PubMed

Sci Total Environ. 2023 Feb 6:162042. doi: 10.1016/j.scitotenv.2023.162042. Online ahead of print.ABSTRACTWater quality and phytoplankton community composition are important factors that can indicate freshwater ecosystem health. We combined water quality, phytoplankton community, and metabolomic data from algae and water sampled from two embayments in Lake Ontario, Hamilton Harbour and the Bay of Quinte, over ten weeks from August to October in the year 2020. Metabolomics was performed using liquid chromatography tandem mass spectroscopy (LC-MS/MS) to identify changes in intracellular metabolites within algae communities over time, and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) was used to characterize putative isomers of extracellular metabolites at sub-ppb mass accuracy. Results from this study indicate that Hamilton Harbour and the Bay of Quinte are two very different ecosystems with respect to water quality, phytoplankton metabolites, and phytoplankton community composition. Community composition is strongly driven by conductivity and nitrates in Hamilton Harbour, while the opposite is true in the Bay of Quinte. Metabolites including α-aminobutyric acid and glycine were found in larger abundance within algal communities at both locations, while taurine was more predominant in algal communities from the Bay of Quinte. These metabolic profiles could reflect the different communities of phytoplankton, and be alternative indicators of algal bloom growth.PMID:36754333 | DOI:10.1016/j.scitotenv.2023.162042

Biomed Chromatogr. 2023 Feb 8:e5598. doi: 10.1002/bmc.5598. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to investigate the effect of Pikang oral liquid (PK) on psoriasis and analyze its possible mechanism from the perspective of metabolism.METHODS: A psoriasis-form mouse model established using imiquimod (IMQ) was used to evaluate the anti-psoriatic effects of PK. The serum samples were analyzed by high-resolution nuclear magnetic resonance (1 H NMR) based metabonomics. Nine amino acids were furthere quantitatively analyzed by ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS).RESULTS: This study suggested that PK treatment markedly attenuated IMQ-induced psoriasis in a dose-dependent manner. 1 HNMR based multivariate trajectory analysis revealed that PK had a certain regression effect on eight differential metabolites. The quantitative results showed that PK could regulate significantly the serum levels of alanine, histidine and arginine to the healthy control levels.CONCLUSIONS: The mechanism of PK on anti-psoriasis may be associated with the restoration of the disturbance in the amino acid metabolism, energy metabolism, and lipid metabolism and so on. Quantitative results further confirmed that amino acid metabolism play an key role in the pathogenesis of psoriasis. Our investigation provided a holistic view of PK for intervention psoriasis and provided the scientific information in vivo about a clinical value of PK for psoriasis.PMID:36754046 | DOI:10.1002/bmc.5598

Cell Metab. 2023 Feb 7;35(2):299-315.e8. doi: 10.1016/j.cmet.2023.01.009.ABSTRACTFOXP3+ regulatory T cells (Tregs) are central for peripheral tolerance, and their deregulation is associated with autoimmunity. Dysfunctional autoimmune Tregs display pro-inflammatory features and altered mitochondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter immune function and to promote autoimmunity. By investigating longitudinal transcriptional changes of human Tregs, we identified that HS induces metabolic reprogramming, recapitulating features of autoimmune Tregs. Mechanistically, extracellular HS raises intracellular Na+, perturbing mitochondrial respiration by interfering with the electron transport chain (ETC). Metabolic disturbance by a temporary HS encounter or complex III blockade rapidly induces a pro-inflammatory signature and FOXP3 downregulation, leading to long-term dysfunction in vitro and in vivo. The HS-induced effect could be reversed by inhibition of mitochondrial Na+/Ca2+ exchanger (NCLX). Our results indicate that salt could contribute to metabolic reprogramming and that short-term HS encounter perturb metabolic fitness and long-term function of human Tregs with important implications for autoimmunity.PMID:36754020 | DOI:10.1016/j.cmet.2023.01.009

Cell Metab. 2023 Feb 7;35(2):233-235. doi: 10.1016/j.cmet.2023.01.007.ABSTRACTIn Nature Medicine, Surendran and colleagues recently reported the analysis of human plasma metabolomic data for 913 metabolites in ∼20,000 individuals, identifying 2,599 metabolite-genetic variant associations and >400 metabolite signatures comprised of jointly regulated metabolites. This extensive atlas of variant-metabolite relationships reveals novel genomic mechanisms driving metabolic phenotypes.PMID:36754017 | DOI:10.1016/j.cmet.2023.01.007

Food Chem. 2022 Dec 22;412:135048. doi: 10.1016/j.foodchem.2022.135048. Online ahead of print.ABSTRACTIn this study, the anti-obesity mechanism of Ganpu tea (GPT) from the perspectives of microbiome, metabolome and transcriptome was investigated. GPT significantly reduced the high-fat-diet (HFD)-induced levels of inflammatory cytokines and the expansion of lipid droplets and white adipose tissue. GPT also improved HFD-induced gut microbiome imbalance by significantly reducing the proportion of Firmicutes to Bacteroidota. Metabolomic data showed that HFD-induced metabolic disorder was regulated by GPT and probably characterised by being related to 4-aminobutyraldehyde and 5-acetylamino-6-amino-3-methyluracil. Transcriptome showed that the improvement of obesity was mainly related to the IL-17 signaling pathway and the metabolism of xenobiotics by cytochrome P450. Spearman's correlation analysis indicated that gut microbiota were significantly correlated with inflammatory factors, genes and metabolites. Metabolome-transcriptome analysis showed that GPT reversed obesity mainly through the carbohydrate metabolism, amino acid metabolism and lipid metabolism.Collectively, GPT may be used as a health drink to prevent or treat obesity.PMID:36753939 | DOI:10.1016/j.foodchem.2022.135048

J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Feb 2;1217:123626. doi: 10.1016/j.jchromb.2023.123626. Online ahead of print.ABSTRACTPien-Tze-Huang (PTH) is a well-known traditional Chinese patent medicine with excellent liver-protection effect. However, the mechanism of hepatoprotective action has not yet been entirely elucidated. The aim of this study was to investigate the mechanism of protective effect of PTH on alcohol-induced liver injury in rats using cytokine analysis and untargeted metabolomics approaches. An alcoholic liver disease (ALD) model with SD rats was established, and PTH was administered according to the prescribed dose. The hepatoprotective effect of PTH was evaluated by pathological observation of liver tissue and changes in biochemical index activity and cytokines in serum. Serum samples were analyzed by ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS), and differentially expressed metabolites were screened by multivariate statistical analysis. KEGG combined with metabolic pathway analysis were used to evaluate the underlying metabolic pathways. Results showed liver histopathology injury was attenuated. The levels of IL-6, TNF-α and NF-κB were significantly decreased in rats intervened with PTH groups, suggesting that it may alleviate inflammation via suppressing the inflammatory cytokines signaling pathway. Eighty differentially expressed metabolites were found and identified. Pathway analysis indicated that the hepatoprotective effects of PTH occurred through the regulation of inflammatory cytokines signaling pathway, primary bile acid biosynthesis, vitamin B6 metabolism pathway, cholesterol metabolism, and tyrosine metabolism. PTH showed favorable hepatoprotective effect through multiple pathways. This study has great importance in fully revealing the mechanism of hepatoprotective action and can help improve the clinical application of PTH.PMID:36753840 | DOI:10.1016/j.jchromb.2023.123626

Food Chem. 2023 Feb 2;413:135598. doi: 10.1016/j.foodchem.2023.135598. Online ahead of print.ABSTRACTFlavonoids are major nutrients in sea buckthorn berries. However, the effects of drying methods on flavonoids in sea buckthorn berries are unclear. In this study, ultra-performance liquid chromatography and metabolomics were adopted to analyse the effects of hot air drying (HAD) and infrared drying (IRD) on flavonoid compounds and antioxidant capacity in sea buckthorn berries. In total, 97 metabolites belonging to 12 classes were identified, including 26 flavones, 23 flavonols, and 11 flavanones. Additionally, 32 differential metabolites were identified among groups. Isorhamnetin and quercetin contents increased in response to HAD and IRD, while (-)-epigallocatechin and (-)-gallocatechin contents decreased. Differential metabolism of flavonoid compounds occurred mainly via the flavonoid biosynthesis and secondary metabolite biosynthesis pathways. Flavonoid compound degradation might be associated with antioxidant activity during drying. This study elucidated the effect of drying on nutritional components of sea buckthorn berries and may guide the improvement of quality during food processing.PMID:36753785 | DOI:10.1016/j.foodchem.2023.135598

Clin Nutr. 2023 Jan 14;42(3):384-393. doi: 10.1016/j.clnu.2023.01.011. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Metabolomic profiling is a systematic approach to identifying biomarkers for dietary patterns. Yet, metabolomic markers for dietary patterns in pregnant individuals have not been investigated. The aim of this study was to identify plasma metabolomic markers and metabolite panels that are associated with the Mediterranean diet in pregnant individuals.METHODS: This is a prospective study of 186 pregnant individuals who had both dietary intake and metabolomic profiles measured from the Fetal Growth Studies-Singletons cohort. Dietary intakes during the peri-conception/1st trimester and the second trimester were accessed at 8-13 and 16-22 weeks of gestation, respectively. Adherence to the Mediterranean diet was measured by the alternate Mediterranean Diet (aMED) score. Fasting plasma samples were collected at 16-22 weeks and untargeted metabolomics profiling was performed using the mass spectrometry-based platforms. Metabolites individually or jointly associated with aMED scores were identified using linear regression and least absolute shrinkage and selection operator (LASSO) regression models with adjustment for potential confounders, respectively.RESULTS: Among 459 annotated metabolites, 64 and 41 were individually associated with the aMED scores of the diet during the peri-conception/1st trimester and during the second trimester, respectively. Fourteen metabolites were associated with the Mediterranean diet in both time windows. Most Mediterranean diet-related metabolites were lipids (e.g., acylcarnitine, cholesteryl esters (CEs), linoleic acid, long-chain triglycerides (TGs), and phosphatidylcholines (PCs), amino acids, and sugar alcohols. LASSO regressions also identified a 10 metabolite-panel that were jointly associated with aMED score of the diet during the peri-conception/1st trimester (AUC: 0.74; 95% CI: 0.57, 0.91) and a 3 metabolites-panel in the 2nd trimester (AUC: 0.68; 95% CI: 0.50, 0.86).CONCLUSION: We identified plasma metabolomic markers for the Mediterranean diet among pregnant individuals. Some of them have also been reported in previous studies among non-pregnant populations, whereas others are novel. The results from our study warrant replication in pregnant individuals by future studies.CLINICAL TRIAL REGISTRATION NUMBER: This study was registered at ClinicalTrials.gov.PMID:36753781 | DOI:10.1016/j.clnu.2023.01.011

J Agric Food Chem. 2023 Feb 8. doi: 10.1021/acs.jafc.2c07844. Online ahead of print.ABSTRACTLentil seed coats are rich in antioxidant polyphenols that are important for plant defense and have potential as valorized byproducts. Although biochemical differences among lentil seed coat colors have been previously studied, differences among seed coat patterns remain largely unexplored. This study used mass spectrometry-based untargeted metabolomics to investigate polyphenol differences among lentil seed coat patterns to search for biochemical pathways potentially responsible for seed coat pattern differences. Comparing patterned with non-patterned green lentil seed coats, 28 significantly upregulated metabolites were found in patterned seed coats; 19 of them were identified as flavones. Flavones were virtually absent in non-patterned seed coats, thereby strongly suggesting a blockage in their flavone biosynthetic pathway. Although the black pattern is not readily discernible on black seed coats, many of the same flavones found in green marbled seed coats were also found in black seed coats, indicating that black seed coats likely have a marbled pattern.PMID:36753710 | DOI:10.1021/acs.jafc.2c07844

Sci Transl Med. 2023 Feb 8;15(682):eade3782. doi: 10.1126/scitranslmed.ade3782. Epub 2023 Feb 8.ABSTRACTPreservation quality of donor hearts is a key determinant of transplant success. Preservation duration beyond 4 hours is associated with primary graft dysfunction (PGD). Given transport time constraints, geographical limitations exist for donor-recipient matching, leading to donor heart underutilization. Here, we showed that metabolic reprogramming through up-regulation of the enzyme immune response gene 1 (IRG1) and its product itaconate improved heart function after prolonged preservation. Irg1 transcript induction was achieved by adding the histone deacetylase (HDAC) inhibitor valproic acid (VPA) to a histidine-tryptophan-ketoglutarate solution used for donor heart preservation. VPA increased acetylated H3K27 occupancy at the IRG1 enhancer and IRG1 transcript expression in human donor hearts. IRG1 converts aconitate to itaconate, which has both anti-inflammatory and antioxidant properties. Accordingly, our studies showed that Irg1 transcript up-regulation by VPA treatment increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in mice, which was accompanied by increased antioxidant protein expression [hemeoxygenase 1 (HO1) and superoxide dismutase 1 (SOD1)]. Deletion of Irg1 in mice (Irg1-/-) negated the antioxidant and cardioprotective effects of VPA. Consistent with itaconate's ability to inhibit succinate dehydrogenase, VPA treatment of human hearts increased itaconate availability and reduced succinate accumulation during preservation. VPA similarly increased IRG1 expression in pig donor hearts and improved its function in an ex vivo cardiac perfusion system both at the clinical 4-hour preservation threshold and at 10 hours. These results suggest that augmentation of cardioprotective immune-metabolomic pathways may be a promising therapeutic strategy for improving donor heart function in transplantation.PMID:36753565 | DOI:10.1126/scitranslmed.ade3782

Funct Integr Genomics. 2023 Feb 8;23(1):57. doi: 10.1007/s10142-023-00982-9.ABSTRACTThe agricultural sector and environmental safety both work hand in hand to promote sustainability in important issues like soil health, plant nutrition, food safety, and security. The conventional methods have greatly harmed the environment and people's health and caused soil fertility and quality to decline as well as deteriorate. Keeping in view the excessive exploitation and cascade of degradation events due to unsustainable farming practices, the need of the hour demands choosing an appropriate, eco-friendly strategy to restore soil health, plant nutrition, and environmental aspects. The priority highlights a need for a sustainable and environment-friendly upgradation of the present agricultural systems to utilize the beneficial aspects related to harnessing the gene-microbiome strategies which would help in the restoration and replenishment of the microbial pool. Thus, exploring the microbiome is the utmost priority which gives a deep insight into the different aspects related to soil and plant and stands out as an important contributor to plant health and productivity. "Microbes" are important drivers for the biogeochemical cycles and targets like sustainability and safety. This essential microbial bulk (soil microbiome) is greatly influenced by agricultural/farming practices. Therefore, with the help of microbiome engineering technologies like meta-transcriptomics, meta-proteomics, metabolomics, and novel gene-altering techniques, we can easily screen out the highly diverse and balanced microbial population in the bulk of soil, enhancing the soil's health and productivity. Importantly, we need to change our cultivation strategies to attain such sustainability. There is an urgent need to revert to natural/organic systems of cultivation patterns where the microbiome hub can be properly utilized to strengthen soil health, decrease insect pest and disease incidence, reduce greenhouse gas emissions, and ultimately prevent environmental degradation. Through this article, we wish to propose a shift in the cultivation pattern from chemical to the novel, upgraded gene-assisted designed eco-friendly methodologies which can help in incorporating, exploring, and harnessing the right microbiome consortium and can further help in the progression of environmentally friendly microbiome technologies for agricultural safety and productivity.PMID:36752963 | DOI:10.1007/s10142-023-00982-9

Mol Omics. 2023 Feb 8. doi: 10.1039/d2mo00320a. Online ahead of print.ABSTRACTType 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by increased blood glucose levels. Patients with T2DM have a high risk of developing atherosclerotic coronary artery disease (CAD). CAD with T2DM has a complex etiology and the understanding of the pathophysiology of coronary artery disease (CAD) in the presence of diabetes is poor. Here, we have used LC-MS/MS-based untargeted metabolomics to unveil the alterations of metabolites in the serum of South-Indian patients diagnosed with T2DM, CAD and T2DM along with CAD (T2DM-CAD) compared with the healthy subjects (CT). Using untargeted metabolomics and network-based approaches, a set of metabolites highly co-expressed with T2DM-CAD pathogenesis were identified. Our results revealed that these metabolites belong to essential pathways such as amino acid metabolism, fatty acid metabolism and carbohydrate metabolism. The candidate metabolites identified by metabolomics study are branch chain amino acids, L-arginine, linoleic acid, L-serine, L-cysteine, fructose-6-phosphate, glycerol, creatine and 3-phosphoglyceric acid, and explain the pathogenesis of T2DM-assisted CAD. The identified metabolites could be used as potential prognostic markers to predict CAD in patients diagnosed with T2DM.PMID:36752683 | DOI:10.1039/d2mo00320a

Rheumatology (Oxford). 2023 Feb 8:kead068. doi: 10.1093/rheumatology/kead068. Online ahead of print.ABSTRACTOBJECTIVE: We describe a family with a novel mutation in the TNF Receptor Superfamily Member 1A gene (TNFRSF1A) causing tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with renal AA-amyloidosis.METHODS: Case series of affected family members. We further investigated the plasma metabolome of these patients in comparison to healthy controls using mass spectrometry.RESULTS: In all symptomatic family members, we detected the previously undescribed variant c.332A>G (p.Q111R) in the TNFRSF1A gene. Canakinumab proved an effective treatment option leading to remission in all treated patients. One patient with suspected renal amyloidosis showed near normalisation of proteinuria under treatment. Analysis of the metabolome revealed 31 metabolic compounds to be upregulated and 35 compounds to be downregulated compared with healthy controls. The most dysregulated metabolites belonged to pathways identified as arginine biosynthesis, phenylalanine, tyrosine & tryptophan biosynthesis and cysteine & methionine metabolism. Interestingly, the metabolic changes observed in all three TRAPS patients seemed independent of treatment with canakinumab and subsequent remission.CONCLUSION: We present a novel mutation in the TNFRSF1A gene associated with amyloidosis. Canakinumab is an effective treatment for individuals with this new likely pathogenic variant. Alterations in the metabolome were most prominent in the pathways related to arginine biosynthesis, tryptophan metabolism and metabolism of cysteine & methionine and seemed to be unaffected by treatment with canakinumab. Further investigation is needed to determine the role of these metabolomic changes in the pathophysiology of TRAPS.PMID:36752501 | DOI:10.1093/rheumatology/kead068

Plant Biotechnol J. 2023 Feb 8. doi: 10.1111/pbi.14024. Online ahead of print.ABSTRACTFlavonoids have a major contribution to the fruit quality in cultivated strawberries and are regulated by MYB, bHLH, and WD40 transcriptional factors. We reported here the identification of the FaMYB5, an R2R3-MYB transcription factor, which positively regulated the accumulation of anthocyanins and proanthocyanidins through the trans-activation of the F3'H and LAR. The strawberry FaEGL3 and FaLWD1/FaLWD1-like interact with the R2R3-FaMYB5 to form an MYB-bHLH-WD40 complex (MBW), enhancing the regulatory efficiency. The R2R3-FaMYB5 was constitutively expressed in various tissues and in fruits of different developmental stages, which was strikingly contrasting to the fruit-specific expression patterns of FaMYB10. Meanwhile, R2R3-FaMYB5 failed to promote a stable accumulation of anthocyanin glycosides in the mature fruits of the myb10 mutant, mainly due to the suppressed expression of TT19. The R2R3-FaMYB5 was regulated by an antisense long non-coding RNA lncRNA-myb5. Additionally, the R2R3-FaMYB5 protein could interact with FaBT2 and was degraded through the ubiquitin/26S proteasome pathway. Transcriptome and metabolome data showed that R2R3-FaMYB5 enhanced the gene expression and the metabolites accumulation involved in the flavonoid, phenylpropanoid, and lignin biosynthesis pathways. Collectively, we conclude that the FaMYB5 is an R2R3-MYB activator involved in the composition of MBW, which positively regulates the biosynthesis of anthocyanin and proanthocyanidin. These findings provided new insights into the molecular mechanisms that regulate flavonoids in strawberry fruits.PMID:36752420 | DOI:10.1111/pbi.14024

Am J Med Genet A. 2023 Feb 7. doi: 10.1002/ajmg.a.63131. Online ahead of print.ABSTRACTTMEM70 deficiency causing mitochondrial complex V deficiency, nuclear type 2 (MIM: 614052) is the most common nuclear encoded defect affecting ATP synthase and has been well described in the literature as being characterized by neonatal or infantile onset of poor feeding, hypotonia, lethargy, respiratory compromise, heart failure, lactic acidosis, hyperammonemia, and 3-methylglutaconic aciduria progressing to a phenotype of developmental delay, failure to thrive, short stature, nonprogressive cardiomyopathy, microcephaly, facial dysmorphisms, hypospadias, persistent pulmonary hypertension of the newborn, and Wolff-Parkinson-White syndrome, as well as metabolic crises followed by developmental regression. The patient with TMEM70 deficiency herein reported has the unique presentation of aortic root dilatation, differing facial dysmorphisms, and no history of neonatal metabolic decompensation or developmental delay, as well as a plasma metabolomics signature, including elevated 3-methylglutaconic acid, 3-methylglutarylcarnitine, alanine, and lactate, in addition to the commonly described increased 3-methylglutaconic acid on urine organic acid analysis that helped aid in the diagnostic interpretation of variants of uncertain significance in TMEM70.PMID:36751706 | DOI:10.1002/ajmg.a.63131

J Zhejiang Univ Sci B. 2023 Feb 15;24(2):157-171. doi: 10.1631/jzus.B2200213.ABSTRACTThe development of acute liver injury can result in liver cirrhosis, liver failure, and even liver cancer, yet there is currently no effective therapy for it. The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lyciumbarbarum polysaccharides (LBPs) on acute liver injury induced by carbon tetrachloride (CCl4). To create a model of acute liver injury, experimental canines received an intraperitoneal injection of 1 mL/kg of CCl4 solution. The experimental canines in the therapy group were then fed LBPs (20 mg/kg). CCl4-induced liver structural damage, excessive fibrosis, and reduced mitochondrial density were all improved by LBPs, according to microstructure data. By suppressing Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1), promoting the production of sequestosome 1 (SQSTM1)/p62, nuclear factor erythroid 2-related factor 2 (Nrf2), and phase II detoxification genes and proteins downstream of Nrf2, and restoring the activity of anti-oxidant enzymes like catalase (CAT), LBPs can restore and increase the antioxidant capacity of liver. To lessen mitochondrial damage, LBPs can also enhance mitochondrial respiration, raise tissue adenosine triphosphate (ATP) levels, and reactivate the respiratory chain complexes I‒V. According to serum metabolomics, the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism. 9-Hydroxyoctadecadienoic acid (9-HODE), lysophosphatidylcholine (LysoPC/LPC), and phosphatidylethanolamine (PE) may be potential indicators of acute liver injury. This study confirmed that LBPs, an effective hepatoprotective drug, may cure acute liver injury by lowering oxidative stress, repairing mitochondrial damage, and regulating metabolic pathways.PMID:36751701 | DOI:10.1631/jzus.B2200213

Clin Kidney J. 2022 Sep 21;16(2):272-284. doi: 10.1093/ckj/sfac215. eCollection 2023 Feb.ABSTRACTBACKGROUND: Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the kidneys. Beyond serving as a crucial endogenous regulator of the renin-angiotensin system, ACE2 also possess a unique function to facilitate amino acid absorption. Our observational study sought to explore the relationship between urine ACE2 (uACE2) and renal outcomes in coronavirus disease 2019 (COVID-19).METHODS: In a cohort of 104 patients with COVID-19 without acute kidney injury (AKI), 43 patients with COVID-19-mediated AKI and 36 non-COVID-19 controls, we measured uACE2, urine tumour necrosis factor receptors I and II (uTNF-RI and uTNF-RII) and neutrophil gelatinase-associated lipocalin (uNGAL). We also assessed ACE2 staining in autopsy kidney samples and generated a propensity score-matched subgroup of patients to perform a targeted urine metabolomic study to describe the characteristic signature of COVID-19.RESULTS: uACE2 is increased in patients with COVID-19 and further increased in those that developed AKI. After adjusting uACE2 levels for age, sex and previous comorbidities, increased uACE2 was independently associated with a >3-fold higher risk of developing AKI [odds ratio 3.05 (95% confidence interval 1.23‒7.58), P = .017]. Increased uACE2 corresponded to a tubular loss of ACE2 in kidney sections and strongly correlated with uTNF-RI and uTNF-RII. Urine quantitative metabolome analysis revealed an increased excretion of essential amino acids in patients with COVID-19, including leucine, isoleucine, tryptophan and phenylalanine. Additionally, a strong correlation was observed between urine amino acids and uACE2.CONCLUSIONS: Elevated uACE2 is related to AKI in patients with COVID-19. The loss of tubular ACE2 during SARS-CoV-2 infection demonstrates a potential link between aminoaciduria and proximal tubular injury.PMID:36751625 | PMC:PMC9494506 | DOI:10.1093/ckj/sfac215

J Exp Clin Cancer Res. 2023 Feb 7;42(1):42. doi: 10.1186/s13046-023-02607-2.ABSTRACTBACKGROUND: Clear cell renal cell carcinoma (ccRCC), with its hallmark phenotype of high cytosolic lipid content, is considered a metabolic cancer. Despite the implication of this lipid-rich phenotype in ccRCC tumorigenesis, the roles and regulators of de novo lipid synthesis (DNL) in ccRCC remain largely unexplained.METHODS: Our bioinformatic screening focused on ccRCC-lipid phenotypes identified glutathione peroxidase 8 (GPX8), as a clinically relevant upstream regulator of DNL. GPX8 genetic silencing was performed with CRISPR-Cas9 or shRNA in ccRCC cell lines to dissect its roles. Untargeted metabolomics, RNA-seq analyses, and other biochemical assays (e.g., lipid droplets staining, fatty acid uptake, cell proliferation, xenograft, etc.) were carried out to investigate the GPX8's involvement in lipid metabolism and tumorigenesis in ccRCC. The lipid metabolic function of GPX8 and its downstream were also measured by isotope-tracing-based DNL flux measurement.RESULTS: GPX8 knockout or downregulation substantially reduced lipid droplet levels (independent of lipid uptake), fatty acid de novo synthesis, triglyceride esterification in vitro, and tumor growth in vivo. The downstream regulator was identified as nicotinamide N-methyltransferase (NNMT): its knockdown phenocopied, and its expression rescued, GPX8 silencing both in vitro and in vivo. Mechanically, GPX8 regulated NNMT via IL6-STAT3 signaling, and blocking this axis suppressed ccRCC survival by activating AMPK. Notably, neither the GPX8-NNMT axis nor the DNL flux was affected by the von Hippel Lindau (VHL) status, the conventional regulator of ccRCC high lipid content.CONCLUSIONS: Taken together, our findings unravel the roles of the VHL-independent GPX8-NNMT axis in ccRCC lipid metabolism as related to the phenotypes and growth of ccRCC, which may be targeted for therapeutic purposes.PMID:36750850 | DOI:10.1186/s13046-023-02607-2

Metabolomics. 2023 Feb 7;19(2):12. doi: 10.1007/s11306-023-01975-2.ABSTRACTINTRODUCTION: Our untargeted metabolic data unveiled that Acyl-CoAs undergo dephosphorylation, however little is known about these novel metabolites and their physiology/pathology relevance.OBJECTIVES: To understand the relationship between acyl-CoAs dephosphorylation and energy status as implied in our previous work, we seek to investigate how ischemia (energy depletion) triggers metabolic changes, specifically acyl-CoAs dephosphorylation in this work.METHODS: Rat hearts were isolated and perfused in Langendorff mode for 15 min followed by 0, 5, 15, and 30 minutes of global ischemia. The heart tissues were harvested for metabolic analysis.RESULTS: As expected, ATP and phosphocreatine were significantly decreased during ischemia. Most short- and medium-chain acyl-CoAs progressively increased with ischemic time from 0 to 15 min, whereas a 30-minute ischemia did not lead to further change. Unlike other acyl-CoAs, propionyl-CoA accumulated progressively in the hearts that underwent ischemia from 0 to 30 min. Progressive dephosphorylation occurred to all assayed acyl-CoAs and free CoA regardless their level changes during the ischemia.CONCLUSION: The present work further confirms that dephosphorylation of acyl-CoAs is an energy-dependent process and how this dephosphorylation is mediated warrants further investigations. It is plausible that dephosphorylation of acyl-CoAs and limited anaplerosis are involved in ischemic injuries to heart. Further investigations are warranted to examine the mechanisms of acyl-CoA dephosphorylation and how the dephosphorylation is possibly involved in ischemic injuries.PMID:36750484 | DOI:10.1007/s11306-023-01975-2

Wei Sheng Yan Jiu. 2023 Jan;52(1):123-128. doi: 10.19813/j.cnki.weishengyanjiu.2023.01.021.ABSTRACTOBJECTIVE: To explore the differential metabolites in the serum of infants with iron deficiency anemia(IDA) and non iron deficiency anemia, and to explore the potential biomarkers.METHODS: Non-targeted metabolomics of 30 infants with iron deficiency anemia aged 6-11 months and 30 infants with non iron deficiency anemia aged 6-11 months were analyzed by ultra-high performance liquid chromatography with time of flight mass spectrometry using Acquity UPLC BEH C_(18) column(100 mm×2.1 mm, 1.8 μm). The differences of metabolites between the two groups were analyzed by principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA). Differential metabolites were screened according to OPLS-DA variable importance projection(VIP) >1. The related metabolic pathways involved in the markers were analyzed based on the KEGG database.RESULTS: Differences in serum metabolic profiles between iron deficiency anemia group and non iron deficiency anemia group were observed. The 44 potential biomarkers were mainly lipids. Combined with pathway analysis, the metabolic pathways related to different metabolites included glycerophosphingolipid metabolism and sphingolipid metabolism.CONCLUSION: There are differences in lipid metabolites between infants with non iron deficiency anemia and iron deficiency anemia, suggesting that the occurrence and progress of iron deficiency anemia are related to lipid metabolism.PMID:36750340 | DOI:10.19813/j.cnki.weishengyanjiu.2023.01.021