PubMed

J Endocr Soc. 2023 Aug 24;7(9):bvad110. doi: 10.1210/jendso/bvad110. eCollection 2023 Aug 2.ABSTRACT[This corrects the article DOI: 10.1210/jendso/bvad091.].PMID:37873502 | PMC:PMC10590642 | DOI:10.1210/jendso/bvad110

bioRxiv. 2023 Oct 2:2023.10.02.560557. doi: 10.1101/2023.10.02.560557. Preprint.ABSTRACTHow the microaerobic pathogen Campylobacter jejuni establishes its niche and expands in the gut lumen during infection is poorly understood. Using six-week-old ferrets as a natural disease model, we examined this aspect of C. jejuni pathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized with C. jejuni , ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease after C. jejuni infection in ferrets reflects closely how human C. jejuni infection proceeds. Rapid growth of C. jejuni and associated intestinal inflammation was observed within two-three days of infection. We observed pathophysiological changes that were noted by cryptic hyperplasia through the induction of tissue repair systems, accumulation of undifferentiated amplifying cells on the colon surface, and instability of HIF-1α in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. A C. jejuni mutant lacking lctP , which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion by C. jejuni to a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter ( lctP ) led to discovery of a putative thiol based redox switch regulator (LctR) that may repress lctP transcription under anaerobic conditions. Our work provides new insights into the pathogenicity of C. jejuni .SIGNIFICANCE: There is a gap in knowledge about the mechanisms by which C. jejuni populations expand during infection. Using an animal model which accurately reflects human infection without the need to alter the host microbiome or the immune system prior to infection, we explored pathophysiological alterations of the gut after C. jejuni infection. Our study identified the gut metabolite L-lactate as playing an important role as a growth substrate for C. jejuni during acute infection. We identified a DNA binding protein, LctR, that binds to the lctP promoter and may repress lctP expression, resulting in decreased lactate transport under low oxygen levels. This work provides new insights about C. jejuni pathogenicity.PMID:37873437 | PMC:PMC10592923 | DOI:10.1101/2023.10.02.560557

medRxiv. 2023 Oct 2:2023.09.30.23296261. doi: 10.1101/2023.09.30.23296261. Preprint.ABSTRACTHeart failure with preserved ejection fraction (HFpEF) accounts for >50% of all heart failure world-wide and remains a major unmet medical need. The most effective recently approved treatments were first developed for diabetes, suggesting metabolic defects are paramount. Myocardial metabolomics in human HFpEF has identified reduced fatty acid and branched chain amino acid catabolism, but the status of glycolysis is unknown. Here we performed targeted metabolomics and protein analysis of glycolytic pathway enzymes in myocardial biopsies of patients with HFpEF versus HF with reduced ejection fraction (HFrEF0 or non-failing controls. Glucose was increased in HFpEF myocardium, but immediate downstream glycolytic metabolites (glucose-6 phosphate, fructose 1,6 diphosphate), were more reduced in HFpEF than the other groups, as were their associated synthetic enzymes hexokinase and phosphofructokinase. Pyruvate was also reduced in HFpEF versus controls. These changes were either not present or substantially less so in HFrEF. Suppression of proximal glycolysis was also coupled to lower metabolites and proteins in the pentose phosphate pathway but was independent of diabetes or obesity. These findings support marked metabolic inflexibility in HFpEF and identifies very proximal blockade in glucose metabolism. Efforts to improve metabolic use of carbohydrates in HFpEF will likely need to target these proximal glycolytic enzymes.PMID:37873321 | PMC:PMC10593049 | DOI:10.1101/2023.09.30.23296261

medRxiv. 2023 Oct 2:2023.09.30.23296386. doi: 10.1101/2023.09.30.23296386. Preprint.ABSTRACTA growing body of literature has attempted to characterize how traffic-related air pollution (TRAP) affects molecular and subclinical biological processes in ways that could lead to cardiorespiratory disease. To provide a streamlined synthesis of what is known about the multiple mechanisms through which TRAP could lead cardiorespiratory pathology, we conducted a systematic review of the epidemiological literature relating TRAP exposure to methylomic, proteomic, and metabolomic biomarkers in adult populations. Using the 139 papers that met our inclusion criteria, we identified the omic biomarkers significantly associated with short-or long-term TRAP and used these biomarkers to conduct pathway and network analyses. We considered the evidence for TRAP-related associations with biological pathways involving lipid metabolism, cellular energy production, amino acid metabolism, inflammation and immunity, coagulation, endothelial function, and oxidative stress. Our analysis suggests that an integrated multi-omics approach may provide critical new insights into the ways TRAP could lead to adverse clinical outcomes. We advocate for efforts to build a more unified approach for characterizing the dynamic and complex biological processes linking TRAP exposure and subclinical and clinical disease, and highlight contemporary challenges and opportunities associated with such efforts.PMID:37873294 | PMC:PMC10592990 | DOI:10.1101/2023.09.30.23296386

bioRxiv. 2023 Oct 9:2023.10.06.561131. doi: 10.1101/2023.10.06.561131. Preprint.ABSTRACTCancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses Kras G12D/+ ;Lkb1 -/- (KL) but not Kras G12D/+ ;p53 -/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.PMID:37873106 | PMC:PMC10592603 | DOI:10.1101/2023.10.06.561131

ArXiv. 2023 Oct 12:arXiv:2310.07990v1. Preprint.ABSTRACTBACKGROUND: Missing data is a common challenge in mass spectrometry-based metabolomics, which can lead to biased and incomplete analyses. The integration of whole-genome sequencing (WGS) data with metabolomics data has emerged as a promising approach to enhance the accuracy of data imputation in metabolomics studies.METHOD: In this study, we propose a novel method that leverages the information from WGS data and reference metabolites to impute unknown metabolites. Our approach utilizes a multi-view variational autoencoder to jointly model the burden score, polygenetic risk score (PGS), and linkage disequilibrium (LD) pruned single nucleotide polymorphisms (SNPs) for feature extraction and missing metabolomics data imputation. By learning the latent representations of both omics data, our method can effectively impute missing metabolomics values based on genomic information.RESULTS: We evaluate the performance of our method on empirical metabolomics datasets with missing values and demonstrate its superiority compared to conventional imputation techniques. Using 35 template metabolites derived burden scores, PGS and LD-pruned SNPs, the proposed methods achieved r2-scores > 0.01 for 71.55% of metabolites.CONCLUSION: The integration of WGS data in metabolomics imputation not only improves data completeness but also enhances downstream analyses, paving the way for more comprehensive and accurate investigations of metabolic pathways and disease associations. Our findings offer valuable insights into the potential benefits of utilizing WGS data for metabolomics data imputation and underscore the importance of leveraging multi-modal data integration in precision medicine research.PMID:37873011 | PMC:PMC10593076

J Food Sci. 2023 Oct 23. doi: 10.1111/1750-3841.16784. Online ahead of print.ABSTRACTFoliar spraying to improve the quality of fruits is a general approach nowadays. In this study, 10 ppm nano-selenium (nano-Se) diluted with distilled water was sprayed on peach leaves every 10 days for a total of 7 sprays during the fruit set period. And then their fruit quality was compared with that of control group. It was found that the firmness, soluble solid concentration, total phenol, and proanthocyanidin content of the peaches were raised after the nano-Se treatment. Moreover, the ascorbic acid glutathione loop (ASA-GSH loop) was fully activated in the nano-Se treated group, and the associated antioxidant capacity and enzyme activity were significantly increased. Metabolomics revealed that nano-Se could upregulate some metabolites, such as phenylalanine, naringenin, and pinocembrin, to fully activate the metabolism of phenylpropanoids. Further, based on transcriptomics, nano-Se treatment was found to affect fruit quality by regulating genes related to phenylpropanoid metabolism, such as arogenate/prephenate dehydratase (ADT), genes related to abscisic acid metabolism such as (+)-abscisic acid 8'-hydroxylase (CYP707A), and some transcription factors such as MYB. Based on the comprehensive analysis of physicochemical indicators, metabolomics, and transcriptomics, it was found that nano-Se improved fruit quality by activating phenylpropanoid metabolism and enhancing antioxidant capacity. This work provides insights into the mechanism of the effect of nano-Se fertilizer on peach fruit quality. PRACTICAL APPLICATION: The firmness and soluble solid concentration of peaches are higher after nano-Se treatment, which is more in line with people's demand for hard soluble peaches like "Yingzui." The antioxidant capacity, antioxidant substance content, and antioxidant enzyme activity of nano-Se-treated peaches are higher, with potential storage resistance and health effects on human body. The mechanism of nano-Se affecting peach quality was analyzed by metabolomics and transcriptomics, which is a reference and guide for the research and application of nano-Se.PMID:37872835 | DOI:10.1111/1750-3841.16784

New Phytol. 2023 Oct 23. doi: 10.1111/nph.19332. Online ahead of print.ABSTRACTC4 plants typically operate a CO2 concentration mechanism from mesophyll (M) cells into bundle sheath (BS) cells. NADH dehydrogenase-like (NDH) complex is enriched in the BS cells of many NADP-malic enzyme (ME) type C4 plants and is more abundant in C4 than in C3 plants, but to what extent it is involved in the CO2 concentration mechanism remains to be experimentally investigated. We created maize and rice mutants deficient in NDH function and then used a combination of transcriptomic, proteomic, and metabolomic approaches for comparative analysis. Considerable decreases in growth, photosynthetic activities, and levels of key photosynthetic proteins were observed in maize but not rice mutants. However, transcript abundance for many cyclic electron transport (CET) and Calvin-Benson cycle components, as well as BS-specific C4 enzymes, was increased in maize mutants. Metabolite analysis of the maize ndh mutants revealed an increased NADPH : NADP ratio, as well as malate, ribulose 1,5-bisphosphate (RuBP), fructose 1,6-bisphosphate (FBP), and photorespiration intermediates. We suggest that by optimizing NADPH and malate levels and adjusting NADP-ME activity, NDH functions to balance metabolic and redox states in the BS cells of maize (in addition to ATP supply), coordinating photosynthetic transcript abundance and protein content, thus directly regulating the carbon flow in the two-celled C4 system of maize.PMID:37872738 | DOI:10.1111/nph.19332

BMC Genomics. 2023 Oct 23;24(1):630. doi: 10.1186/s12864-023-09725-3.ABSTRACTBackground Puccinia arachidis fungus causes rust disease in the peanut plants (Arachis hypogaea L.), which leads to high yield loss. Metabolomic profiling of Arachis hypogaea was performed to identify the pathogen-induced production of metabolites involved in the defense mechanism of peanut plants. In this study, two peanut genotypes, one susceptible (JL-24) and one resistant (GPBD-4) were inoculated with Puccinia arachidis fungal pathogen. The metabolic response was assessed at the control stage (0 day without inoculation), 2 DAI (Day after inoculation), 4 DAI and 6 DAI by Gas Chromatography-Mass Spectrometry (GC-MS). Results About 61 metabolites were identified by NIST library, comprising sugars, phenols, fatty acids, carboxylic acids and sugar alcohols. Sugars and fatty acids were predominant in leaf extracts compared to other metabolites. Concentration of different metabolites such as salicylic acid, mannitol, flavonoid, 9,12-octadecadienoic acid, linolenic acid and glucopyranoside were higher in resistant genotype than in susceptible genotype during infection. Systemic acquired resistance (SAR) and hypersensitive reaction (HR) components such as oxalic acid was elevated in resistant genotype during pathogen infection. Partial least square-discriminant analysis (PLS-DA) was applied to GC-MS data for revealing metabolites profile between resistant and susceptible genotype during infection. Conclusion The phenol content and oxidative enzyme activity i.e. catalase, peroxidase and polyphenol oxidase were found to be very high at 4 DAI in resistant genotype (p-value < 0.01). This metabolic approach provides information about bioactive plant metabolites and their application in crop protection and marker-assisted plant breeding.PMID:37872498 | DOI:10.1186/s12864-023-09725-3

Nat Metab. 2023 Oct;5(10):1656-1672. doi: 10.1038/s42255-023-00903-x. Epub 2023 Oct 23.ABSTRACTMetabolomic epidemiology is the high-throughput study of the relationship between metabolites and health-related traits. This emerging and rapidly growing field has improved our understanding of disease aetiology and contributed to advances in precision medicine. As the field continues to develop, metabolomic epidemiology could lead to the discovery of diagnostic biomarkers predictive of disease risk, aiding in earlier disease detection and better prognosis. In this Review, we discuss key advances facilitated by the field of metabolomic epidemiology for a range of conditions, including cardiometabolic diseases, cancer, Alzheimer's disease and COVID-19, with a focus on potential clinical utility. Core principles in metabolomic epidemiology, including study design, causal inference methods and multi-omic integration, are briefly discussed. Future directions required for clinical translation of metabolomic epidemiology findings are summarized, emphasizing public health implications. Further work is needed to establish which metabolites reproducibly improve clinical risk prediction in diverse populations and are causally related to disease progression.PMID:37872285 | DOI:10.1038/s42255-023-00903-x

Zhonghua Gan Zang Bing Za Zhi. 2023 Sep 20;31(9):928-935. doi: 10.3760/cma.j.cn501113-20230717-00007.ABSTRACTObjective: This study focuses on Na(+)-taurocholate cotransporting polypeptide (NTCP) deficiency to analyze and investigate the value of the serum bile acid profile for facilitating the diagnosis and differential diagnosis. Methods: Clinical data of 66 patients with cholestatic liver diseases (CLDs) diagnosed and treated in the Department of Pediatrics of the First Affiliated Hospital of Jinan University from early April 2015 to the end of December 2021 were collected, including 32 cases of NTCP deficiency (16 adults and 16 children), 16 cases of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), 8 cases of Alagille syndrome, and 10 cases of biliary atresia. At the same time, adult and pediatric healthy control groups (15 cases each) were established. The serum bile acid components of the study subjects were qualitatively and quantitatively analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry. The data were plotted and compared using statistical SPSS 19.0 and GraphPad Prism 5.0 software. The clinical and bile acid profiles of children with NTCP deficiency and corresponding healthy controls, as well as differences between NTCP deficiency and other CLDs, were compared using statistical methods such as t-tests, Wilcoxon rank sum tests, and Kruskal-Wallis H tests. Results: Compared with the healthy control, the levels of total conjugated bile acids, total primary bile acids, total secondary bile acids, glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were increased in NTCP deficiency patients (P < 0.05). Compared with adults with NTCP deficiency, the levels of total conjugated bile acids and total primary bile acids were significantly increased in children with NTCP deficiency (P < 0.05). The serum levels of taurochenodeoxycholic acid, glycolithocholate, taurohyocholate, and tauro-α-muricholic acid were significantly increased in children with NTCP deficiency, but the bile acid levels such as glycodeoxycholic acid, glycolithocholate, and lithocholic acid were decreased (P < 0.05). The serum levels of secondary bile acids such as lithocholic acid, deoxycholic acid, and hyodeoxycholic acid were significantly higher in children with NTCP deficiency than those in other CLD groups such as NICCD, Alagille syndrome, and biliary atresia (P < 0.05). Total primary bile acids/total secondary bile acids, total conjugated bile acids/total unconjugated bile acids, taurocholic acid, serum taurodeoxycholic acid, and glycodeoxycholic acid effectively distinguished children with NTCP deficiency from other non-NTCP deficiency CLDs. Conclusion: This study confirms that serum bile acid profile analysis has an important reference value for facilitating the diagnosis and differential diagnosis of NTCP deficiency. Furthermore, it deepens the scientific understanding of the changing characteristics of serum bile acid profiles in patients with CLDs such as NTCP deficiency, provides a metabolomic basis for in-depth understanding of its pathogenesis, and provides clues and ideas for subsequent in-depth research.PMID:37872088 | DOI:10.3760/cma.j.cn501113-20230717-00007

Zhonghua Gan Zang Bing Za Zhi. 2023 Sep 20;31(9):901-904. doi: 10.3760/cma.j.cn501113-20230802-00029.ABSTRACTWith China's outstanding achievements in the prevention and treatment of hepatitis, hereditary cholestasis caused by genetic variants has gradually become an important cause of death or transplantation in children with liver disease. The continuous identification of new pathogenic genes expands the disease spectrum and clinician's understanding of disease. The disease characteristics and clinical manifestations of hereditary cholestasis caused by different gene variants vary, and the severity of diseases caused by the same gene variants and the response to treatment are also significantly different. Therefore, early genetic diagnosis is of great value for improving the clinical management of patients. In terms of treatment, in addition to traditional drugs and surgery, targeted therapy and gene therapy are also gradually moving towards clinical application. Advances in metabolomics, gene editing technology, and structural biology have made it possible to provide personalized and precise treatment of children with hereditary cholestasis in the future; however, this which will put forward higher requirements for on relevant practitioners.PMID:37872084 | DOI:10.3760/cma.j.cn501113-20230802-00029

Clin J Am Soc Nephrol. 2023 Oct 23. doi: 10.2215/CJN.0000000000000318. Online ahead of print.ABSTRACTBACKGROUND: Children with chronic kidney disease (CKD) are at risk for impaired neurocognitive functioning. We investigated metabolomic associations with neurocognition in children with CKD.METHODS: We leveraged data from the Chronic Kidney Disease in Children (CKiD) study and the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) study. CKiD is a multi-institutional cohort that enrolled children age 6 months to 16 years with estimated glomerular filtration rate (eGFR) 30-90ml/min/1.73m2 (n=569). NiCK is a single center cross-sectional study of participants aged 8-25 years with eGFR<90ml/min/1.73m2 (n=60) and matched healthy controls (n=67). Untargeted metabolomics quantification was performed on plasma (CKiD, 622 metabolites) and serum (NiCK, 825 metabolites) samples. Four neurocognitive domains were assessed (intelligence, attention regulation, working memory, and parent ratings of executive function). Repeat assessments were performed in CKiD at 2-year intervals. Linear regression and linear mixed-effects regression analyses adjusting for age, sex, delivery history, hypertension, proteinuria, CKD duration, and glomerular vs. non-glomerular diagnosis were used to identify metabolites associated with neurocognitive z-scores. Analyses were performed with and without adjustment for eGFR.RESULTS: There were multiple metabolite associations with neurocognition observed in at least two of the analytic samples (CKiD baseline, CKiD follow-up, NiCK CKD). Most of these metabolites were significantly elevated in children with CKD compared to healthy controls in NiCK. Notable signals included associations with parental ratings of executive function: phenylacetylglutamine, indoleacetylglutamine, and trimethylamine N-oxide, - and with intelligence: gamma-glutamyl amino acids and aconitate.CONCLUSIONS: Several metabolites were associated with neurocognitive dysfunction in pediatric CKD, implicating gut microbiome-derived substances, mitochondrial dysfunction and altered energy metabolism, circulating toxins, and redox homeostasis.PMID:37871960 | DOI:10.2215/CJN.0000000000000318

Helicobacter. 2023 Oct 23:e13030. doi: 10.1111/hel.13030. Online ahead of print.ABSTRACTThe microbiota actively and extensively participates in the regulation of human metabolism, playing a crucial role in the development of metabolic diseases. Helicobacter pylori (H. pylori), when colonizing gastric epithelial cells, not only induces local tissue inflammation or malignant transformation but also leads to systemic and partial changes in host metabolism. These shifts can be mediated through direct contact, toxic components, or indirect immune responses. Consequently, they influence various molecular metabolic events that impact nutritional status and iron absorption in the host. Unraveling the intricate and diverse molecular interaction links between H. pylori and human metabolism modulation is essential for understanding pathogenesis mechanisms and developing targeted treatments for related diseases. However, significant challenges persist in comprehensively understanding the complex association networks among H. pylori itself, the infected host's status, the host microbiome, and the immune response. Previous metabolomics research has indicated that H. pylori infection and eradication may selectively shape the metabolite and microbial profiles of gastric lesions. Yet, it remains largely unknown how these diverse metabolic pathways, including isovaleric acid, cholesterol, fatty acids, and phospholipids, specifically modulate gastric carcinogenesis or affect the host's serum metabolism, consequently leading to the development of metabolic-associated diseases. The direct contribution of H. pylori to metabolisms still lacks conclusive evidence. In this review, we summarize recent advances in clinical evidence highlighting associations between chronic H. pylori infection and metabolic diseases, as well as its potential molecular regulatory patterns.PMID:37871913 | DOI:10.1111/hel.13030

Exp Eye Res. 2023 Oct 21:109689. doi: 10.1016/j.exer.2023.109689. Online ahead of print.ABSTRACTThis study aimed to identify the corneal metabolic biomarkers for moderate and high myopia in human. We enrolled 221 eyes from 221 subjects with myopia to perform the femtosecond laser small incision lenticule extraction (SMILE) surgery. Among these, 71 eyes of 71 subjects were enrolled in the low myopic group, 75 eyes of 75 subjects in the moderate myopic group and 75 eyes of 75 subjects in the high myopic group. The untargeted metabolomics analysis was performed to analyze the corneal tissues extracted during the SMILE surgery using an ultra-high-performance liquid chromatography (UHPLC) coupled to a quadrupole time-of-flight (Q-TOF) mass spectrometry (MS). The one-way analysis of variance (ANOVA) was used to identify the different metabolites among the three myopic groups, the orthogonal partial least-squares discriminant analysis (OPLS-DA) model was used to reveal the different metabolites between moderate myopia and low myopia, and between high myopia and low myopia. The Venn gram was used to find the overlapped metabolites of the three datasets of the different metabolites. The stepwise multiple linear regression analysis was used to determine the metabolic molecules associated with manifest refractive spherical equivalents (MRSE). The Receiver Operating Characteristics (ROC) analysis was performed to reveal the corneal biomarkers for moderate and high myopia. The hub biomarker was further selected by the networks among different metabolites created by the Cytoscape software. A total of 1594 metabolites were identified in myopic corneas. 321 metabolites were different among the three myopic groups, 106 metabolites were different between high myopic corneas and low myopic corneas, 104 metabolites were different between moderate myopic corneas and low myopic corneas, and 30 metabolic molecules overlapped among the three datasets. The multivariate linear regression analysis revealed the myopic degree was significantly influenced by the corneal levels of azelaic acid, arginine-proline (Arg-Pro), 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, and hypoxanthine. The ROC curve analysis showed that azelaic acid, Arg-Pro and hypoxanthine were effective in discriminating low myopia from moderate to high myopia with the area under the curve (AUC) values as 0.982, 0.991 and 0.982 for azelaic acid, Arg-Pro and hypoxanthine respectively. The network analysis suggested that Arg-Pro had the maximum connections among these three biomarkers. Thus, this study identified azelaic acid, Arg-Pro and hypoxanthine as corneal biomarkers to discriminate low myopia from moderate to high myopia, with Arg-Pro serving as the hub biomarker for moderate and high myopia.PMID:37871883 | DOI:10.1016/j.exer.2023.109689

Exp Eye Res. 2023 Oct 21:109688. doi: 10.1016/j.exer.2023.109688. Online ahead of print.ABSTRACTHeimler syndrome (HS) is a rare autosomal recessive hereditary disease that is caused by biallelic variants in peroxisomal biogenic factor 1 gene (PEX1), peroxisomal biogenic factor 6 gene (PEX6) or peroxisomal biogenic factor 26 gene (PEX26), resulting in intracellular peroxisomal dysfunction (PBDs). We report a patient with HS with a new compound heterozygous PEX1 variant. Exon sequencing was used to screen pathologic variants in the patient. Retinal characteristics and serum metabolome alterations were evaluated. Scanning laser ophthalmoscope showed a large area of retinal choroidal atrophy at the posterior pole of the retina, with scattered patchy subretinal pigmentation. Optical coherence tomography showed fovea atrophy accompanied by retinal retinoschisis in the right eye and macular retinoschisis and edema in the left eye. The electroretinogram showed obviously reduced amplitudes of a- and b-waves under photopic and scotopic conditions in both eyes. Visual field tests showed a reduced central visual field in both eyes. Exon sequencing identified the compound heterozygous variant including c.2966T > C and c.1670+1G > T of the PEX1 gene, with the latter being novel. Nontargeted determination of total lipid metabolites and targeted determination of medium- and long-chain fatty acids in the serum of the patient and his healthy sibling were tested. This study identified a new compound heterozygous PEX1 variant, expanding our understanding of phenotypes in HS.PMID:37871882 | DOI:10.1016/j.exer.2023.109688

J Insect Physiol. 2023 Oct 21:104581. doi: 10.1016/j.jinsphys.2023.104581. Online ahead of print.ABSTRACTCold tolerance of ectotherms can vary strikingly among species and populations. Variation in cold tolerance can reflect differences in genomes and transcriptomes that confer cellular-level protection from cold; additionally, shifts in protein function and abundance can be altered by other cellular constituents as cold-exposed insects often have shifts in their metabolomes. Even without a cold challenge, insects from different populations may vary in cellular composition that could alter cold tolerance, but investigations of constitutive differences in metabolomes across wild populations remain rare. To address this gap, we reared Bombus vosnesenskii queens collected from Oregon and California (USA) that differ in cold tolerance (CTmin = -6 °C and 0 °C, respectively) in common garden conditions, and measured offspring metabolomes using untargeted LC-MS/MS. Oregon bees had higher levels of metabolites associated with carbohydrate (sorbitol, lactitol, maltitol, and sorbitol-6-phosphate) and amino acid (hydroxyproline, ornithine, and histamine) metabolism. Exogenous metabolites, likely derived from the diet, also varied between Oregon and California bees, suggesting population-level differences in toxin metabolism. Overall, our results reveal constitutive differences in metabolomes for bumble bees reared in common garden conditions from queens collected in different locations despite no previous cold exposure.PMID:37871769 | DOI:10.1016/j.jinsphys.2023.104581

Am J Vet Res. 2023 Oct 27:1-13. doi: 10.2460/ajvr.23.08.0186. Online ahead of print.ABSTRACTOBJECTIVE: To identify metabolites and metabolic pathways affected in dogs with aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES) compared to healthy control (CON) dogs of similar ages and breeds. To improve our understanding of ACHES pathophysiology and identify novel candidate biomarkers associated with ACHES.ANIMALS: A prospective case-control study. Privately owned dogs with ACHES (n = 19) and healthy (CON) dogs (n = 9) were recruited between February 18, 2015, and April 18, 2018.METHODS: A prospective case-control study. Plasma and urine were collected from ACHES and CON dogs. The Cornell University Proteomics and Metabolomics Core Facility conducted an untargeted metabolomic analysis.RESULTS: After controlling for age, sex, and weight, 111 plasma and 207 urine metabolites significantly differed between ACHES and CON dogs. Data reduction and cluster analysis revealed robust segregation between ACHES and CON dogs. Enrichment analysis of significant compounds in plasma or urine identified altered metabolic pathways, including those related to AA metabolism, cellular energetics, and lipid metabolism. Biomarker analysis identified metabolites that best-distinguished ACHES from CON dogs, including pyruvic acid isomer and glycerol-3-phosphate in the plasma and an alanine isomer and choline in the urine.CLINICAL RELEVANCE: Our findings provide an in-depth analysis of metabolic perturbations associated with ACHES. Several affected metabolic pathways (eg, lipid metabolism) offer a new understanding of ACHES pathophysiology. Novel candidate biomarkers warrant further evaluation to determine their potential to aid in ACHES diagnosis, prognosis, and treatment monitoring.PMID:37871610 | DOI:10.2460/ajvr.23.08.0186

Environ Int. 2023 Oct 5;181:108247. doi: 10.1016/j.envint.2023.108247. Online ahead of print.ABSTRACTBACKGROUND: Climate change has led to the frequent occurrence of high-temperature weather, which has various adverse effects on health, ranging from blood metabolism to systemic organ function. In particular, the sequelae of heat stress injury in most people are related to the nervous system. However, the mechanisms between heat stress and mental health conditions, especially heat stress and anxiety, remain unclear.OBJECTIVE: We attempted to elucidate the effect of heat exposure intervention on anxiety levels in the population and its mechanism.METHODS: We first carried out a randomized controlled trial in 20 college students in Beijing, China, to observe the results of the effects of heat exposure intervention on human anxiety. Then, we collected blood samples before and after heat exposure experiment and used metabolomic and transcriptomic approaches to quantify serum metabolites and ELISA measurements to explore the underlying mechanisms.RESULTS: We found that even 1.5-hour heat exposure intervention significantly increased anxiety levels. Heat stress-induced anxiety was mediated by the activation of the HPA axis, inflammation, oxidative stress, and subsequently unbalanced neurotransmitters. Metabolites such as BDNF, GABA, and glucocorticoids released by the adrenal glands are biomarkers of heat stress-induced anxiety.CONCLUSIONS: We have demonstrated a causal link between heat stress and anxiety, explored possible biological pathway between heat stress and anxiety. Heat stress can cause the activation of the HPA axis and lead to changes in the body's metabolism, resulting in a series of changes such as inflammation and oxidative stress, leading to anxiety. This study reveals hidden health cost of climate change that has been underexplored, and also reminds us the importance of immediate climate actions.PMID:37871510 | DOI:10.1016/j.envint.2023.108247

Poult Sci. 2023 Sep 30;102(12):103155. doi: 10.1016/j.psj.2023.103155. Online ahead of print.ABSTRACTFatty liver hemorrhagic syndrome is a widespread metabolic disease in laying hens that decreases egg production and even causes death in severe cases. Many traditional Chinese medicine ingredients, such as saikosaponin a (SSa), have been shown to alleviate fatty liver, but the underlying mechanisms remain unclear. In this study, we aimed to explore the alleviation of dietary SSa on excessive hepatic lipid deposition and the interactions between intestinal microbiota and bile acid (BA) in laying hens. Fifty-four 35-wk-old laying hens were randomly allocated into 3 treatment groups with 6 replicates (3 birds per replicate) and fed with a basal diet (CON), high-energy and low-protein diet (HELP), and HELP diet with 30 mg/kg SSa (HELP + SSa). SSa reversed diet-induced egg production rate decrease (P < 0.05). SSa could potently ameliorate HELP-induced accumulation of hepatic cholesterol and liver injury via the increase (P < 0.05) of mRNA expression of BA synthesis gene, such as cholesterol 7 alpha-hydroxylase 1. SSa treatment alleviated gut dysbiosis, especially reducing (P < 0.05) the relative abundance of bile salt hydrolase (BSH)-producing bacteria such as Lactobacillus, Bifidobacterium, and Turicibacter. Ileal BA metabolomic analysis revealed that SSa increased (P < 0.05) the content of tauro-conjugated BAs, mainly taurochenodeoxycholic acid and tauro-α-muricholic acid. The mRNA expression of farnesoid X receptor (FXR) and fibroblast growth factor 19 were decreased (P < 0.05) in intestine, which was associated with increased gene expression of enzymes in the BA synthesis that reduced the levels of cholesterol. Moreover, SSa treatment inhibited intestinal BA reabsorption via decreasing (P < 0.05) the mRNA expression of apical sodium-dependent bile acid transporter. Our findings indicated that SSa reduced liver cholesterol accumulation and alleviated fatty liver in laying hens through microbiota-BA-intestinal FXR crosstalk.PMID:37871490 | DOI:10.1016/j.psj.2023.103155