PubMed

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

Nat Prod Bioprospect. 2023 Oct 23;13(1):44. doi: 10.1007/s13659-023-00406-y.ABSTRACTSince ancient times, the inhabitants of dry areas have depended on the date palm (Phoenix dactylifera L.) as a staple food and means of economic security. For example, dates have been a staple diet for the inhabitants of the Arabian Peninsula and Sahara Desert in North Africa for millennia and the local culture is rich in knowledge and experience with the benefits of dates, suggesting that dates contain many substances essential for the human body. Madinah dates are considered one of the most important types of dates in the Arabian Peninsula, with Ajwa being one of the most famous types and grown only in Madinah, Saudi Arabia. Date seeds are traditionally used for animal feed, seed oil production, cosmetics, and as a coffee substitute. Phytochemical compounds that have been detected in date fruits and date seeds include phenolic acids, carotenoids, and flavonoids. Phenolic acids are the most prevalent bioactive constituents that contribute to the antioxidant activity of date fruits. The bioactive properties of these phytochemicals are believed to promote human health by reducing the risk of diseases such as chronic inflammation. Ajwa dates especially are thought to have superior bioactivity properties. To investigate these claims, in this study, we compare the metabolic profiles of Ajwa with different types of dates collected from Saudi Arabia and Tunisia. We show by UHPLC-MS that date seeds contain several classes of flavonoids, phenolic acids, and amino acid derivatives, including citric acid, malic acid, lactic acid, and hydroxyadipic acid. Additionally, GC-MS profiling showed that date seeds are richer in metabolite classes, such as hydrocinnamic acids (caffeic, ferulic and sinapic acids), than flesh samples. Deglet N fruit extract (minimum inhibitory concentration: 27 MIC/μM) and Sukkari fruit extract (IC50: 479 ± 0.58μg /mL) have higher levels of antibacterial and antioxidative activity than Ajwa fruits. However, the seed analysis showed that seed extracts have better bioactivity effects than fruit extracts. Specifically, Ajwa extract showed the best MIC and strongest ABTS radical-scavenging activity among examined seed extracts (minimum inhibitory concentration: 20 μM; IC50: 54 ± 3.61μg /mL). Our assays are a starting point for more advanced in vitro antibacterial models and investigation into the specific molecules that are responsible for the antioxidative and anti-bacterial activities of dates.PMID:37870666 | DOI:10.1007/s13659-023-00406-y

Arch Toxicol. 2023 Oct 23. doi: 10.1007/s00204-023-03620-2. Online ahead of print.ABSTRACTChanges in pharmacokinetics and endogenous metabolites may underlie additive biological effects of concomitant use of antipsychotics and opioids. In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine + methadone (QTP + MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC-MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225-296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP + MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered.PMID:37870577 | DOI:10.1007/s00204-023-03620-2

Nucleic Acids Res. 2023 Oct 23:gkad880. doi: 10.1093/nar/gkad880. Online ahead of print.ABSTRACTDiverse individuals age at different rates and display variable susceptibilities to tissue aging, functional decline and aging-related diseases. Centenarians, exemplifying extreme longevity, serve as models for healthy aging. The field of human aging and longevity research is rapidly advancing, garnering significant attention and accumulating substantial data in recent years. Omics technologies, encompassing phenomics, genomics, transcriptomics, proteomics, metabolomics and microbiomics, have provided multidimensional insights and revolutionized cohort-based investigations into human aging and longevity. Accumulated data, covering diverse cells, tissues and cohorts across the lifespan necessitates the establishment of an open and integrated database. Addressing this, we established the Human Aging and Longevity Landscape (HALL), a comprehensive multi-omics repository encompassing a diverse spectrum of human cohorts, spanning from young adults to centenarians. The core objective of HALL is to foster healthy aging by offering an extensive repository of information on biomarkers that gauge the trajectory of human aging. Moreover, the database facilitates the development of diagnostic tools for aging-related conditions and empowers targeted interventions to enhance longevity. HALL is publicly available at https://ngdc.cncb.ac.cn/hall/index.PMID:37870433 | DOI:10.1093/nar/gkad880

J Vis Exp. 2023 Oct 6;(200). doi: 10.3791/66012.ABSTRACTBrown adipose tissue (BAT) plays a crucial role in regulating metabolic homeostasis through a unique energy expenditure process known as non-shivering thermogenesis. To achieve this, BAT utilizes a diverse menu of circulating nutrients to support its high metabolic demand. Additionally, BAT secretes metabolite-derived bioactive factors that can serve as either metabolic fuels or signaling molecules, facilitating BAT-mediated intratissue and/or intertissue communication. This suggests that BAT actively participates in systemic metabolite exchange, an interesting feature that is beginning to be explored. Here, we introduce a protocol for in vivo mouse-level optimized BAT arteriovenous metabolomics. The protocol focuses on relevant methods for thermogenic stimulations and an arteriovenous blood sampling technique using Sulzer's vein, which selectively drains interscapular BAT-derived venous blood and systemic arterial blood. Next, a gas chromatography-based metabolomics protocol using those blood samples is demonstrated. The use of this technique should expand the understanding of BAT-regulated metabolite exchange at the inter-organ level by measuring the net uptake and release of metabolites by BAT.PMID:37870308 | DOI:10.3791/66012

J Agric Food Chem. 2023 Oct 23. doi: 10.1021/acs.jafc.3c05117. Online ahead of print.ABSTRACTSafflower (Carthamus tinctorius L.) is a multipurpose economic crop that is distributed worldwide. Flavonoid glycosides are the main bioactive components in safflower, but only a few UDP-glycosyltransferases (UGT) have been identified. Three differentially expressed UGT genes related with the accumulation of 9 flavonoid O-glycosides were screened from metabolomics and transcriptome analysis. Safflower corolla protoplasts were used to confirm the glycosylation ability of UGT candidates in vivo for the first time. The astragalin content was significantly increased only when CtUGT3 was overexpressed. CtUGT3 also showed flavonoid 3-OH and 7-OH glycosylation activities in vitro. Molecular modeling and site-directed mutagenesis revealed that G15, T136, S276, and E384 were critical catalytic residues for the glycosylation ability of CtUGT3. These results demonstrate that CtUGT3 has a flavonoid 3-OH glycosylation function and is involved in the biosynthesis of astragalin in safflower. This study provides a reference for flavonoid biosynthesis genes research in nonmodel plants.PMID:37870279 | DOI:10.1021/acs.jafc.3c05117

Ann Surg. 2023 Oct 23. doi: 10.1097/SLA.0000000000006137. Online ahead of print.ABSTRACTOBJECTIVE: To investigate if ischemia alters donor kidney metabolism and whether these changes associate with organ function.SUMMARY BACKGROUND DATA: An unmet need in kidney transplantation is the ability to predict post-transplant organ function before transplantation. Key to such viability testing is a profound understanding of the organ's complex biochemistry and how ischemia, inevitable during the transplantation process, influences this.METHODS: First, metabolic changes in glucose, lactate and 20 amino acids induced by no, 1h of warm, or 22h of cold ischemia were investigated during 4h perfusion of pig kidneys with autologous whole blood (n=6/group), simulating the ischemia-reperfusion phase of transplantation. Next, we confirmed similar metabolic changes during normothermic preservation of pig (n=3/group; n=4 for cold ischemia) and discarded human kidneys (n=6) perfused with a red-blood cell based perfusate.RESULTS: At 2h of perfusion with autologous whole blood, abundances of 17/20 amino acids were significantly different between groups, reflecting the type of ischemia. Amino acid changes at 15 min and 2h of perfusion correlated with future kidney function during perfusion. Similar metabolic patterns were observed during perfusion preservation of pig and discarded human donor kidneys, suggesting an opportunity to assess kidney viability before transplantation.CONCLUSIONS: Perfusate metabolite changes during normothermic kidney perfusion represent a unique non-invasive opportunity to assess graft viability. These findings now need validation in transplant studies.PMID:37870241 | DOI:10.1097/SLA.0000000000006137

Vet Q. 2023 Oct 23:1-17. doi: 10.1080/01652176.2023.2273891. Online ahead of print.ABSTRACTHigh-protein diets may aid weight loss and weight maintenance programs in both humans and dogs, although the effect of dietary protein levels on gut metabolism and functionality has not been studied in depth. The current study aimed to investigate the effect of an altered dietary protein:carbohydrate ratio on gut function in adult dogs by means of faecal metabolomic fingerprinting. More specifically, functional metabolic differences in dogs fed a high-protein/low-carbohydrate (HPLC) vs. low-protein/high-carbohydrate (LPHC) diet were studied by equally allocating twelve clinically healthy (6 lean and 6 obese) Beagles into two groups in a cross-over design, with each group receiving two isocaloric diets for four weeks. The faecal metabolome revealed that different protein:carbohydrate ratio can influence host and/or gut microbiome metabolism and function, while no effect was observed on the body condition. Targeted analysis demonstrated that the HPLC diet significantly increased the concentration of indole, spermidine and pipecolinic acid and decreased the concentration of azelaic acid, D-fructose, mannose, and galactose (P < 0.05). Multivariate modelling (OPLS-DA) of the untargeted faecal metabolome revealed distinctly different metabolomic profiles following the HPLC vs. LPHC diet, with 18 altered pathways. The HPLC diet influenced amino acid and lipid metabolism, potentially promoting weight loss and immune function, whereas the LPHC diet affected carbohydrate fermentation and may promote anti-oxidative function.PMID:37869782 | DOI:10.1080/01652176.2023.2273891

Front Physiol. 2023 Oct 6;14:1273342. doi: 10.3389/fphys.2023.1273342. eCollection 2023.ABSTRACTThis study aims to explore the molecular regulatory mechanisms of acute exercise in the skeletal muscle of mice. Male C57BL/6 mice were randomly assigned to the control group, and the exercise group, which were sacrificed immediately after an acute bout of exercise. The study was conducted to investigate the metabolic and transcriptional profiling in the quadriceps muscles of mice. The results demonstrated the identification of 34 differentially expressed metabolites (DEMs), with 28 upregulated and 6 downregulated, between the two groups. Metabolic pathway analysis revealed that these DEMs were primarily enriched in several, including the citrate cycle, propanoate metabolism, and lysine degradation pathways. In addition, the results showed a total of 245 differentially expressed genes (DEGs), with 155 genes upregulated and 90 genes downregulated. KEGG analysis indicated that these DEGs were mainly enriched in various pathways such as ubiquitin mediated proteolysis and FoxO signaling pathway. Furthermore, the analysis revealed significant enrichment of DEMs and DEGs in signaling pathways such as protein digestion and absorption, ferroptosis signaling pathway. In summary, the identified multiple metabolic pathways and signaling pathways were involved in the exercise-induced physiological regulation of skeletal muscle, such as the TCA cycle, oxidative phosphorylation, protein digestion and absorption, the FoxO signaling pathway, ubiquitin mediated proteolysis, ferroptosis signaling pathway, and the upregulation of KLF-15, FoxO1, MAFbx, and MuRF1 expression could play a critical role in enhancing skeletal muscle proteolysis.PMID:37869715 | PMC:PMC10587468 | DOI:10.3389/fphys.2023.1273342

Exp Ther Med. 2023 Sep 28;26(5):533. doi: 10.3892/etm.2023.12232. eCollection 2023 Nov.ABSTRACTExposure to hypoxia disrupts energy metabolism and induces inflammation. However, the pathways and mechanisms underlying energy metabolism disorders caused by hypoxic conditions remain unclear. In the present study, a hypoxic animal model was created and transcriptomic and non-targeted metabolomics techniques were applied to further investigate the pathways and mechanisms of hypoxia exposure that disrupt energy metabolism. Transcriptome results showed that 3,007 genes were significantly differentially expressed under hypoxic exposure, and Gene Ontology annotation analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes (DEGs) were mainly involved in energy metabolism and were significantly enriched in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) pathway. The DEGs IDH3A, SUCLA2, and MDH2 in the TCA cycle and the DEGs NDUFA3, NDUFS7, UQCRC1, CYC1 and UQCRFS1 in the OXPHOS pathway were validated using mRNA and protein expression, and the results showed downregulation. The results of non-targeted metabolomics showed that 365 significant differential metabolites were identified under plateau hypoxia stress. KEGG enrichment analysis showed that the differential metabolites were mainly enriched in metabolic processes, such as energy, nucleotide and amino acid metabolism. Hypoxia exposure disrupted the TCA cycle and reduced the synthesis of amino acids and nucleotides by decreasing the concentration of cis-aconitate, α-ketoglutarate, NADH, NADPH and that of most amino acids, purines, and pyrimidines. Bioinformatics analysis was used to identify inflammatory genes related to hypoxia exposure and some of them were selected for verification. It was shown that the mRNA and protein expression levels of IL1B, IL12B, S100A8 and S100A9 in kidney tissues were upregulated under hypoxic exposure. The results suggest that hypoxia exposure inhibits the TCA cycle and the OXPHOS signalling pathway by inhibiting IDH3A, SUCLA2, MDH2, NDUFFA3, NDUFS7, UQCRC1, CYC1 and UQCRFS1, thereby suppressing energy metabolism, inducing amino acid and nucleotide deficiency and promoting inflammation, ultimately leading to kidney damage.PMID:37869643 | PMC:PMC10587886 | DOI:10.3892/etm.2023.12232

RSC Adv. 2023 Oct 19;13(44):30665-30679. doi: 10.1039/d3ra04037b. eCollection 2023 Oct 18.ABSTRACTMetabolomics and molecular networking approaches have expanded rapidly in the field of biological sciences and involve the systematic identification, visualization, and high-throughput characterization of bioactive metabolites in natural products using sophisticated mass spectrometry-based techniques. The popularity of natural products in pharmaceutical therapies has been influenced by medicinal plants with a long history of ethnobotany and a vast collection of bioactive compounds. Here, we selected four medicinal plants Cleistocalyx operculatus, Terminalia chebula, Ficus lacor, and Ficus semicordata, the biochemical characteristics of which remain unclear owing to the inherent complexity of their plant metabolites. In this study, we aimed to evaluate the potential of these aforementioned plant extracts in inhibiting the enzymatic activity of α-amylase and α-glucosidase, respectively, followed by the annotation of secondary metabolites. The methanol extract of Ficus semicordata exhibited the highest α-amylase inhibition with an IC50 of 46.8 ± 1.8 μg mL-1, whereas the water fraction of Terminalia chebula fruits demonstrated the most significant α-glucosidase inhibition with an IC50 value of 1.07 ± 0.01 μg mL-1. The metabolic profiling of plant extracts was analyzed through Liquid Chromatography-Mass Spectrometry (LC-HRMS) of the active fractions, resulting in the annotation of 32 secondary metabolites. Furthermore, we applied the Global Natural Product Social Molecular Networking (GNPS) platform to evaluate the MS/MS data of Terminalia chebula (bark), revealing that there were 205 and 160 individual ion species observed as nodes in the methanol and ethyl acetate fractions, respectively. Twenty-two metabolites were tentatively identified from the network map, of which 11 compounds were unidentified during manual annotation.PMID:37869390 | PMC:PMC10585453 | DOI:10.1039/d3ra04037b