Asp-tRNAAsn/Glu-tRNAGln amidotransferase A subunit-like amidase mediates the degradation of insecticide flonicamid by Variovorax boronicumulans CGMCC 4969.

The main metabolic product of the pyridinecarboxamide insecticide flonicamid, N-(4-trifluoromethylnicotinyl)glycinamide (TFNG-AM), has been shown to have very high mobility in soil, leading to its accumulation in the environment. Catabolic pathways of flonicamid have been widely reported, but few studies have focused on the metabolism of TFNG-AM. Here, the rapid transformation of TFNG-AM and production of the corresponding acid product N-(4-trifluoromethylnicotinoyl) glycine (TFNG) by the plant growth-promoting bacterium Variovorax boronicumulans CGMCC 4969 were investigated. With TFNG-AM at an initial concentration of 0.86 mmol/L, 90.70 % was transformed by V. boronicumulans CGMCC 4969 resting cells within 20 d, with a degradation half-life of 4.82 d. A novel amidase that potentially mediated this transformation process, called AmiD, was identified by bioinformatic analyses. The gene encoding amiD was cloned and expressed recombinantly in Escherichia coli, and the enzyme AmiD was characterized. Key amino acid residue Val154, which is associated with the catalytic activity and substrate specificity of signature family amidases, was identified for the first time by homology modeling, structural alignment, and site-directed mutagenesis analyses. When compared to wild-type recombinant AmiD, the mutant AmiD V154G demonstrated a 3.08-fold increase in activity toward TFNG-AM. The activity of AmiD V154G was greatly increased toward aromatic L-phenylalanine amides, heterocyclic TFNG-AM and IAM, and aliphatic asparagine, whereas it was dramatically lowered toward benzamide, phenylacetamide, nicotinamide, acetamide, acrylamide, and hexanamid. Quantitative PCR analysis revealed that AmiD may be a substrate-inducible enzyme in V. boronicumulans CGMCC 4969. The mechanism of transcriptional regulation of AmiD by a member of the AraC family of regulators encoded upstream of the amiD gene was preliminarily investigated. This study deepens our understanding of the mechanisms of metabolism of toxic amides in the environment, providing new ideas for microbial bioremediation.

Association Between CYP24A1 Polymorphisms and Bladder Cancer Risk in the Chinese Han Population.

In this cohort of 217 bladder cancer patients and 484 healthy controls, we explored the association between CYP24A1 variants (rs2762934, rs1570669, rs6068816, rs2296241) and bladder cancer risk in the Chinese Han population. Utilizing the Agena MassARRAY system, we genotyped four selected CYP24A1 polymorphisms. Logistic regression revealed a significant association of rs2762934 and rs1570669 with elevated bladder cancer risk, while rs6068816 exhibited a protective effect. Bioinformatics analysis of CYP24A1 expression in normal and cancerous bladder tissues indicated higher expression in normal tissue. In conclusion, our findings highlight the potential role of CYP24A1 variants in bladder cancer susceptibility.

Hypolipidemic effect and gut microbiota regulation of Gypenoside aglycones in rats fed a high-fat diet.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynostemma pentaphyllum (Thunb.) Makino has traditional applications in Chinese medicine to treat lipid abnormalities. Gypenosides (GPs), the main bioactive components of Gynostemma pentaphyllum, have been reported to exert hypolipidemic effects through multiple mechanisms. The lipid-lowering effects of GPs may be attributed to the aglycone portion resulting from hydrolysis of GPs by the gut microbiota. However, to date, there have been no reports on whether gypenoside aglycones (Agl), the primary bioactive constituents, can ameliorate hyperlipidemia by modulating the gut microbiota. AIM OF THE STUDY: This study explored the potential therapeutic effects of gypenoside aglycone (Agl) in a rat model of high-fat diet (HFD)-induced hyperlipidemia. METHODS: A hyperlipidemic rat model was established by feeding rats with a high-fat diet. Agl was administered orally, and serum lipid levels were analyzed. Molecular techniques, including RT-polymerase chain reaction (PCR) and fecal microbiota sequencing, were used to investigate the effects of Agl on lipid metabolism and gut microbiota composition. RESULTS: Agl administration significantly reduced serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) and mitigated hepatic damage induced by HFD. Molecular investigations have revealed the modulation of key lipid metabolism genes and proteins by Agl. Notably, Agl treatment enriched the gut microbiota with beneficial genera, including Lactobacillus, Akkermansia, and Blautia and promoted specific shifts in Lactobacillus murinus, Firmicutes bacterium CAG:424, and Allobaculum stercoricanis. CONCLUSION: This comprehensive study established Agl as a promising candidate for the treatment of hyperlipidemia. It also exhibits remarkable hypolipidemic and hepatoprotective properties. The modulation of lipid metabolism-related genes, along with the restoration of gut microbiota balance, provides mechanistic insights. Thus, Agl has great potential for clinical applications in hyperlipidemia management.

Network pharmacology prediction, molecular docking and in vitro experiment explored the potential mechanism of Gaoyuan'an capsule in improving hypoxia tolerance.

BACKGROUND: Tibetan medicine Gaoyuan'an capsule (GYAC) is widely used to prevent pulmonary edema at high altitude, but the specific mechanism has not been explored. In this study, we analyzed the mechanism of GYAC in hypoxia tolerance, and provided a new idea for the prevention and treatment of altitude disease. METHODS: The effective components and corresponding targets of GYAC were screened out by the Chinese herbal medicine network database, and the key targets of hypoxia tolerance were retrieved by Genecards, OMIM and PubMed database. Cytoscape 3.7.2 was used to construct GYAC ingredient-target-hypoxia tolerance-related target network. GO function annotation and KEGG enrichment analysis were performed to predict the pathways in which target genes may be involved, and molecular docking was used to verify the binding ability of the compound to target genes. In vitro, the above results were further verified by molecular experiment. RESULTS: We found that GYAC can improve hypoxia tolerance by regulating various target genes, including IL6, IFNG, etc. The main regulatory pathways were HIF-1 signaling pathway. Molecular docking showed that the affinity between luteolin and target genes (IL6, IFNG) were better. In vitro, we observed that hypoxia can inhibit cell viability and promote apoptosis of H9C2 cell. And hypoxia can promote the expression of LDH. After the addition of luteolin, the decrease of cell viability, the increase of cell apoptosis, LDH release and the decrease of mitochondrial membrane potential were inhibited. Besides, inflammatory related factors (IL-6, IL-10, IL-2, IFNG and VEGFA) expression were also inhibited hypoxic cell models. CONCLUSIONS: The results of network pharmacology and molecular docking showed that luteolin, a monomeric component of GYAC, played a role in hypoxia tolerance through a variety of target genes, such as IL6, IFNG. What's more, we have discovered that luteolin can reduce the inflammatory response in cardiac myocytes, thereby alleviating mitochondrial damage, and ultimately enhancing the hypoxia tolerance of H9C2 cardiomyocytes.

Recent advances in understanding the regulatory mechanism of plasma membrane H+-ATPase through the brassinosteroid signaling pathway.

The polyhydroxylated steroid phytohormone brassinosteroids (BRs) control many aspects of plant growth, development and responses to environmental changes. Plasma membrane (PM) H+-ATPase, the well-known PM proton pump, is a central regulator in plant physiology, which mediates not only plant growth and development, but also adaptation to stresses. Recent studies highlight that PM H+-ATPase is at least partly regulated via the BR signaling. Firstly, the BR cell surface receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) and multiple key components of BR signaling directly or indirectly influence PM H+-ATPase activity. Secondly, the SMALL AUXIN UP RNA (SAUR) gene family physically interacts with BRI1 to enhance organ development of Arabidopsis by activating PM H+-ATPase. Thirdly, RNA-sequencing (RNA-seq) assays showed that the expression of some SAUR genes is upregulated under the light or sucrose conditions, which is related to the phosphorylation state of the penultimate residue of PM H+-ATPase in a time-course manner. In this review, we describe the structural and functional features of PM H+-ATPase, and summarize recent progress toward understanding the regulatory mechanism of PM H+-ATPase by BRs, and briefly introduce how PM H+-ATPase activity is modulated by its own biterminal regions and the post-translational modifications.

Identification of Six Pathogenic Genes for Tibetan Familial Ventricular Septal Defect by Whole Exome Sequencing.

INTRODUCTION: Ventricular septal defect (VSD) is the most common congenital heart malformation in children. This study aimed to investigate potential pathogenic genes associated with Tibetan familial VSD. METHODS: Whole genomic DNA was extracted from eight Tibetan children with VSD and their healthy parents (a total of 16 individuals). Whole-exome sequencing was performed using the Illumina HiSeq platform. After filtration, detection, and annotation, single nucleotide variations and insertion-deletion markers were examined. Comparative evaluations using the Sorting Intolerant from Tolerant, PolyPhen V2, Mutation Taster, and Combined Annotation Dependent Depletion databases were conducted to predict harmful mutant genes associated with the etiology of Tibetan familial VSD. RESULTS: A total of six missense mutations in genetic disease-causing genes associated with the development of Tibetan familial VSD were identified: activin A receptor type II-like 1 (c.652 C > T: p.R218 W), ATPase cation transporting 13A2 (c.1363 C > T: p.R455 W), endoplasmic reticulum aminopeptidase 1 (c.481 G > A: p.G161 R), MRI1 (c.629 G > A: p.R210Q), tumor necrosis factor receptor-associated protein 1 (c.224 G > A: p.R75H), and FBN2 (c.2260 G > A: p.G754S). The Human Gene Mutation Database confirmed activin A receptor type II-like 1, MRI1, and tumor necrosis factor receptor-associated protein 1 as pathogenic mutations, while FBN2 was classified as a probable pathogenic mutation. CONCLUSIONS: This novel study directly screens genetic variations associated with Tibetan familial VSD using whole-exome sequencing, providing new insights into the pathogenesis of VSD.

Physiological Mechanisms Underlying Tassel Symptom Formation in Maize Infected with Sporisorium reilianum.

Head smut is a soil-borne fungal disease caused by Sporisorium reilianum that infects maize tassels and ears. This disease poses a tremendous threat to global maize production. A previous study found markedly different and stably heritable tassel symptoms in some maize inbred lines with Sipingtou blood after infection with S. reilianum. In the present study, 55 maize inbred lines with Sipingtou blood were inoculated with S. reilianum and classified into three tassel symptom types (A, B, and C). Three maize inbred lines representing these classes (Huangzao4, Jing7, and Chang7-2, respectively) were used as test materials to investigate the physiological mechanisms of tassel formation in infected plants. Changes in enzyme activity, hormone content, and protein expression were analyzed in all three lines after infection and in control plants. The activities of peroxidase (POD), superoxide dismutase (SOD), and phenylalanine-ammonia-lyase (PAL) were increased in the three typical inbred lines after inoculation. POD and SOD activities showed similar trends between lines, with the increase percentage peaking at the V12 stage (POD: 57.06%, 63.19%, and 70.28% increases in Huangzao4, Jing7, and Chang7-2, respectively; SOD: 27.01%, 29.62%, and 47.07% in Huangzao4, Jing7, and Chang7-2, respectively. These were all higher than in the disease-resistant inbred line Mo17 at the same growth stage); this stage was found to be key in tassel symptom formation. Levels of gibberellic acid (GA3), indole-3-acetic acid (IAA), and abscisic acid (ABA) were also altered in the three typical maize inbred lines after inoculation, with changes in GA3 and IAA contents tightly correlated with tassel symptoms after S. reilianum infection. The differentially expressed proteins A5H8G4, P09233, and Q8VXG7 were associated with changes in enzyme activity, whereas P49353, P13689, and P10979 were associated with changes in hormone contents. Fungal infection caused reactive oxygen species (ROS) and nitric oxide (NO) bursts in the three typical inbred lines. This ROS accumulation caused biofilm disruption and altered host signaling pathways, whereas NO signaling triggered strong secondary metabolic responses in the host and altered the activities of defense-related enzymes. These factors together resulted in the formation of varying tassel symptoms. Thus, interactions between S. reilianum and susceptible maize materials were influenced by a variety of signals, enzymes, hormones, and metabolic cycles, encompassing a very complex regulatory network. This study preliminarily identified the physiological mechanisms leading to differences in tassel symptoms, deepening our understanding of S. reilianum-maize interactions.

Impact of missense TSBP1 variants on the susceptibility to coronary heart disease.

BACKGROUND: A genome-wide association study has recognized C6orf10-BTNL2 polymorphism in coronary artery disease. The goal of this study was to explore the potential correlation of nine missense TSBP1 variants with coronary heart disease (CHD) risk in the Chinese Han population. METHODS: Nine TSBP1 missense single nucleotide polymorphisms (SNPs) were selected for genotyping by the Agena MassARRAY platform. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to analyze the contribution of TSBP1 SNPs to CHD predisposition by logistic regression models adjusted by age, sex, drinking, and smoking. The correlation of TSBP1 variants with clinical data in CHD patients was examined by Kruskal-Wallis test. RESULTS: rs9268368-C (p = 0.039, OR = 1.18, 95 % CI: 1.01-1.38) was related to an increased risk of CHD, while rs3749966-C (p = 0.032, OR = 0.49, 95 % CI: 0.25-0.96) and rs3129941-A (p = 0.011, OR = 0.74, 95 % CI: 0.59-0.93) might be protective factors against CHD occurrence in the Chinese Han population. We also observed the effects of demographic characteristics (age, sex, alcohol consumption, and smoking) and complications (hypertension and diabetes) on the interactive association of TSBP1 polymorphisms with CHD susceptibility. rs139993810 was related to the levels of high-density lipoprotein cholesterol (HDL-C, p = 0.030). CONCLUSIONS: Our findings determined the association of TSBP1 rs9268368, rs3749966, and rs3129941 with CHD occurrence in the Chinese Han population, and highlighted the influence of demographic characteristics and complications on the interactive association of TSBP1 polymorphisms with CHD risk.

Distinct Metabolites in Osteopenia and Osteoporosis: A Systematic Review and Meta-Analysis.

Multiple studies have indicated that distinct metabolites are involved in the occurrence and development of osteopenia (ON) and osteoporosis (OP); however, these metabolites in OP and ON have not yet been classified and standardized. This systematic review and meta-analysis included 21 articles aiming to investigate the distinct metabolites in patients with ON and OP. The quality of the included articles was generally high; seventeen studies had >7 stars, and the remaining four received 6 stars. This systematic review showed that three metabolites (phosphatidylcholine (PC) (lipid metabolites), galactose (carbohydrate metabolites), and succinic acid (other metabolites)) increased, four (glycylglycine (gly-gly), cystine (amino acids), sphingomyelin (SM) (lipid metabolites) and glucose (carbohydrate metabolites)) decreased, and five (glutamine, hydroxyproline, taurine (amino acids), lysophosphatidylcholine (LPC) (lipid metabolites), and lactate (other metabolites)) had conflicting directions in OP/ON. The results of the meta-analysis show that gly-gly (MD = -0.77, 95%CI -1.43 to -0.11, p = 0.02) and cystine (MD = -5.52, 95%CI -7.35 to -3.68, p < 0.00001) decreased in the OP group compared with the healthy control group. Moreover, LPC (MD = 1.48, 95%CI 0.11 to 2.86, p = 0.03) increased in the OP group compared with the healthy control group. These results indicate that distinct metabolites were associated with ON and OP, which could be considered a predictor for OP.

CTSF: An Intrusion Detection Framework for Industrial Internet Based on Enhanced Feature Extraction and Decision Optimization Approach.

The traditional Transformer model primarily employs a self-attention mechanism to capture global feature relationships, potentially overlooking local relationships within sequences and thus affecting the modeling capability of local features. For Support Vector Machine (SVM), it often requires the joint use of feature selection algorithms or model optimization methods to achieve maximum classification accuracy. Addressing the issues in both models, this paper introduces a novel network framework, CTSF, specifically designed for Industrial Internet intrusion detection. CTSF effectively addresses the limitations of traditional Transformers in extracting local features while compensating for the weaknesses of SVM. The framework comprises a pre-training component and a decision-making component. The pre-training section consists of both CNN and an enhanced Transformer, designed to capture both local and global features from input data while reducing data feature dimensions. The improved Transformer simultaneously decreases certain training parameters within CTSF, making it more suitable for the Industrial Internet environment. The classification section is composed of SVM, which receives initial classification data from the pre-training phase and determines the optimal decision boundary. The proposed framework is evaluated on an imbalanced subset of the X-IIOTID dataset, which represent Industrial Internet data. Experimental results demonstrate that with SVM using both "linear" and "rbf" kernel functions, CTSF achieves an overall accuracy of 0.98875 and effectively discriminates minor classes, showcasing the superiority of this framework.

Enhanced Anticoagulation of Hierarchy Liquid Infused Surfaces in Blood Flow.

Liquid infused surfaces (LIS) hold remarkable potential in anticoagulation. However, liquid loss of LIS in the bloodstream remains a challenge toward its clinical application. Here, micronano hierarchy structures are obtained on the titanium alloy substrate by regulating the microspheres' distribution. When the gap between the microspheres is smaller than the diameter of the red blood cell (RBC), the LIS is more stable under the blood wash and presents a better anticoagulation performance. The proper interval is found to prevent the RBCs from entering the gap and remove the liquid on the surface. The retained thickness of the liquid film is measured by the atomic force microscopy (AFM) technique. The LIS is applied on the front guide vane of an artificial heart pump and exhibits significant improvement on anticoagulation in the blood circulation in vitro for 25 h. The techniques and findings can be used to optimize the anticoagulation performance of LIS-related biomedical implant devices.

Nrf2-mediated macrophage function in benign prostatic hyperplasia: Novel molecular insights and implications.

One of the most common urological diseases is benign prostatic hyperplasia (BPH), with a high prevalence in the middle-aged and elderly male population. Patient's mental and physical health is affected significantly by this condition, causing them considerable discomfort. During the development of BPH, a synergistic effect occurs in response to inflammation, oxidative stress, and apoptosis induced by the activation of macrophages. The nuclear factor erythroid2-related factor 2 (Nrf2) signaling pathway can mediate macrophage activation and inhibit prostate hyperplasia by suppressing pro-inflammatory factors, anti-oxidative stress disorder, and initiating apoptosis. The purpose of this study was to review the mechanism of action of Nrf2 signaling pathway-mediated macrophage activation on the immune microenvironment of BPH and to summarize the Chinese medicine based on Nrf2 to provide an overview of BPH treatment options.

Differential Metabolites in Osteoarthritis: A Systematic Review and Meta-Analysis.

(1) Many studies have attempted to utilize metabolomic approaches to explore potential biomarkers for the early detection of osteoarthritis (OA), but consistent and high-level evidence is still lacking. In this study, we performed a systematic review and meta-analysis of differential small molecule metabolites between OA patients and healthy individuals to screen promising candidates from a large number of samples with the aim of informing future prospective studies. (2) Methods: We searched the EMBASE, the Cochrane Library, PubMed, Web of Science, Wan Fang Data, VIP Date, and CNKI up to 11 August 2022, and selected relevant records based on inclusion criteria. The risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. We performed qualitative synthesis by counting the frequencies of changing directions and conducted meta-analyses using the random effects model and the fixed-effects model to calculate the mean difference and 95% confidence interval. (3) Results: A total of 3798 records were identified and 13 studies with 495 participants were included. In the 13 studies, 132 kinds of small molecule differential metabolites were extracted, 58 increased, 57 decreased and 17 had direction conflicts. Among them, 37 metabolites appeared more than twice. The results of meta-analyses among four studies showed that three metabolites increased, and eight metabolites decreased compared to healthy controls (HC). (4) Conclusions: The main differential metabolites between OA and healthy subjects were amino acids (AAs) and their derivatives, including tryptophan, lysine, leucine, proline, phenylalanine, glutamine, dimethylglycine, citrulline, asparagine, acetylcarnitine and creatinine (muscle metabolic products), which could be potential biomarkers for predicting OA.

Lnc-Malat1 promotes slow myofiber-type transformation through sponging miR-129-5p in C2C12 myotubes.

Long non-coding metastasis-associated lung adenocarcinoma transcript (lnc-Malat1) emerges as a novel regulator in skeletal muscle development, while its function and the related mechanism is not fully revealed yet. In this study, knockdown of lnc-Malat1 by siRNA significantly inhibited the expression of myoblast marker genes (MyHC, MyoD, and MyoG) and slow muscle fiber marker genes (MyHC I), together with repressed expression of mitochondria-related genes COX5A, ACADM, CPTA1, FABP3, and NDUFA1. Overexpression of lnc-Malat1 exerted an opposite effect, promoting myoblast differentiation and slow muscle fiber formation. Dual luciferase reporter assay revealed a direct interaction between lnc-Malat1 and miR-129-5p, and overexpression of lnc-Malat1 significantly inhibited miR-129-5p expression, thereby elevating the expression of Mef2a, miR-129-5p target protein. In addition, enforced expression of lnc-Malat1 restored the inhibitory effect of miR-129-5p on myoblast differentiation and MyHC I expression. Taken together, our results suggest that lnc-Malat1 promotes myoblast differentiation, and maintains the slow muscle fiber phenotype via adsorbing miR-129-5p.

Analysis of Metabolites in Gout: A Systematic Review and Meta-Analysis.

(1) Background: Many studies have attempted to explore potential biomarkers for the early detection of gout, but consistent and high levels of evidence are lacking. In this study, metabolomics was used to summarize the changes of metabolites in the literature and explore the potential value of metabolites in predicting the occurrence and development of gout. (2) Methods: We searched the databases including the EMBASE, the Cochrane Library, PubMed, Web of Science, VIP Date, Wanfang Data, and CNKI, and the screening was fulfilled on 30 July 2022. The records were screened according to the inclusion criteria and the risk of bias was assessed. Qualitative analysis was performed for all metabolites, and meta-analysis was performed for metabolite concentrations using random effects to calculate the Std mean difference and 95% confidence interval. (3) Results: A total of 2738 records were identified, 33 studies with 3422 participants were included, and 701 metabolites were identified. The qualitative analysis results showed that compared with the healthy control group, the concentration of 56 metabolites increased, and 22 metabolites decreased. The results of the meta-analysis indicated that 17 metabolites were statistically significant. (4) Conclusions: Metabolites are associated with gout. Some specific metabolites such as uric acid, hypoxanthine, xanthine, KYNA, guanosine, adenosine, creatinine, LB4, and DL-2-Aminoadipic acid have been highlighted in the development of gout.

Prognostic impact of blood urea nitrogen to albumin ratio on patients with sepsis: a retrospective cohort study.

To investigate the ability of the ratio of blood urea nitrogen (BUN) to serum albumin ratio (BAR) in patients with sepsis in intensive care units (ICUs) to predict the prognosis of short-and long-term death. Data are from the Marketplace for Intensive Care Medical Information IV (MIMIC-IV v2.0) database for patients with sepsis as defined by SEPSIS-3. The primary outcome was 30-day mortality and the secondary outcome was 360-day mortality. Kaplan-Meier (KM) survival curves were plotted to describe differences in BAR mortality in different subgroups and area under the curve (AUC) analysis was performed to compare the predictive value of sequential organ failure assessment (SOFA), BAR, blood urea nitrogen (BUN) and albumin. Multivariate Cox regression models and subgroup analysis were used to determine the correlation between BAR and 30-day mortality and 360-day mortality. A total of 7656 eligible patients were enrolled in the study with a median BAR of 8.0 mg/g, including 3837 in the ≤ 8.0 group and 3819 in the BAR > 8.0 group, with 30-day mortality rates of 19.1% and 38.2% (P < 0.001) and 360-day mortality rates of 31.1% and 55.6% (P < 0.001). Multivariate Cox regression models showed an increased risk of death for 30-day mortality (HR = 1.219, 95% CI 1.095-1.357; P < 0.001) and 360-day mortality (HR = 1.263, 95% CI 1.159-1.376; P < 0.001) in the high BAR group compared to the low BAR group. For the 30-day outcome, the area under the curve (AUC) was 0.661 for BAR and 0.668 for 360-day BAR. In the subgroup analysis, BAR remained an isolated risk factor for patient death. As a clinically inexpensive and readily available parameter, BAR can be a valuable forecaster of prognosis in patients with sepsis in the intensive care unit.

The Association of Methylation Level in the CYP39A1 Gene with High Altitude Pulmonary Edema in the Chinese Population.

Background: High altitude pulmonary edema (HAPE) is still the most common fatal disease at high altitudes. DNA methylation proceeds with an important role in HAPE progression. This study was designed to investigate the association between CYP39A1 methylation and HAPE. Methods: Peripheral blood samples were enrolled from 106 participants (53 HAPE patients and 53 healthy subjects) to study the association of CYP39A1 methylation with HAPE. DNA methylation site in the promoter region of CYP39A1 was detected by Sequenom MassARRAY EpiTYPER platform. Results: Probability analysis showed that the methylation probabilities of CYP39A1_1_CpG_5 and CYP39A1_3_CpG_21 are significant differences between the cases and controls (p< 0.05). The methylation level analysis indicated that CYP39A1_1_CpG_2.3.4, CYP39A1_5_CpG_6.7, and CYP39A1_5_CpG_9.10 were higher methylation in HAPE compared to the controls (p< 0.05). CYP39A1_3_CpG_21 and CYP39A1_4_CpG_3 exhibited a lower methylation level in HAPE than that in the controls (p< 0.05). The association analysis given that CYP39A1_1_CpG_2.3.4 (OR 2.56, p= 0.035), CYP39A1_5_CpG_6.7 (OR 3.99, p= 0.003), CYP39A1_5_CpG_9.10 (OR 3.99, p= 0.003), CYP39A1_5_CpG_16.17.18 (OR 2.53, p= 0.033), and CYP39A1_5_CpG_20 (OR 3.05, p= 0.031) are associated with an increased risk of HAPE. Whereas CYP39A1_1_CpG_5 (OR 0.33, p= 0.016) and CYP39A1_3_CpG_21 (OR 0.18, p= 0.005) have a protective role in HAPE. Besides, age-stratification analysis showed that CYP39A1_1_CpG_5 (OR 0.16, p= 0.014) and CYP39A1_3_CpG_21 (OR 0.08, p= 0.023) had a protective impact on HAPE in people aged ≤32 years. CYP39A1_5_CpG_6.7 (OR 6.70, p= 0.008) and CYP39A1_5_CpG_9.10 (OR 6.70, p= 0.008) were related to an increased susceptibility to HAPE aged >32 years. Moreover, the diagnostic value of CYP39A1_3_CpG_21 (AUC = 0.712, p< 0.001) was significantly better than other CpG sites. Conclusion: The methylation level of CYP39A1 was associated with a risk of HAPE in the Chinese population, which provided new perspective for preventing and diagnosing of HAPE.

Case report: NUDT15 polymorphism and severe azathioprine-induced myelosuppression in a young Chinese female with systematic lupus erythematosus: a case analysis and literature review.

Azathioprine is clinically used as an immunosuppressant for treating autoimmune diseases. However it has narrow therapeutic indices due to frequent myelosuppression. Polymorphic variants of genes coding for thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X motif 15 (NUDT15) are critical determinants of AZA intolerance, and the differences in frequencies of the two genetic variants exist among people of different ethnicities. Most reports regarding NUDT15 variant, AZA-induced myelosuppression occurred in patients with inflammatory bowel disease and acute lymphoblastic leukemia. Moreover, detailed clinical characteristics were not frequently reported. Here we present the case of a young Chinese female with the NUDT15 c.415C>T (rs116855232, TT) homozygous variant and wild-type TPMT*2 (rs1800462), TPMT*3B (rs1800460), and TPMT*3C (rs1142345) who received high doses of AZA (2.3 mg/kg/d) for systematic lupus erythematosus and had not been told to undergo routine blood cell counts during AZA ingestion. The patient had suffered from severe AZA-induced myelosuppression and alopecia. Moreover, dynamic changes in blood cell counts and responses to treatment were observed. We also conducted a systematic review of published case reports of patients exclusively with NUDT15 c.415C>T homozygous or heterozygous variants to review the characteristics of dynamic changes in blood cells so as to provide reference information for clinical treatment.

Association between GLS Gene Polymorphisms and the Susceptibility to Lung Cancer in the Chinese Han Population.

BACKGROUND: Lung cancer is one of the most serious malignant tumors endangering human health and life. This study focused on evaluating the association between single nucleotide polymorphisms (SNPs) of the glutaminase (GLS) and lung cancer susceptibility in the Chinese Han population. METHODS: A total of 684 lung cancer patients and 684 healthy individuals were enrolled. Five GLS SNPs (rs143584207 C/A, rs117985587 T/C, rs74271715 G/T, rs2355570 G/A, and rs6713444 A/G) were screened as candidate genetic loci. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the association between GLS SNPs and lung cancer susceptibility. False-positive report probability (FPRP) analysis further verified whether the positive results deserved attention. Finally, the multi-factor dimensionality reduction (MDR) method was applied to analyze the interactions between SNPs. RESULTS: The overall analysis revealed that GLS rs143584207 and rs6713444 were significantly associated with lung cancer susceptibility. The subgroup and clinical information analyses further revealed that GLS rs143584207 and rs6713444 could remarkably reduce lung cancer susceptibility in different subgroups (age >60, females, body mass index (BMI) <24, and lung adenocarcinoma). Rs143584207 could significantly reduce lung cancer susceptibility in non-smokers. Additionally, rs6713444 also had a protective effect on patients with advanced lung cancer. CONCLUSIONS: Our study indicated that GLS rs143584207 and rs6713444 could strikingly reduce lung cancer susceptibility in the Chinese Han population, which will give a new direction for the timely treatment of lung cancer.

The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. The whole concept of NAFLD has now moved into metabolic dysfunction-associated fatty liver disease (MAFLD) to emphasize the strong metabolic derangement as the basis of the disease. Several studies have suggested that hepatic gene expression was altered in NAFLD and NAFLD-related metabolic comorbidities, particularly mRNA and protein expression of phase I and II drug metabolism enzymes (DMEs). NAFLD may affect the pharmacokinetic parameters. However, there were a limited number of pharmacokinetic studies on NAFLD at present. Determining the pharmacokinetic variation in patients with NAFLD remains challenging. Common modalities for modeling NAFLD included: dietary induction, chemical induction, or genetic models. The altered expression of DMEs has been found in rodent and human samples with NAFLD and NAFLD-related metabolic comorbidities. We summarized the pharmacokinetic changes of clozapine (CYP1A2 substrate), caffeine (CYP1A2 substrate), omeprazole (Cyp2c29/CYP2C19 substrate), chlorzoxazone (CYP2E1 substrate), midazolam (Cyp3a11/CYP3A4 substrate) in NAFLD. These results led us to wonder whether current drug dosage recommendations may need to be reevaluated. More objective and rigorous studies are required to confirm these pharmacokinetic changes. We have also summarized the substrates of the DMEs aforementioned. In conclusion, DMEs play an important role in the metabolism of drugs. We hope that future investigations should focus on the effect and alteration of DMEs and pharmacokinetic parameters in this special patient population with NAFLD.