Deep Profiling of Plasma Proteoforms with Engineered Nanoparticles for Top-Down Proteomics.

The dynamic range challenge for the detection of proteins and their proteoforms in human plasma has been well documented. Here, we use the nanoparticle protein corona approach to enrich low-abundance proteins selectively and reproducibly from human plasma and use top-down proteomics to quantify differential enrichment for the 2841 detected proteoforms from 114 proteins. Furthermore, nanoparticle enrichment allowed top-down detection of proteoforms between ∼1 µg/mL and ∼10 pg/mL in absolute abundance, providing up to a 105-fold increase in proteome depth over neat plasma in which only proteoforms from abundant proteins (>1 µg/mL) were detected. The ability to monitor medium and some low-abundant proteoforms through reproducible enrichment significantly extends the applicability of proteoform research by adding depth beyond albumin, immunoglobins, and apolipoproteins to uncover many involved in immunity and cell signaling. As proteoforms carry unique information content relative to peptides, this report opens the door to deeper proteoform sequencing in clinical proteomics of disease or aging cohorts.

Elevated serum cholesterol levels during pregnancy as predictors for postpartum hypercholesterolemia: A prospective cohort study.

OBJECTIVE: To identify the associations between gestational cholesterol levels and the risk of postpartum hypercholesterolemia, and to establish trimester-specific reference values. METHODS: Serum lipids at gestational weeks 6-8, 16, 24, and 36, and 42 days postpartum were derived from 905 pregnant women of a prospective cohort. The major outcome was postpartum hypercholesterolemia. Logistic regression and restricted cubic splines were conducted to estimate the associations between cholesterol levels at specific gestational ages and postpartum hypercholesterolemia. Associations of the trend of changes in cholesterol levels during pregnancy with postpartum hypercholesterolemia were evaluated by linear mixed-effect model and linear or logistic regression. Reference values were computed by the receiver operating characteristic curves. RESULTS: Serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and the ratios of TC/HDL-C and LDL-C/HDL-C all increased during pregnancy and decreased at 42 days postpartum. The elevated levels of TC and LDL-C, decreased levels of HDL-C in pregnancy, and their rapid change rates were positively associated with higher risks of postpartum hypercholesterolemia. The established reference values from the first to the third trimester were below 5.47, 6.35, and 7.22 mmol/L for TC; below 2.83, 3.82, and 4.21 mmol/L for LDL-C; and more than 1.50, 1.55, and 1.50 mmol/L for HDL-C, respectively. CONCLUSION: Maternal cholesterol levels and their trend of change during pregnancy were predictors of postpartum hypercholesterolemia. Trimester-specific reference values were established in a Chinese population.

Interventions and behaviour change techniques for improving physical activity level in working-age people (18-60 years) with type 2 diabetes: A systematic review and network meta-analysis.

BACKGROUND: The escalating prevalence of type 2 diabetes within the working-age population (18-60 years) imposes a substantial societal burden. Whilst physical activity is crucial for diabetes management, limited evidence exists to inform optimal strategies for promoting physical activity in this population. We aimed to evaluate and compare the effect of interventions for increasing physical activity in working-age adults with type 2 diabetes. METHODS: We searched Web of Science, the Cochrane Library, Medline, Embase, PsycINFO, ClinicalTrials.gov, and ICTRP from inception to April 30, 2023. Randomised controlled trials that reported the effect of interventions (education, training or behavioural) to promote physical activity (either self-reported or objective) in people aged 18-60 years were included. Two independent reviewers conducted summary data extraction and quality assessment. Pairwise random-effects, Frequentist network meta-analyses, and subgroup analysis were used to obtain pooled effects. RESULTS: A total of 52 trials were included in this systematic review. Compared to control group, the physical activity interventions demonstrated statistically significant effects on objectively measured physical activity (SMD 0.77, 95 % CI 0.27-1.27), self-reported physical activity (SMD 0.88, 95 % CI 0.40-1.35), and overall physical activity (SMD 0.82, 95 % CI 0.48-1.16); a statistically and clinically meaningful reduction on glycated haemoglobin A1c (HbA1c) was also identified (MD -0.50 %, 95 % CI -0.66, -0.35). In terms of intervention types, education interventions exerted the largest effect on objectively measured physical activity; however, psychological interventions had the largest effects on overall physical activity compared to other intervention types. Four behaviour change techniques were related to statistically significant reduction in HbA1c: goal setting (outcome), information about health consequences, demonstration of the behaviour, and prompts/cues. Subgroup analysis showed that delivery mode, intervention setting, and facilitator were associated with statistically significant effect on physical activity and HbA1c. CONCLUSIONS: Psychologically modelled education incorporating behaviour change techniques may be the most beneficial way to promote physical activity and glycaemic control in working-age adults with type 2 diabetes. Delivery mode, intervention setting, and facilitator type should be considered when designing interventions for improving physical activity level in working-age people with type 2 diabetes.

α-amanitin induce inflammatory response by activating ROS/NF-κB-NLRP3 signaling pathway in human hepatoma HepG2 cells.

α-amanitin (AMA) is a hepatotoxic mushroom toxin responsible for over 90% of mushroom poisoning fatalities worldwide, seriously endangering human life and health. Few evidences have indicated that AMA leads to inflammatory responses and inflammatory infiltration in vitro and in vivo. However, the molecular mechanism remains unknown. In this study, human hepatocellular carcinomas cells (HepG2) were exposed to AMA at various concentrations for short period of times. Results revealed that AMA increased ROS production and elevated the releases of malondialdehyde (MDA) and lactate dehydrogenase (LDH), resulting in oxidative damage in HepG2 cells. Also, AMA exposure significantly increased the secreted levels of inflammatory cytokines and activated the NLRP3 inflammasome. The inflammatory responses were reversed by NLRP3 inhibitor MCC950 and NF-κB inhibitor Bay11-7082. Additionally, N-acetylcysteine (NAC) blocked the upregulation of the NF-κB/NLRP3 signaling pathway and remarkably alleviated the inflammatory response. These results demonstrated that AMA could induce inflammation through activating the NLRP3 inflammasome triggered by ROS/NF-κB signaling pathway. Our research provides new insights into the molecular mechanism of AMA-induced inflammation damage and may contribute to establish new prevention strategies for AMA hepatotoxicity.

Preparation and Properties of Fluorinated Poly(aryl ether)s with Ultralow Water Absorption and Dielectric Constant by Cross-Linked Network Strategy.

Poly(aryl ether) materials are used in a wide range of applications in the communications and microelectronics fields for their outstanding mechanical and dielectric properties. In order to further improve the comprehensive performance, this work reports a series of cross-linkable poly(aryl ether)s (UCL-PAEn) containing trifluoroisopropyl and perfluorobiphenyl structures using 2,2-bis(4-hydroxyphenyl)hexafluoropropane, 2,2'-diallyl bisphenol A, and perfluorobiphenyl as starting materials. Their chemical structures and the effect of changes in the allyl content on the properties are thoroughly investigated. Owing to the introduction of fluorine atoms and cross-linked networks, the cross-linked poly(aryl ether) films present low dielectric constants (Dk = 1.93-2.24 at 1 MHz), low water absorption (0.14% -0.25%), and hydrophobic film surfaces (94.3-99.4°). Additionally, because of the presence of cross-linked networks, the CL-PAEn films exhibit superior thermal stability, with the 5% weight loss temperatures all above 445 °C and the maximum thermal decomposition rate temperatures all above 550 °C. The cross-linked films also demonstrate excellent mechanical properties, with tensile strength in the range of 57.1 -146.7 MPa and tensile modulus in the range of 1.8 GPa-4.5 GPa.

Pathogenic gene connections in type 2 diabetes and non-alcoholic fatty liver disease: a bioinformatics analysis and mouse model investigations experiments.

BACKGROUND: Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are prevalent metabolic disorders with overlapping pathophysiological mechanisms. A comprehensive understanding of the shared molecular pathways involved in these conditions can advance the development of effective therapeutic interventions. METHODS: We used two datasets sourced from the Gene Expression Omnibus (GEO) database to identify common differentially expressed genes (DEGs) between T2D and NAFLD. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify the enriched biological processes and signaling pathways. In addition, we performed a protein-protein interaction (PPI) network analysis to identify hub genes with pivotal roles. To validate our findings, we established a type 2 diabetic mouse model with NAFLD. RESULTS: Our analysis identified 53 DEGs shared between T2D and NAFLD. Enrichment analysis revealed their involvement in signal transduction, transcriptional regulation, and cell proliferation as well as in the ferroptosis signaling pathways. PPI network analysis identified ten hub genes, namely CD44, CASP3, FYN, KLF4, HNRNPM, HNRNPU, FUBP1, RUNX1, NOTCH3, and ANXA2. We validated the differential expression of FYN, HNRNPU, and FUBP1 in liver tissues of a type 2 diabetic mouse model with NAFLD. CONCLUSIONS: Our study offers valuable insights into the shared molecular mechanisms underlying T2D and NAFLD. The identified hub genes and pathways present promising prospects as therapeutic targets to address these prevalent metabolic disorders.

Heterologous Prime-Boost Immunization Strategies Using Varicella-Zoster Virus gE mRNA Vaccine and Adjuvanted Protein Subunit Vaccine Triggered Superior Cell Immune Response in Middle-Aged Mice.

Purpose: Heterologous immunization using different vaccine platforms has been demonstrated as an efficient strategy to enhance antigen-specific immune responses. In this study, we performed a head-to-head comparison of both humoral and cellular immune response induced by different prime-boost immunization regimens of mRNA vaccine and adjuvanted protein subunit vaccine against varicella-zoster virus (VZV) in middle-aged mice, aiming to get a better understanding of the influence of vaccination schedule on immune response. Methods: VZV glycoprotein (gE) mRNA was synthesized and encapsulated into SM-102-based lipid nanoparticles (LNPs). VZV-primed middle-aged C57BL/6 mice were then subjected to homologous and heterologous prime-boost immunization strategies using VZV gE mRNA vaccine (RNA-gE) and protein subunit vaccine (PS-gE). The antigen-specific antibodies were evaluated using enzyme-linked immunosorbent assay (ELISA) analysis. Additionally, cell-mediated immunity (CMI) was detected using ELISPOT assay and flow cytometry. Besides, in vivo safety profiles were also evaluated and compared. Results: The mRNA-loaded lipid nanoparticles had a hydrodynamic diameter of approximately 130 nm and a polydispersity index of 0.156. Total IgG antibody levels exhibited no significant differences among different immunization strategies. However, mice received 2×RNA-gE or RNA-gE>PS-gE showed a lower IgG1/IgG2c ratio than those received 2×PS-gE and PS-gE> RNA-gE. The CMI response induced by 2×RNA-gE or RNA-gE>PS-gE was significantly stronger than that induced by 2×PS-gE and PS-gE> RNA-gE. The safety evaluation indicated that both mRNA vaccine and protein vaccine induced a transient body weight loss in mice. Furthermore, the protein vaccine produced a notable inflammatory response at the injection sites, while the mRNA vaccine showed no observable inflammation. Conclusion: The heterologous prime-boost strategy has demonstrated that an mRNA-primed immunization regimen can induce a better cell-mediated immune response than a protein subunit-primed regimen in middle-aged mice. These findings provide valuable insights into the design and optimization of VZV vaccines with the potentials to broaden varicella vaccination strategies in the future.

Low storage temperature affects quality and volatile compounds in fresh tomatoes.

To investigate the impact of low temperature on the quality and flavor of ripe red tomatoes, we analyzed transcriptomes and volatile metabolomes of ripe red fruits stored at 0 °C and 20 °C for 8 days. The results showed that 0 °C maintained the sugar content by increasing the expression of sucrose synthetase (SUS) and sucrose transporter (SUT). Low expression of aroma synthesis-related genes, such as alcohol dehydrogenase 1 (ADH1), amino acid decarboxylase 1 A (AADC1A), and branched-chain amino acid aminotransferase 2 (BCAT2), were associated with reduced levels of pentanal, hexanal, 3-methylbutanal, 2-methylbutanal, and 2-phenylethanol. Additionally, the expression of pectinesterase (PE), beta-galactosidase (ß-GAL), and beta-glucosidase (ß-Glu), as well as phytoene synthase1 (PSY1) involved in carotenoid synthesis, was inhibited, thereby maintaining fruits texture and color. Furthermore, storage at 0 °C induced the expression of numerous genes regulating antioxidant and heat shock proteins, which further preserved the postharvest quality of tomatoes.

A cyclic di-GMP-binding adaptor protein interacts with a N5-glutamine methyltransferase to regulate the pathogenesis in Xanthomonas citri subsp. citri.

The second messenger cyclic diguanylate monophosphate (c-di-GMP) regulates a wide range of bacterial behaviours through diverse mechanisms and binding receptors. Single-domain PilZ proteins, the most widespread and abundant known c-di-GMP receptors in bacteria, act as trans-acting adaptor proteins that enable c-di-GMP to control signalling pathways with high specificity. This study identifies a single-domain PilZ protein, XAC3402 (renamed N5MapZ), from the phytopathogen Xanthomonas citri subsp. citri (Xcc), which modulates Xcc virulence by directly interacting with the methyltransferase HemK. Through yeast two-hybrid, co-immunoprecipitation and immunofluorescent staining, we demonstrated that N5MapZ and HemK interact directly under both in vitro and in vivo conditions, with the strength of the protein-protein interaction decreasing at high c-di-GMP concentrations. This finding distinguishes N5MapZ from other characterized single-domain PilZ proteins, as it was previously known that c-di-GMP enhances the interaction between those single-domain PilZs and their protein partners. This observation is further supported by the fact that the c-di-GMP binding-defective mutant N5MapZR10A can interact with HemK to inhibit the methylation of the class 1 translation termination release factor PrfA. Additionally, we found that HemK plays an important role in Xcc pathogenesis, as the deletion of hemK leads to extensive phenotypic changes, including reduced virulence in citrus plants, decreased motility, production of extracellular enzymes and stress tolerance. Gene expression analysis has revealed that c-di-GMP and the HemK-mediated pathway regulate the expression of multiple virulence effector proteins, uncovering a novel regulatory mechanism through which c-di-GMP regulates Xcc virulence by mediating PrfA methylation via the single-domain PilZ adaptor protein N5MapZ.

Genomic investigation of 18,421 lines reveals the genetic architecture of rice.

Understanding how numerous quantitative trait loci (QTL) shape phenotypic variation is an important question in genetics. To address this, we established a permanent population of 18,421 (18K) rice lines with reduced population structure. We generated reference-level genome assemblies of the founders and genotyped all 18K-rice lines through whole-genome sequencing. Through high-resolution mapping, 96 high-quality candidate genes contributing to variation in 16 traits were identified, including OsMADS22 and OsFTL1 verified as causal genes for panicle number and heading date, respectively. We identified epistatic QTL pairs and constructed a genetic interaction network with 19 genes serving as hubs. Overall, 170 masking epistasis pairs were characterized, serving as an important factor contributing to genetic background effects across diverse varieties. The work provides a basis to guide grain yield and quality improvements in rice.

Compared to exercise, the effects of exercise combined with cognitive training in people with mild cognitive impairment: a network meta-analysis.

OBJECTIVES: The study aimed to evaluate the relative effectiveness of exercise combined with cognitive training (E&CT) in improving cognitive function compared to exercise alone. METHOD: PubMed, Embase, Cochrane Central Register of Controlled Trials, SPORTDiscus, and OpenGrey were systematically searched. Additional screenings were performed by reviewing citations of relevant articles. Studies were included if they met inclusion criteria. Both pairwise and network meta-analyses were performed using a random effects model in Stata 15.0. RESULTS: Totally, 46 trials from 54 literature (n = 2846) were eligible for inclusion in the meta-analysis. The network meta-analysis indicated that exercise alone was more efficacious than E&CT in improving global cognition and multicomponent exercise exhibited the highest likelihood (SUCRA value= 89.0%) of being the most effective type. Regarding memory function, E&CT presented greater potential than exercise alone, with the interactive modality ranking first (SUCRA value = 88.4%). Multicomponent exercise was identified as the top intervention for enhancing executive function. The overall quality of the included studies was rated as moderate, and the certainty of evidence ranged from low to high. CONCLUSION: Multicomponent exercise emerged as the optimal intervention for improving global cognition and executive function. Nevertheless, for memory function, the interactive modality of E&CT demonstrated the highest probability of being the most effective choice.

Deep Profiling of Plasma Proteoforms with Engineered Nanoparticles for Top-down Proteomics.

The dynamic range challenge for detection of proteins and their proteoforms in human plasma has been well documented. Here, we use the nanoparticle protein corona approach to enrich low-abundant proteins selectively and reproducibly from human plasma and use top-down proteomics to quantify differential enrichment for the 2841 detected proteoforms from 114 proteins. Furthermore, nanoparticle enrichment allowed top-down detection of proteoforms between ∼1 µg/mL and ∼10 pg/mL in absolute abundance, providing up to 10 5 -fold increase in proteome depth over neat plasma in which only proteoforms from abundant proteins (>1 µg/mL) were detected. The ability to monitor medium and some low abundant proteoforms through reproducible enrichment significantly extends the applicability of proteoform research by adding depth beyond albumin, immunoglobins and apolipoproteins to uncover many involved in immunity and cell signaling. As proteoforms carry unique information content relative to peptides, this report opens the door to deeper proteoform sequencing in clinical proteomics of disease or aging cohorts.

Metabolic score for insulin resistance (METS-IR) predicts all-cause and cardiovascular mortality in the general population: evidence from NHANES 2001-2018.

BACKGROUND: The prevalence of obesity-associated insulin resistance (IR) is increasing along with the increase in obesity rates. In this study, we compared the predictive utility of four alternative indexes of IR [triglyceride glucose index (TyG index), metabolic score for insulin resistance (METS-IR), the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio and homeostatic model assessment of insulin resistance (HOMA-IR)] for all-cause mortality and cardiovascular mortality in the general population based on key variables screened by the Boruta algorithm. The aim was to find the best replacement index of IR. METHODS: In this study, 14,653 participants were screened from the National Health and Nutrition Examination Survey (2001-2018). And TyG index, METS-IR, TG/HDL-C and HOMA-IR were calculated separately for each participant according to the given formula. The predictive values of IR replacement indexes for all-cause mortality and cardiovascular mortality in the general population were assessed. RESULTS: Over a median follow-up period of 116 months, a total of 2085 (10.23%) all-cause deaths and 549 (2.61%) cardiovascular disease (CVD) related deaths were recorded. Multivariate Cox regression and restricted cubic splines analysis showed that among the four indexes, only METS-IR was significantly associated with both all-cause and CVD mortality, and both showed non-linear associations with an approximate "U-shape". Specifically, baseline METS-IR lower than the inflection point (41.33) was negatively associated with mortality [hazard ratio (HR) 0.972, 95% CI 0.950-0.997 for all-cause mortality]. In contrast, baseline METS-IR higher than the inflection point (41.33) was positively associated with mortality (HR 1.019, 95% CI 1.011-1.026 for all-cause mortality and HR 1.028, 95% CI 1.014-1.043 for CVD mortality). We further stratified the METS-IR and showed that significant associations between METS-IR levels and all-cause and cardiovascular mortality were predominantly present in the nonelderly population aged < 65 years. CONCLUSIONS: In conjunction with the results of the Boruta algorithm, METS-IR demonstrated a more significant association with all-cause and cardiovascular mortality in the U.S. population compared to the other three alternative IR indexes (TyG index, TG/HDL-C and HOMA-IR), particularly evident in individuals under 65 years old.

Structure, characterization, and application of a novel thermoreversible emulsion gel fabricated by citrate agar.

A novel thermoreversible emulsion gel was successfully prepared with citrate agar (CA) as the sole emulsifier. Compared with native agar gel emulsion, CA gel emulsion (CAGE) formed a stable emulsion gel when the CA concentration was increased to 1.25 % (w/w). Results of time-temperature scanning experiments showed that the emulsion gel rapidly transformed into liquid emulsion when heated to 40-50 °C and then solidified into emulsion gel after cooling to the critical temperature of solidification. The emulsion gel had stable sol-gel transformation ability after seven cycles repeated heating-cooling treatment (HCT) at 85 °C and 4 °C. However, the stability of emulsion gels gradually decreased because of the large-droplet formation during heating, which affected the CA molecular-reconfiguration network structure in cooling. The conjunction analysis of microstructure and properties of the emulsion gel indicated that its stability depended primarily on the spatial repulsion and electrostatic repulsion provided by CA gel, and the main factor driving thermal reversibility was the temperature-responsive gelation performance of CA. The retention of quercetin was >90.23 % after seven HCTs because CAGEG enhanced the homogeneity and stability of the droplets.

Protective Efficacy of a Novel DNA Vaccine with a CL264 Molecular Adjuvant against Toxoplasma gondii in a Murine Model.

Toxoplasmosis is a significant global zoonosis with devastating impacts, and an effective vaccine against toxoplasmosis for humans has not yet been developed. In this study, we designed and formulated a novel DNA vaccine encoding the inhibitor of STAT1 transcriptional activity (IST) of T. gondii utilizing the eukaryotic expression vector pEGFP-N1 for the first time, with CL264 being a molecular adjuvant. Following intramuscular injection of the vaccine into mice, the levels of antibodies and cytokines were assessed to evaluate the immune response. Additionally, mice were challenged with highly virulent RH-strain tachyzoites of T. gondii, and their survival time was observed. The results show that the levels of IgG in serum, the ratio of IgG2a/IgG1 and the levels of IFN-γ in splenocytes of mice were significantly higher in the pEGFP-TgIST group and the pEGFP-TgIST + CL264 group than in the control group. In addition, the proportion of CD4+/CD8+ T cells was higher in mice immunized with either the pEGFP-TgIST group (p < 0.001) or the pEGFP-TgIST + CL264 group (p < 0.05) compared to the three control groups. Notably, TgIST-immunized mice exhibited prolonged survival times after T. gondii RH strain infection (p < 0.05). Our findings collectively demonstrate that the TgIST DNA vaccine elicits a significant humoral and cellular immune response and offers partial protection against acute T. gondii infection in the immunized mice, which suggests that TgIST holds potential as a candidate for further development as a DNA vaccine.

Detoxification of phoxim by a gut bacterium of Delia antiqua.

The presence of certain associated bacteria has been reported to increase pest resistance to pesticides, which poses a serious threat to food security and the environment. Researches on the above microbe-derived pesticide resistance would bring innovative approaches for pest management. Investigations into the phoxim resistance of Delia antiqua, one Liliaceae crop pests, revealed the contribution of a phoxim-degrading gut bacterium, D39, to this resistance. However, how the strain degraded phoxim was unknown. In this study, the role of D39 in phoxim degradation and resistance was first confirmed. DT, which had an identical taxonomy but lacked phoxim-degrading activity, was analyzed alongside D39 via comparative genomics to identify the potential phoxim degrading genes. In addition, degradation metabolites were identified, and a potential degradation pathway was proposed. Furthermore, the main gene responsible for degradation and the metabolites of phoxim were further validated via prokaryotic expression. The results showed that D39 contributed to resistance in D. antiqua larva by degrading phoxim. Phoxim was degraded by an enzyme encoded by the novel gene phoD in D39 to O,O-diethyl hydrogen phosphorothioate and 2-hydroxyimino-2-phenylacetonitrile. Finally, downstream products were metabolized in the tricarboxylic acid cycle. Further analysis via prokaryotic expression of phoD confirmed its degradation activity. The mechanisms through which gut microbes promote pesticide resistance are elucidated in this study. These results could aid in the development of innovative pest control methods. In addition, this information could also be used to identify microbial agents that could be applied for the remediation of pesticide contamination.

Tomato Pectin Ameliorated Hepatic Steatosis in High-Fat-Diet Mice by Modulating Gut Microbiota and Bile Acid Metabolism.

Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health issue. Changes in the gut microbiota structure and composition are closely related to host pathophysiology processes. Pectin is associated with several beneficial health effects. In the present study, we aimed at investigating the effect of tomato pectin (TP) on hepatic steatosis and exploring the underlying mechanisms by focusing on the regulation of the gut microbiota-bile acid axis. Our results showed that TP attenuated high-fat diet (HFD)-induced liver steatosis and inflammation. TP administration increased the diversity of gut microbiota, enhancing the abundance of beneficial bacteria and suppressing the abundance of harmful or conditional pathogenic bacteria. Further antibiotic-caused microbiome depletion confirmed that the anti-NAFLD activities of TP were dependent on the regulation of gut microbiota. Besides, TP intervention affected feces bile acid metabolism and caused significant changes in functional conjugated bile acids, which in turn inhibited the ileum FXR/FGF15 signaling, leading to stimulation of the hepatic bile acid (BA) production. Furthermore, TP treatment accelerated BA excretion, promoted BA transportation, inhibited BA reabsorption, and facilitated cholesterol efflux to relieve HFD-induced hyperlipidemia. These findings provide a potential dietary intervention strategy for TP against NAFLD via modulation of cross-talk between BAs and gut bacteria.

Role of Ferroptosis Regulation by Nrf2/NQO1 Pathway in Alcohol-Induced Cardiotoxicity In Vitro and In Vivo.

The aim of the present study was to evaluate the cardiotoxic effects of alcohol and its potential toxic mechanism on ferroptosis in mice and H9c2 cells. Mice were intragastrically treated with three different concentrations of alcohol, 7, 14, and 28%, each day for 14 days. Body weight and electrocardiography (ECG) were recorded over the 14 day period. Serum creatine kinase (CK), lactic dehydrogenase (LDH), MDA, tissue iron, and GSH levels were measured. Cardiac tissues were examined histologically, and ferroptosis was assessed. In H9c2 cardiomyocytes, cell viability, reactive oxygen species (ROS), labile iron pool (LIP), and mitochondrial membrane potential (MMP) were measured. The proteins of ferroptosis were evaluated by the western blot technique in vivo and in vitro. The results showed that serum CK, LDH, MDA, and tissue iron levels significantly increased in the alcohol treatment group in a dose-dependent manner. The content of GSH decreased after alcohol treatment. ECG and histological examinations showed that alcohol impaired cardiac function and structure. In addition, the levels of ROS and LIP increased, and MMP levels decreased after alcohol treatment. Ferrostatin-1 (Fer-1) protected cells from lipid peroxidation. Western blotting analysis showed that alcohol downregulated the expression of Nrf2, NQO1, HO-1, and GPX4. The expressions of P53 and TfR were upregulated in vivo and in vitro. Fer-1 significantly alleviated alcohol-induced ferroptosis. In conclusion, the study showed that Nrf2/NQO1-dependent ferroptosis played a vital role in the cardiotoxicity induced by alcohol.

Erratum: Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al.

[This corrects the article DOI: 10.1016/j.omtn.2021.11.010.].

Plasma BDNF/Irisin Ratio Associates with Cognitive Function in Older People.

Background: Reliable blood biomarkers are crucial for early detection and treatment evaluation of cognitive impairment, including Alzheimer's disease and other dementias. Objective: To examine whether plasma biomarkers and their combination are different between older people with mild cognitive impairment (MCI) and cognitively normal individuals, and to explore their relations with cognitive performance. Methods: This cross-sectional study included 250 older adults, including 124 participants with MCI, and 126 cognitively normal participants. Plasma brain-derived neurotrophic factor (BDNF), irisin and clusterin were measured, and BDNF/irisin ratio was calculated. Global cognition was evaluated by the Montreal Cognitive Assessment. Results: Plasma irisin levels, but not BDNF, were significantly different between MCI group and cognitively normal group. Higher irisin concentration was associated with an increased probability for MCI both before and after controlling covariates. By contrast, plasma BDNF concentration, but not irisin, was linearly correlated with cognitive performance after adjusting for covariates. Higher BDNF/irisin ratios were not only correlated with better cognitive performance, but also associated with lower risks of MCI, no matter whether we adjusted for covariates. Plasma BDNF and irisin concentrations increased with aging, whereas BDNF/irisin ratios remained stable. No significant results of clusterin were observed. Conclusions: Plasma BDNF/irisin ratio may be a reliable indicator which not only reflects the odds of the presence of MCI but also directly associates with cognitive performance.