. To validate the prediction efficiency, the models were validated using nomograms, calibration curves, decision curve analysis and external datasets. Furthermore, the expression of FEGs between different groups was verified using reverse transcription quantitative PCR and western blot analysis. In AD, alterations in the expression of FEGs affect the aggregation and infiltration of certain immune cells. This indicated that the occurrence of AD is strongly associated with immune infiltration. Finally, the most appropriate machine learning models were selected, and AD diagnostic models and nomograms were built. The present study provided novel insights that enhance understanding with regard to the molecular mechanism of action of FEGs in AD. Moreover, the present study provided biomarkers that may facilitate the diagnosis of AD.

Comprehensive assessment of mRNA isoform detection methods for long-read sequencing data.

The advancement of Long-Read Sequencing (LRS) techniques has significantly increased the length of sequencing to several kilobases, thereby facilitating the identification of alternative splicing events and isoform expressions. Recently, numerous computational tools for isoform detection using long-read sequencing data have been developed. Nevertheless, there remains a deficiency in comparative studies that systemically evaluate the performance of these tools, which are implemented with different algorithms, under various simulations that encompass potential influencing factors. In this study, we conducted a benchmark analysis of thirteen methods implemented in nine tools capable of identifying isoform structures from long-read RNA-seq data. We evaluated their performances using simulated data, which represented diverse sequencing platforms generated by an in-house simulator, RNA sequins (sequencing spike-ins) data, as well as experimental data. Our findings demonstrate IsoQuant as a highly effective tool for isoform detection with LRS, with Bambu and StringTie2 also exhibiting strong performance. These results offer valuable guidance for future research on alternative splicing analysis and the ongoing improvement of tools for isoform detection using LRS data.

Evaluating the capability of soybean peptides as calcium ion carriers: a study through sequence analysis and molecular dynamics simulations.

Calcium homeostasis imbalance in the body can lead to a variety of chronic diseases. Supplement efficiency is essential. Peptide calcium chelate, a fourth-generation calcium supplement, offers easy absorption and minimal side effects. Its effectiveness relies on peptide's calcium binding capacity. However, research on amino acid sequences in peptides with high calcium binding capacity (HCBC) is limited, affecting the efficient identification of such peptides. This study used soybean peptides (SP), separated and purified by gel chromatography, to obtain HCBC peptide (137.45 µg mg-1) and normal peptide (≤95.78 µg mg-1). Mass spectrometry identified the sequences of these peptides, and an analysis of the positional distribution of characteristic amino acids followed. Two HCBC peptides with sequences GGDLVS (271.55 µg mg-1) and YEGVIL (272.54 µg mg-1) were discovered. Molecular dynamics showed that when either aspartic acid is located near the N-terminal's middle, or glutamic acid is near the end, or in cases of continuous Asp or Glu, the binding speed, probability, and strength between the peptide and calcium ions are superior compared to those at other locations. The study's goal was to clarify how the positions of characteristic amino acids in peptides affect calcium binding, aiding in developing peptide calcium chelates as a novel calcium supplement.

Causal relationship between serum metabolites and juvenile idiopathic arthritis: a mendelian randomization study.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is a condition that occurs when individuals under the age of 16 develop arthritis that lasts for more than six weeks, and the cause is unknown. The development of JIA may be linked to serum metabolites. Nevertheless, the association between JIA pathogenesis and serum metabolites is unclear, and there are discrepancies in the findings across studies. METHODS: In this research, the association between JIA in humans and 486 serum metabolites was assessed using genetic variation data and genome-wide association study. The identification of causal relationships was accomplished through the application of univariate Mendelian randomization (MR) analysis. Various statistical methods, including inverse variance weighted and MR-Egger, were applied to achieve this objective. To ensure that the findings from the MR analysis were trustworthy, a number of assessments were carried out. To ensure the accuracy of the obtained results, a range of techniques were utilised including the Cochran Q test, examination of the MR-Egger intercept, implementation of the leave-one-out strategy, and regression analysis of linkage disequilibrium scores. In order to identify the specific metabolic pathways associated with JIA, our primary objective was to perform pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes. RESULTS: Two-sample summary data MR analyses and sensitivity analyses showed that five metabolites were significantly causally associated with JIA, including two risk factors-kynurenine (odds ratio [OR]: 16.39, 95% confidence interval [CI]: 2.07-129.63, p = 5.11 × 10- 6) and linolenate (OR: 16.48, 95% CI: 1.32-206.22, p = 0.030)-and three protective factors-3-dehydrocarnitine (OR: 0.32, 95% CI: 0.14-0.72, p = 0.007), levulinate (4-oxovalerate) (OR: 0.40, 95% CI: 0.20-0.80, p = 0.010), and X-14,208 (phenylalanylserine) (OR: 0.68, 95% CI: 0.51-0.92, p = 0.010). Furthermore, seven metabolic pathways, including α-linolenic acid metabolism and pantothenate and CoA biosynthesis, are potentially associated with the onset and progression of JIA. CONCLUSION: Five serum metabolites, including kynurenine and 3-dehydrocarnitine, may be causally associated with JIA. These results provide a theoretical framework for developing effective JIA prevention and screening strategies.

scCDC: a computational method for gene-specific contamination detection and correction in single-cell and single-nucleus RNA-seq data.

In droplet-based single-cell and single-nucleus RNA-seq assays, systematic contamination of ambient RNA molecules biases the quantification of gene expression levels. Existing methods correct the contamination for all genes globally. However, there lacks specific evaluation of correction efficacy for varying contamination levels. Here, we show that DecontX and CellBender under-correct highly contaminating genes, while SoupX and scAR over-correct lowly/non-contaminating genes. Here, we develop scCDC as the first method to detect the contamination-causing genes and only correct expression levels of these genes, some of which are cell-type markers. Compared with existing decontamination methods, scCDC excels in decontaminating highly contaminating genes while avoiding over-correction of other genes.

Dietary inflammatory index, dietary total antioxidant capacity, and frailty among older Chinese adults.

OBJECTIVES: Frailty is an age-related syndrome associated with poor health outcomes. Studies in developed countries indicate that the dietary inflammatory index (DII) and dietary total antioxidant capacity (DTAC) are important dietary factors influencing the risk of frailty in older adults. However, few studies have explored the association between DII, DTAC, and frailty among older Chinese adults. The objective of the current study was to examine whether DII and DTAC were associated with pre-frailty or frailty among older Chinese adults. DESIGN: A cross-sectional study. SETTING: Community-based. PARTICIPANTS: We included 6414 participants aged ≥60 years. MEASUREMENTS: Dietary intake was assessed using a validated food frequency questionnaire (FFQ). The DII and energy-adjusted DII (E-DII) were calculated using food parameters. DTAC was estimated using two widely adopted antioxidant scores: DTAC based on ferric reducing antioxidant power and dietary antioxidant quality score (DAQS) obtained from vitamins (vitamins A, C, and E) and minerals (zinc and selenium) with antioxidant functions. Frailty was assessed using the frailty index (FI) calculated from 28 health-related deficits. Individuals were classified as robust (FI ≤ 0.10), pre-frailty (FI > 0.10 to <0.25), or frailty (FI ≥ 0.25). Multiple logistic regression models were used to evaluate the associations of DII and DTAC with pre-frailty and frailty. RESULTS: After adjusting for confounding factors, individuals in the highest DII quintile (Q5) were more likely to have pre-frailty (odds ratio [OR] = 1.56; 95% confidence interval [CI]: 1.25-1.93; P for trend <0.001) than those in the lowest Q1. A similar positive association was detected for E-DII and pre-frailty. A significant association was found between DII and frailty. Compared with the lowest Q1, the highest Q5 of DTAC was negatively correlated with pre-frailty (OR = 0.66; 95% CI: 0.52-0.84; P for trend <0.001) and frailty (OR = 0.71; 95% CI: 0.50-0.1.03; P for trend <0.001). The DAQS yielded results similar to pre-frailty results (OR = 0.72; 95% CI: 0.58-0.89; P < 0.001). There was no evidence suggesting an association between DAQS and frailty. CONCLUSIONS: More proinflammatory diets were linked to higher pre-frailty risk, whereas higher levels of dietary antioxidants were associated with lower pre-frailty and frailty risk among older Chinese adults.

Unraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine.

Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord at early developmental stages and myoblast/myocytes at late stages, highlighting their critical roles in the developing spine. Our work provides insights into the developmental biology of the human spine and the pathogenesis of spine malformation.

CRISPR-TE: a web-based tool to generate single guide RNAs targeting transposable elements.

BACKGROUND: The CRISPR/Cas systems have emerged as powerful tools in genome engineering. Recent studies highlighting the crucial role of transposable elements (TEs) have stimulated research interest in manipulating these elements to understand their functions. However, designing single guide RNAs (sgRNAs) that are specific and efficient for TE manipulation is a significant challenge, given their sequence repetitiveness and high copy numbers. While various sgRNA design tools have been developed for gene editing, an optimized sgRNA designer for TE manipulation has yet to be established. RESULTS: We present CRISPR-TE, a web-based application featuring an accessible graphical user interface, available at https://www.crisprte.cn/ , and currently tailored to the human and mouse genomes. CRISPR-TE identifies all potential sgRNAs for TEs and provides a comprehensive solution for efficient TE targeting at both the single copy and subfamily levels. Our analysis shows that sgRNAs targeting TEs can more effectively target evolutionarily young TEs with conserved sequences at the subfamily level. CONCLUSIONS: CRISPR-TE offers a versatile framework for designing sgRNAs for TE targeting. CRISPR-TE is publicly accessible at https://www.crisprte.cn/ as an online web service and the source code of CRISPR-TE is available at https://github.com/WanluLiuLab/CRISPRTE/ .

Alterations in the sequence and bioactivity of food-derived oligopeptides during simulated gastrointestinal digestion and absorption: a review.

Food-derived oligopeptides (FOPs) exhibit various bioactivities. However, little was known about their sequence changes in the gastrointestinal tract and the effect of changes on bioactivities. FOPs' sequence features, changes and effects on bioactivities have been summarised. The sequence length of FOPs decreases with increased exposure of hydrophobic and basic amino acids at the terminal during simulated gastrointestinal digestion. A decrease in bioactivities after simulated intestinal absorption has correlated with a decrease of Leu, Ile, Arg, Tyr, Gln and Pro. The sequence of FOPs that pass readily through the intestinal epithelium corresponds to transport modes, and FOPs whose sequences remain unchanged after transport are the most bioactive. These include mainly dipeptides to tetrapeptides, consisting of numerous hydrophobic and basic amino acids, found mostly at the end of the peptide chain, especially at the C-terminal. This review aims to provide a foundation for applications of FOPs in nutritional supplements and functional foods.

Decreased expression of TXNIP is associated with poor prognosis and immune infiltration in kidney renal clear cell carcinoma.

The most prevalent and insidious type of kidney cancer is kidney clear cell carcinoma (KIRC). Thioredoxin-interacting protein (TXNIP) encodes a thioredoxin-binding protein involved in cellular energy metabolism, redox homeostasis, apoptosis induction and inflammatory responses. However, the relationship between TXNIP, immune infiltration and its prognostic value in KIRC remains unclear. Thus, the present study evaluated the potential for TXNIP as a prognostic marker in patients with KIRC. Data from The Cancer Genome Atlas were used to assess relative mRNA expression levels of TXNIP in different types of cancer. The protein expression levels of TXNIP were evaluated using the Human Protein Atlas. Enrichment analysis of genes co-expressed with TXNIP was performed to assess relevant biological processes that TXNIP may be involved in. CIBERSORT was used to predict the infiltration of 21 tumor-infiltrating immune cells (TIICs). Univariate and multivariate Cox regression analyses were used to assess the relationship between TXNIP expression and prognosis. Single-cell RNA-sequencing datasets were used to evaluate the mRNA expression levels of TXNIP in certain immune cells in KIRC. The CellMiner database was used to analyze the relationship between TXNIP mRNA expression and drug sensitivity in KIRC. The results from the present study demonstrated that TXNIP expression was significantly decreased in KIRC tissue compared with that in normal tissue, as confirmed by western blotting and reverse transcription-quantitative PCR. In addition, downregulated TXNIP expression was significantly associated with poor prognosis, a high histological grade and an advanced stage. The Cell Counting Kit-8 assay demonstrated that TXNIP overexpression significantly suppressed tumor cell proliferation. Univariate and multivariate Cox regression analyses indicated that TXNIP served as a separate prognostic factor in KIRC. Moreover, TXNIP expression was significantly correlated with the accumulation of several TIICs and its overexpression significantly downregulated the mRNA expression levels of CD25 and cytotoxic T-lymphocyte-associated protein 4, immune cell surface markers in CD4+ T lymphocytes. In conclusion, TXNIP may be used as a possible biomarker to assess unfavorable prognostic outcomes and identify immunotherapy targets in KIRC.

Clinical significance of DTX2 expression in clear cell renal cell carcinoma tissues and its effect on renal cancer cell proliferation, migration and invasion based on TCGA database / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：基于TCGA数据库分析Deltex E3泛素连接酶2（DTX2）在肾透明细胞癌（ccRCC）组织中的表达水平及临床意义，探讨DTX2对ccRCC细胞增殖、迁移和侵袭的影响。方法：利用TIMER数据库分析DTX2在泛癌组织中的表达水平，通过UALCAN数据库进一步验证ccRCC组织和癌旁组织中DTX2 mRNA和蛋白表达差异。使用UALCAN数据库中的TCGA-ccRCC队列数据集，分析ccRCC中DTX2表达与患者临床病理特征的相关性。通过K-M plot数据库分析DTX2表达与ccRCC患者预后的相关性。利用DAVID数据库对DTX2相关基因进行GO和KEGG通路富集分析。通过qPCR法检测DTX2基因在人胚肾293（HEK293）细胞和ccRCC细胞A498、Caki-1中的表达水平。利用siRNA技术分别将DTX2 siRNA及其阴性对照质粒转入A498、Caki-1细胞，采用CCK-8法、平板克隆实验、划痕实验及Transwell侵袭实验分别检测敲低DTX2对细胞增殖、迁移和侵袭的影响。结果：TCGA数据库分析结果表明，与癌旁组织相比，ccRCC组织中DTX2 mRNA和蛋白均呈高表达（均P<0.01）。DTX2表达水平与ccRCC患者的病理分期、临床分级、不同亚型和淋巴结转移相关联（均P<0.01），DTX2高表达与患者的不良预后具有相关性（均P<0.01）。GO功能和KEGG通路富集分析结果显示，DTX2表达相关基因主要参与蛋白酶体介导的泛素依赖性蛋白质分解代谢等生物学过程，并主要富集到了mTOR信号通路等与肿瘤的相关信号通路中（均P<0.05）。体外细胞实验结果表明，A498和Caki-1细胞中DTX2表达水平高于HEK293细胞；敲低DTX2表达可显著降低A498和Caki-1细胞的增殖、迁移及侵袭能力（均P<0.01）。结论：DTX2在ccRCC组织和细胞中呈高表达，其高表达患者的预后较差。敲低DTX2表达可抑制ccRCC细胞增殖、迁移和侵袭，DTX2有望成为ccRCC新的生物标志物和治疗靶点。

Additive interactions between obesity and insulin resistance on hypertension in a Chinese rural population.

BACKGROUND: Adiposity and insulin resistance (IR) are closely associated with hypertension; however, the role of interactions between obesity phenotypes and IR in hypertension is unclear. This study aimed to evaluate the interactions of body mass index (BMI), waist circumference (WC), and body fat percentage (BF%) with IR on hypertension risk. METHODS: We analyzed data from 4888 participants (mean age 57 years, 41.2% men) in the China Northwest Natural Population Cohort, Ningxia Project. BMI, WC, and BF% were determined using bioelectrical impedance analysis devices. IR was estimated using a homeostasis model assessment index (HOMA-IR). Multivariable-adjusted logistic regression was used to evaluate the association between HOMA-IR and hypertension risk. We calculated the relative excess risk and attributable proportion with their 95% confidence intervals (CIs) to assess whether adiposity phenotypes modified the effect of HOMA-IR on hypertension risk. RESULTS: The crude prevalence of hypertension was 52.2%. The multivariable-adjusted odds ratio of HOMA-IR was 1.80 (95% CI: 1.23-2.65) for the risk of hypertension in the highest versus the lowest quartiles, but this association became marginal in models further adjusting for BMI, WC, and BF% (P for trend = 0.056). Relative excess risk and attributable proportion for interaction between high HOMA-IR and high BF% were 0.32 (0.04-0.59) and 0.33 (0.06-0.60), respectively. Additionally, high truncal and leg BF% and high HOMA-IR accounted for the hypertension risk in women, but not in men. We did not observe any significant interactions between BMI or WC and HOMA-IR on hypertension. CONCLUSION: BF% modified the association between IR and increased risk of hypertension in women with high truncal and leg BF%, but not in men.

Selenium-Enriched Soybean Peptides as Novel Organic Selenium Compound Supplements: Inhibition of Occupational Air Pollution Exposure-Induced Apoptosis in Lung Epithelial Cells.

The occupational groups exposed to air pollutants, particularly PM2.5, are closely linked to the initiation and advancement of respiratory disorders. The aim of this study is to investigate the potential protective properties of selenium-enriched soybean peptides (Se-SPeps), a novel Se supplement, in mitigating apoptosis triggered by PM2.5 in A549 lung epithelial cells. The results indicate a concentration-dependent reduction in the viability of A549 cells caused by PM2.5, while Se-SPeps at concentrations of 62.5-500 µg/mL showed no significant effect. Additionally, the Se-SPeps reduced the production of ROS, proinflammatory cytokines, and apoptosis in response to PM2.5 exposure. The Se-SPeps suppressed the PM2.5-induced upregulation of Bax/Bcl-2 and caspase-3, while also restoring reductions in p-Akt in A549 cells. The antiapoptotic effects of Se-SPeps have been found to be more effective compared to SPeps, SeMet, and Na2SeO3 when evaluated at an equivalent protein or Se concentration. Our study results furnish evidence that supports the role of Se-SPeps in reducing the harmful effects of PM2.5, particularly in relation to its effect on apoptosis, oxidative stress, and inflammation.