PubMed

J Neuroinflammation. 2022 Dec 26;19(1):313. doi: 10.1186/s12974-022-02675-9.ABSTRACTBACKGROUND: Little is known about the association between gut microbiota and intestinal injury under a state of chronic cerebral hypoperfusion (CCH). Here, the effects of gut microbiota and short-chain fatty acids (SCFAs), as important metabolic products, on intestinal function and potential mechanisms after CCH were investigated.METHODS: Rats were subjected to bilateral common carotid artery occlusion (BCCAo) to induce CCH. The gut microbiota and metabolites of SCFAs were assessed by 16S rRNA sequencing and targeted metabolomics, respectively. Transcriptomic analysis of colon tissues was also conducted. Subsequently, potential molecular pathways and differentially expressed genes were verified by western blot, immunoprecipitation, and immunofluorescence analyses. Furthermore, the integrity of the colonic barrier was evaluated by hematoxylin and eosin and mucin 2 staining and expression levels of tight junction proteins. Besides, colonic inflammation was further assessed by flow cytometry and expression levels of inflammatory cytokines. In addition, colonic mitochondrial dysfunction was analyzed via membrane potential, reactive oxygen species, electron transport chain (ETC) activities, adenosine triphosphate content, and mitochondrial ultrastructure.RESULTS: CCH modified gut microbial composition and microbial metabolism of SCFAs, which may be associated with inhibition of mitochondrial ETC activities and oxidative phosphorylation, leading to dysregulation of mitochondrial energy metabolism. Furthermore, CCH induced differentiation of pathogenic Th17 cells, promoted the formation of complexes of interferon regulatory factor 4 and signal transducer and activator of transcription 3 (STAT3), and increased the phosphorylation of STAT3. This was associated with an impairment of colonic barrier function and chronic colonic inflammation. In contrast, FMT and SCFA replenishment ameliorated CCH-induced gut microbial dysbiosis by increasing the intestinal content of Ruminococcus_sp_N15_MGS_57 and modulating microbial metabolism of SCFAs by increasing acetic acid contents associated with an improvment of the balance between Tregs and Th17 cells, mitochondrial ETC activities, and oxidative phosphorylation to prevent colonic inflammation and dysregulation of mitochondrial energy metabolism.CONCLUSION: These findings indicate that FMT and SCFA replenishment present a promising therapeutic strategy against colonic dysfunction under a state of chronic cerebral ischemia.PMID:36567333 | DOI:10.1186/s12974-022-02675-9

Curr Pharm Des. 2022 Dec 22. doi: 10.2174/1381612829666221222115134. Online ahead of print.ABSTRACTBACKGROUND: The neurotransmitter metabolism in spontaneously hypertensive rats (SHR) is disordered, and these disturbances in neurotransmitter levels can further exacerbate the development of hypertension. Neurotransmitters can affect the expression of circadian clock genes.OBJECTIVE: To clarify the time-dependent internal mechanism of the imbalance of the target neurotransmitter metabolic rhythm of spontaneously hypertensive rats, the circadian research was carried out by the method of targeted metabolomics and molecular biology technology.METHODS: We have explored the mechanism of isorhynchophylline regulating the circadian rhythm through the ERK signaling pathway and thus treating hypertension by detecting the changes of central hypothalamic biological clock rhythm genes after isorhynchophylline intervention, from hypothalamic neurotransmitter rhythmicity.RESULTS: The expression of rhythm genes in normal rats showed a certain rhythm at 6 time points, while the expression of rhythm genes in model rats decreased, and the gene rhythm returned to normal after isorhynchophylline treatment. Cosine analysis of 12 neurotransmitters in hypothalamus showed that there were 6 rhythmic neurotransmitters in the normal group, while in the model group, 4 of the 6 neurotransmitters lost their rhythmicity, and the rhythmicity returned to normal after isorhynchophylline intervention. Compared with the normal group, the expression of ERK protein in the model group increased significantly and decreased after isorhynchophylline treatment.CONCLUSION: The mechanism of isorhynchophylline treating hypertension is not only the regulation of serum neurotransmitters rhythm, but also acting on rhythm genes in the feedback loop of the central biological clock.PMID:36567301 | DOI:10.2174/1381612829666221222115134

Adv Sci (Weinh). 2022 Dec 25:e2204038. doi: 10.1002/advs.202204038. Online ahead of print.ABSTRACTAbdominal aortic aneurysm (AAA) is a common vascular disease associated with significant phenotypic alterations in vascular smooth muscle cells (VSMCs). Gasdermin D (GSDMD) is a pore-forming effector of pyroptosis. In this study, the role of VSMC-specific GSDMD in the phenotypic alteration of VSMCs and AAA formation is determined. Single-cell transcriptome analyses reveal Gsdmd upregulation in aortic VSMCs in angiotensin (Ang) II-induced AAA. VSMC-specific Gsdmd deletion ameliorates Ang II-induced AAA in apolipoprotein E (ApoE)-/- mice. Using untargeted metabolomic analysis, it is found that putrescine is significantly reduced in the plasma and aortic tissues of VSMC-specific GSDMD deficient mice. High putrescine levels trigger a pro-inflammatory phenotype in VSMCs and increase susceptibility to Ang II-induced AAA formation in mice. In a population-based study, a high level of putrescine in plasma is associated with the risk of AAA (p < 2.2 × 10-16 ), consistent with the animal data. Mechanistically, GSDMD enhances endoplasmic reticulum stress-C/EBP homologous protein (CHOP) signaling, which in turn promotes the expression of ornithine decarboxylase 1 (ODC1), the enzyme responsible for increased putrescine levels. Treatment with the ODC1 inhibitor, difluoromethylornithine, reduces AAA formation in Ang II-infused ApoE-/- mice. The findings suggest that putrescine is a potential biomarker and target for AAA treatment.PMID:36567267 | DOI:10.1002/advs.202204038

J Dairy Sci. 2022 Dec 23:S0022-0302(22)00747-0. doi: 10.3168/jds.2022-22224. Online ahead of print.ABSTRACTThe transition period from late pregnancy to early lactation is a vital time of the lifecycle of dairy cows due to the marked metabolic challenges. Besides, the liver is the pivot point of metabolism in cattle. Nevertheless, the hepatic physiological molecular adaptation during the transition period has not been elucidated, especially from the metabolomics and proteomics view. Therefore, the present study aims to investigate the hepatic metabolic alterations in transition cows by using integrative metabolomics and proteomics methods. Gas chromatography quadrupole-time-of-flight mass spectrometry-based metabolomics and data-independent acquisition-based quantitative proteomics methods were used to analyze liver tissues collected from 8 healthy multiparous Holstein dairy cows 21 d before and after calving. In total, 44 metabolites and 250 proteins were identified as differentially expressed from 233 metabolites and 3,539 proteins detected from the liver biopsies during the transition period. Complementary functional analysis of different metabolites and proteins indicated the upregulated gluconeogenesis, TCA cycles, AA degradation, fatty acid oxidation, AMP-activated protein kinase signaling pathway, peroxisome proliferator-activated receptor signaling pathway, and ribosome proteins in postpartum dairy cows. In terms of the metabolites and proteins, glucose-6-phosphate, fructose-6-phosphate, carnitine palmitoyltransferase 1A, and phosphoenolpyruvate carboxykinase played a significant role in these pathways. The upregulated oxidative status may be accompanied by the pathways mentioned above. In addition, the upregulated glucagon and insulin signaling pathways also indicated the significant requirement for glucose in postpartum dairy cows. These outcomes, from the view of global metabolites and proteins, may present a better comprehension of the biology of the transition period, which can be helpful in further developing nutritional regulation strategies targeting the liver to help cows overcome this metabolically challenging time.PMID:36567250 | DOI:10.3168/jds.2022-22224

Metab Eng. 2022 Dec 22:S1096-7176(22)00156-2. doi: 10.1016/j.ymben.2022.12.007. Online ahead of print.ABSTRACTCurrently, the biological production of L-malic acid (L-MA) is mainly based on the fermentation of filamentous fungi at near-neutral pH, but this process requires large amounts of neutralizing agents, resulting in the generation of waste salts when free acid is obtained in the downstream process, and the environmental hazards associated with the waste salts limit the practical application of this process. To produce L-MA in a more environmentally friendly way, we metabolically engineered the acid-tolerant yeast Pichia kudriavzevii and achieved efficient production of L-MA through low pH fermentation. First, an initial L-MA-producing strain that relies on the reductive tricarboxylic acid (rTCA) pathway was constructed. Subsequently, the L-MA titer and yield were further increased by fine-tuning the flux between the pyruvate and oxaloacetate nodes. In addition, we found that the insufficient supply of NADH for cytoplasmic malate dehydrogenase (MDH) hindered the L-MA production at low pH, which was resolved by overexpressing the soluble pyridine nucleotide transhydrogenase SthA from E. coli. Transcriptomic and metabolomic data showed that overexpression of EcSthA contributed to the activation of the pentose phosphate pathway and provided additional reducing power for MDH by converting NADPH to NADH. Furthermore, overexpression of EcSthA was found to help reduce the accumulation of the by-product pyruvate but had no effect on the accumulation of succinate. In microaerobic batch fermentation in a 5-L fermenter, the best strain, MA009-10-URA3 produced 199.4 g/L L-MA with a yield of 0.94 g/g glucose (1.27 mol/mol), with a productivity of 1.86 g/L/h. The final pH of the fermentation broth was approximately 3.10, meaning that the amount of neutralizer used was reduced by more than 50% compared to the common fermentation processes using filamentous fungi. To our knowledge, this is the first report of the efficient bioproduction of L-MA at low pH and represents the highest yield of L-MA in yeasts reported to date.PMID:36566973 | DOI:10.1016/j.ymben.2022.12.007

Food Chem Toxicol. 2022 Dec 22:113585. doi: 10.1016/j.fct.2022.113585. Online ahead of print.ABSTRACTPolyethylene terephthalate (PET) are widely used in our daily life while they may be broken to smaller fractions as nano-sized PET (nPET) in the environment. The toxicity of nPET is still less studied. This work first evaluated the LD50 of different size of nPET (200 nm, S-nPET; 700 nm, B-nPET) in mice, then studied the health effects of single exposure to S/B-nPET at 200 mg/kg bw for 30 days. It was found that the LD50 was 266 mg/kg bw for S-nPET and 523 mg/kg bw for B-nPET, respectively, showing a size-dependent effect. S-nPET caused weight loss, cyst, intestinal obstruction, organ damage and mortality (40%), and perturbed gut microbiome and metabolome especially lipid metabolism, such as upregulated cholesterol, glycocholic, propionic acid, niacinamide, ectoine and xanthine, and downregulated arachidonic acid, anserine, histamine, while B-nPET did not. Serological analysis found S-nPET brought more lipid metabolic immune and neurological damage than B-nPET, confirming the size-dependent effect. To the best of our knowledge, this is the first report on the systematic toxicity of nPET to mice. Further studies are warranted for life-long effects of nPET. The protocol applied in this work may also be used for the study of the health effects of other plastics.PMID:36566972 | DOI:10.1016/j.fct.2022.113585

Clin Chim Acta. 2022 Dec 22:S0009-8981(22)01400-0. doi: 10.1016/j.cca.2022.11.033. Online ahead of print.ABSTRACTINTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is the most serious iatrogenic complication of ovulation stimulation during assisted reproductive technology. The main objective of this study was to investigate intrafollicular fluid metabolic change profiles of OHSS in non-ovarian etiologic infertility women (CON) and polycystic ovarian syndrome patients (PCOS).METHODS: 87 infertile women were divided into four subgroups: CON-Norm (CON with normal ovarian response), CON-OHSS (CON with OHSS), PCOS-Norm (PCOS with normal ovarian response), and PCOS-OHSS (PCOS with OHSS). The intrafollicular fluid metabolic profiles were analyzed with gas chromatography-mass spectrometry. The multivariable-adjusted conditional logistic regression was applied to assess the association of metabolites with OHSS risk.RESULTS: We identified 17 and 3 metabolites that related to OHSS risk in CON and PCOS, respectively. 13 OHSS risk-related metabolites in CON were unsaturated fatty acids, 8 of which were also the significantly altered metabolites between all PCOS and CON-Norm.CONCLUSION: Our study may shed light on the role of intrafollicular fluid metabolic abnormalities in the pathophysiology of OHSS. The findings suggested that there might be some metabolic heterogeneities underlying the development of OHSS in CON and PCOS women and indicated possible shared etiological factors in the development of PCOS and OHSS.PMID:36566958 | DOI:10.1016/j.cca.2022.11.033

Clin Chim Acta. 2022 Dec 22:S0009-8981(22)01418-8. doi: 10.1016/j.cca.2022.12.016. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is a neurodegenerative disease with significant socioeconomic burden worldwide. Although genetics and environmental factors play a role, AD is highly associated with insulin resistance (IR) disorders such as metabolic syndrome (MS), obesity, and type two diabetes mellitus (T2DM). These findings highlight a shared pathogenesis. The use of metabolomics as a downstream systems' biology (omics) approach can help to identify these shared metabolic traits and assist in the early identification of at-risk groups and potentially guide therapy. Targeting the shared AD-IR metabolic trait with lifestyle interventions and pharmacological treatments may offer promising AD therapeutic approach. In this narrative review, we reviewed the literature on the AD-IR pathogenic link, the shared genetics and metabolomics biomarkers between AD and IR disorders, as well as the lifestyle interventions and pharmacological treatments which target this pathogenic link.PMID:36566957 | DOI:10.1016/j.cca.2022.12.016

Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Dec 22:159275. doi: 10.1016/j.bbalip.2022.159275. Online ahead of print.ABSTRACTA hepatic crown-like structure (hCLS) formed by macrophages accumulating around lipid droplets and dead cells in the liver is a unique feature of nonalcoholic steatohepatitis (NASH) that triggers progression of liver fibrosis. As hCLS plays a key role in the progression of NASH fibrosis, hCLS formation has emerged as a potential therapeutic target. n-3 polyunsaturated fatty acids (n-3 PUFAs) have potential suppressive effects on NASH fibrosis; however, the mechanisms underlying this effect are poorly understood. Here, we report that n-3 PUFA-enriched Fat-1 transgenic mice are resistant to hCLS formation and liver fibrosis in a NASH model induced by a combination of high-fat diet, CCl4 and a Liver X receptor (LXR) agonist. Liquid chromatography-tandem mass spectrometry-based mediator lipidomics revealed that the amount of endogenous n-3 PUFA-derived metabolites, such as 17,18-dihydroxyeicosatetraenoic acid (17,18-diHETE), and 19,20-epoxy docosapentaenoic acid (19,20-EpDPE), was significantly elevated in Fat-1 mice, along with hCLS formation. In particular, DHA-derived 19,20-EpDPE produced by Cyp4f18 attenuated the hCLS formation and liver fibrosis in a G protein-coupled receptor 120 (GPR120)-dependent manner. These results indicated that 19,20-EpDPE is an endogenous active metabolite that mediates the preventive effect of n-3 PUFAs against NASH fibrosis.PMID:36566874 | DOI:10.1016/j.bbalip.2022.159275

Sci Total Environ. 2022 Dec 22:161086. doi: 10.1016/j.scitotenv.2022.161086. Online ahead of print.ABSTRACTThe relationship between granular size and anaerobic ammonium oxidation (anammox) performance in the anammox granular sludge (AnGS) system has been extensively observed. However, the metabolic pathways regulated by communication and cross-feedings among anammox consortia remain unclear. The reactor operation and metabolomics analyses were combined to explore the influence of microbiota cooperation on metabolic pathways and granule properties under low temperature (18 °C) and nitrite inhibition. Anammox activity was sustained under challenging circumstances by active quorum sensing among anammox consortia in AnGS with diameters larger than 1.4 mm, which promoted nucleotide metabolism. Cross-feedings among anammox consortia increased the levels of molybdopterin cofactor and folate meanwhile decreasing the cost of carbon fixation metabolism, which supported anabolism and maintained the content of heme c and extracellular polymeric substance. These metabolic insights into the AnGS system provide a new view for anammox process overcoming the low temperature and nitrite stress.PMID:36566861 | DOI:10.1016/j.scitotenv.2022.161086

Neoplasia. 2022 Dec 23;36:100868. doi: 10.1016/j.neo.2022.100868. Online ahead of print.ABSTRACTIncreasing evidence suggests a role of the gut microbiome in the development of colorectal cancer (CRC) and that it can serve as a biomarker for early diagnosis. This review aims to give an overview of the current status of published studies regarding the microbiome as a screening tool for early CRC detection. A literature search was conducted using PubMed and EMBASE in August 2022. Studies assessing the efficacy of microbiome-derived biomarkers based on noninvasive derived samples were included. Not relevant studies or studies not specifying the stage of CRC or grouping them together in the analysis were excluded. The risk of bias for screening tools was performed using the QUADAS-2 checklist. A total of 28 studies were included, ranging from 2 to 462 for CRC and 18 to 665 advanced adenoma patient inclusions, of which only two investigated the co-metabolome as biomarker. The diagnostic performance of faecal bacteria-derived biomarkers had an AUC ranging from 0.28-0.98 for precursor lesions such as advanced adenomas and 0.54-0.89 for early CRC. Diagnostic performance based on the co-metabolome showed an AUC ranging from 0.69 - 0.84 for precursor lesions and 0.65 - 0.93 for early CRC. All models improved when combined with established clinical early detection markers such as gFOBT. A high level of heterogeneity was seen in the number of inclusions and methodology used in the studies. The faecal and oral gut microbiome has the potential to complement existing CRC screening tools, however current evidence suggests that this is not yet ready for routine clinical use.PMID:36566591 | DOI:10.1016/j.neo.2022.100868

J Chromatogr A. 2022 Dec 18;1688:463727. doi: 10.1016/j.chroma.2022.463727. Online ahead of print.ABSTRACTIn this study, the chromatographic behavior of mixed-mode and hydrophilic interaction liquid chromatography (HILIC) with the mixed-mode HILIC/strong anion-exchange (SAX) column HILICpak VT-50 2D and the two HILIC columns Atlantis Premier BEH Z-HILIC and Acquity Premier BEH Amide was assessed with regard to their separation capability of the metabolites from the glycolysis and pentose phosphate pathways. Chromatographic conditions were evaluated with the aim of achieving separation of the isomeric glycolytic phosphorylated carbohydrate metabolites free from isomeric interferences and thus allowing for selective targeted analysis by liquid chromatography with tandem mass spectrometry (MS/MS) using multiple reaction monitoring acquisition. The effects of pH values (8.0/9.0/10.0) of the ammonium bicarbonate buffer and gradient time were investigated during HILIC-MS/MS analysis, with the optimal conditions found at pH = 10.0. Separation of the pentose phosphate isomers (ribose 5- and 1-phosphate, xylulose 5-phosphate and ribulose 5-phosphate) was achieved on the mixed-mode HILIC/SAX (HILICpak VT-50 2D) column and HILIC BEH Amide column. Column performance was evaluated based on the direct comparison of chromatographic parameters, i.e. peak width at 50% and peak tailing factors of the individual metabolites. Parity plots were generated allowing a direct comparison between the normalized retention times and assessment of orthogonality of all 3 stationary phases evaluated. Separation of 7 biologically relevant hexose monophosphates metabolites turned out to be challenging by HILIC-MS/MS, with the BEH Amide providing the best individual results for such a separation. However, fructose 6-phosphate and glucose 1-phosphate co-eluted. Therefore, an on-line heart-cutting HILIC-Mixed Mode 2D-LC-QToF experiment was conducted, allowing the separation of this critical isomer pair. In this setup, the BEH Amide column in the 1D separated the majority of target metabolites, while a heart-cut of the peak from totally coeluted fructose 6-phosphate and glucose 1-phosphate was separated in the 2D with HILICpak VT50-2D column, thus allowing undisturbed determination of the glycolytic phosphorylated carbohydrate metabolites due to their chromatographic separation from hexose monophosphate metabolites. The assay specificity towards 7 common hexose monophosphates was characterized (glucose 1- and 6-phosphate, galactose 1- and 6-phosphate, fructose 6-phosphate, mannose 1- and 6-phosphate). The selectivity of some rare hexose monophosphates (allose 6-phosphate, tagatose 6-phosphate, sorbose 1-phosphate) was also tested.PMID:36566570 | DOI:10.1016/j.chroma.2022.463727

Food Chem. 2022 Dec 17;408:135232. doi: 10.1016/j.foodchem.2022.135232. Online ahead of print.ABSTRACTDual-platform metabolomics combined with multivariate data analysis was used to investigate the effects of adding fish gelatin (FGH) at different degrees of hydrolysis (DH) on the growth and metabolic pathways of different species of Lactobacillus in fermented milk. The results showed that the promotion effect of FGH on Lactobacillus was related to the species of probiotics. The corresponding metabolic pathways also changed, with the promotion of Lactobacillus by FGH mainly regulated through amino acid metabolism, lipid metabolism, and nucleotide metabolism pathways. The excess DH inhibited the growth of L. paracasei by adjusting its metabolic state through reducing nucleotide requirements, allocating protein resources, and adopting a stress response. In conclusion, this study revealed the effectiveness of dual-platform metabolomics in explaining the metabolic mechanisms of probiotics, providing theoretical support and a scientific basis for the development of functional fermented foods.PMID:36566542 | DOI:10.1016/j.foodchem.2022.135232

Eur J Pharmacol. 2022 Dec 21:175481. doi: 10.1016/j.ejphar.2022.175481. Online ahead of print.ABSTRACTThe positive and pro-economic trend in the management of cancer treatment is the search for the antineoplastic potential of known, widely used and safe drugs with a different clinical purpose. A good candidate seems to be moxifloxacin with broad-spectrum antibacterial activity, which as the member of the fourth generation fluoroquinolone is known to affect not only bacterial but also eukaryotic DNA topoisomerases, however at high concentration. Due to the fact that the modification of parent drug with lipid component can improve anticancer potential by increasing of bioavailability, selectivity, and cytotoxic efficiency, we evaluated the mechanisms of cytotoxic activity of novel moxifloxacin conjugates with fatty acids and verified metabolic profile in SW480, SW620 and PC3 cell lines. Our study revealed that cytotoxic potential of moxifloxacin conjugates was stronger than free moxifloxacin, moreover, they remained non-toxic to normal HaCaT cells. PC3 were more sensitive to MXF conjugates than colon cancer cells. The most promising cytotoxic activity exhibited conjugate 4m and 16m with oleic and stearic acid reducing viability of PC3 and SW620 cells. Tested conjugates activated caspases 3/7 and induced late-apoptosis, mainly in PC3 and SW620 cells. However, the most pronounced inhibition of NF-κB activation and IL-6 secretion was observed in SW480. Metabolomic analysis indicated influence of the moxifloxacin conjugates on intensity of lipid derivatives with the most successful metabolite profile in PC3. Our findings suggested the cytotoxic potential of moxifloxacin conjugates, especially with oleic and stearic acid can be beneficial in oncological therapy, including their possible anti-inflammatory and known antibacterial effect.PMID:36566005 | DOI:10.1016/j.ejphar.2022.175481

Prog Neuropsychopharmacol Biol Psychiatry. 2022 Dec 21:110702. doi: 10.1016/j.pnpbp.2022.110702. Online ahead of print.ABSTRACTSirtuin 6 (SIRT6) is a nuclear silencing information regulator that is widely expressed in brain. Inhibition of SIRT6 in the brain induced antidepressant effects in rodents. However, SIRT6 knockout in neurons induced developmental retardation and cognitive impairments. In this study, a mouse strain of astrocyte conditional knockout SIRT6 (AKO) was constructed. Unlike whole brain SIRT6 knockout mice, AKO mice did not show growth retardation. We showed that SIRT6 knockout in astrocytes did not impair the learning and memory ability of mice. Chronic unpredictable mild stress (CUMS) was used to evaluate the anti-depression and anti-anxiety effects in mice. In tail suspension test and forced swimming test, AKO mice did not show depression like phenotype induced by CUMS. In addition, knockout of SIRT6 in astrocytes alleviated the high anxiety level induced by CUMS in light and dark box test, open field test and elevated cross maze test. Three box social test showed that the deletion of SIRT6 in astrocytes changed the social preference of mice. Re-expression of SIRT6 in astrocytes mediated by adeno-associated virus reversed the social preference of AKO mice, but the re-expression also eliminated the anti-depression and anti-anxiety effects in AKO mice. Deletion of SIRT6 in astrocytes change the purine metabolic homeostasis of medial prefrontal cortex in mice. The results of transcriptomics and metabolomics analysis showed that the deletion of SIRT6 would change the purine metabolic pathway of cultured astrocytes and increase the contents of inosine and the second messenger cyclic adenosine monophosphate in astrocytes. In conclusion, knockout of SIRT6 in astrocytes induced anti-depression and anti-anxiety effects in mice without impairing the development and cognitive ability of mice.PMID:36565979 | DOI:10.1016/j.pnpbp.2022.110702

Sci Total Environ. 2022 Dec 21:161054. doi: 10.1016/j.scitotenv.2022.161054. Online ahead of print.ABSTRACTBACKGROUND: Everyday, humans are exposed to a mixture of environmental chemicals some of which have endocrine and/or metabolism disrupting actions which may contribute to non-communicable diseases. The adverse health impacts of real-world chemical exposure, characterized by chronic low doses of a mixture of chemicals, are only recently emerging. Biosolids derived from human waste represent the environmental chemical mixtures humans are exposed to in real life. Prior studies in sheep have shown aberrant reproductive and metabolic phenotypes in offspring after maternal biosolid exposure.OBJECTIVE: To determine if exposure to biosolids perturbs the maternal metabolic milieu of pregnant ewes, in a fetal sex-specific manner.METHODS: Ewes were grazed on inorganic fertilizer (Control) or biosolid-treated pastures (BTP) from before mating and throughout gestation. Plasma from pregnant ewes (Control n = 15, BTP n = 15) obtained mid-gestation were analyzed by untargeted metabolomics. Metabolites were identified using Agilent MassHunter. Multivariate analyses were done using MetaboAnalyst 5.0 and confirmed using SIMCA.RESULTS: Univariate and multivariate analysis of 2301 annotated metabolites identified 193 differentially abundant metabolites (DM) between control and BTP sheep. The DM primarily belonged to the super-class of lipids and organic acids. 15-HeTrE, oleamide, methionine, CAR(3:0(OH)) and pyroglutamic acid were the top DM and have been implicated in the regulation of fetal growth and development. Fetal sex further exacerbated differences in metabolite profiles in the BTP group. The organic acid class of metabolites was abundant in animals with male fetuses. Prenol lipid, sphingolipid, glycerolipid, alkaloid, polyketide and benzenoid classes showed fetal sex-specific responses to biosolids.DISCUSSION: Our study illustrates that exposure to biosolids significantly alters the maternal metabolome in a fetal sex-specific manner. The altered metabolite profile indicates perturbations to fatty acid, arginine, branched chain amino acid and one‑carbon metabolism. These factors are consistent with, and likely contributes to, the adverse phenotypic outcomes reported in the offspring.PMID:36565874 | DOI:10.1016/j.scitotenv.2022.161054

J Environ Radioact. 2022 Dec 22;258:107090. doi: 10.1016/j.jenvrad.2022.107090. Online ahead of print.ABSTRACTAs a radioactive heavy metal element with a long half-life, uranium causes environmental pollution when it enters the surrounding soil. This study analyzed the changes about soil enzyme activity, non-targeted metabolomics, microbial community structure and function microbial community structure and function to assess the differences in the effects of uranium stress on rhizosphere and non-rhizosphere soil. Results showed that uranium stress significantly inhibited the activities of urease and sucrase in rhizosphere and non-rhizosphere, which had less effect on rhizosphere. Compare to the non-rhizosphere soil, the uranium stress induced the production of gibberellin A1, to promoted several metabolic pathways, such as nitrogen and PTS (Phosphotransferase system) metabolic in rhizosphere soil. The species and abundance of Aspergillus, Acidobacter, and Synechococcus in both rhizosphere and non-rhizosphere soil were decreased by uranium stress. However, the microorganisms in rhizosphere soil were less inhibited according to the soil metabolism and microbial network map analysis. Furthermore, the Chujaibacter in rhizosphere soil under uranium stress was found significantly positively correlated with lipid and organic oxygen compounds. Overall, the results indicated that ryegrass roots significantly alleviated the effects of uranium stress on soil microbial activity and population abundances, thus playing a protective role. The study also provided a theoretical basis for in-depth understanding of the biological effects, prevention and control mechanisms of uranium-contaminated soil.PMID:36565664 | DOI:10.1016/j.jenvrad.2022.107090

J Chromatogr A. 2022 Dec 17;1688:463718. doi: 10.1016/j.chroma.2022.463718. Online ahead of print.ABSTRACTTo address the chemical complexity is indispensable in a number of research fields. Herb metabolome is typically composed by more than one class of structure analogs produced via different biosynthetic pathways. Multidimensional chromatography (MDC), due to the greatly enhanced separation space, offers the potential solution to comprehensive characterization of herbal metabolites. Here, we presented a strategy, by integrating MDC and quadrupole time-of-flight mass spectrometry (QTOF-MS), to accomplish the in-depth herbal metabolites characterization. Using the metabolome of two Astragalus species (A. membranaceus var. mongholicus,AMM; A. membranaceus, AM) as the case, an off-line three-dimensional liquid chromatography (3D-LC) system was established: hydrophilic interaction chromatography using an XAmide column as the first dimension (1D) for fractionating the total extract, on-line reversed-phase × reversed-phase liquid chromatography separately configuring a CSH Fluoro-Phenyl column and a Cosmocore C18 column as the second dimension (2D) and the third dimension (3D) of chromatography to enable the explicit separation of three well fractionated samples. Moreover, the negative-mode collision-induced dissociation by QTOF-MS under the optimized condition could provide diversified fragments that were useful for the structural elucidation of AMM and AM. An in-house library (composed by 247 known compounds) and comparison with 43 reference standards were utilized to assist more reliable characterization. We could characterize 513 compounds from two Astragalus species (344 from AMM and 323 from AM), including 236 flavonoids, 150 triterpenoids, 18 organic acids, and 109 others. Conclusively, the established MDC approach gained excellent performance favoring the analogs-oriented in-depth characterization of herbal metabolites, but received uncompromising analytical efficiency.PMID:36565652 | DOI:10.1016/j.chroma.2022.463718

Plant Physiol Biochem. 2022 Dec 19;194:696-707. doi: 10.1016/j.plaphy.2022.12.016. Online ahead of print.ABSTRACTTartary buckwheat is rich in flavonoids, which not only play an important role in the plant-environment interaction, but are also beneficial to human health. Rutin is a therapeutic flavonol which is massively accumulated in Tartary buckwheat. It has been demonstrated that transcription factors control rutin biosynthesis. However, the transcriptional regulatory network of rutin is not fully clear. In this study, through transcriptome and target metabolomics, we validated the role of FtMYB102 and FtbHLH4 TFs at the different developmental stages of Tartary buckwheat. The elevated accumulation of rutin in the sprout appears to be closely associated with the expression of FtMYB102 and FtbHLH4. Yeast two-hybrid, transient luciferase activity and co-immunoprecipitation demonstrated that FtMYB102 and FtbHLH4 can interact and form a transcriptional complex. Moreover, yeast one-hybrid showed that both FtMYB102 and FtbHLH4 directly bind to the promoter of chalcone isomerase (CHI), and they can coordinately induce CHI expression as shown by transient luciferase activity assay. Finally, we transferred FtMYB102 and FtbHLH4 into the hairy roots of Tartary buckwheat and found that they both can promote the accumulation of rutin. Our results indicate that FtMYB102 and FtbHLH4 can form a transcriptional complex by inducing CHI expression to coordinately promote the accumulation of rutin.PMID:36565614 | DOI:10.1016/j.plaphy.2022.12.016

Cardiovasc Diabetol. 2022 Dec 23;21(1):288. doi: 10.1186/s12933-022-01716-0.ABSTRACTBACKGROUND: Metabolic syndrome (MetS) has been proposed as a clinically identifiable high-risk state for the prediction and prevention of cardiovascular diseases and type 2 diabetes mellitus. As a promising "omics" technology, metabolomics provides an innovative strategy to gain a deeper understanding of the pathophysiology of MetS. The study aimed to systematically investigate the metabolic alterations in MetS and identify biomarker panels for the identification of MetS using machine learning methods.METHODS: Nuclear magnetic resonance-based untargeted metabolomics analysis was performed on 1011 plasma samples (205 MetS patients and 806 healthy controls). Univariate and multivariate analyses were applied to identify metabolic biomarkers for MetS. Metabolic pathway enrichment analysis was performed to reveal the disturbed metabolic pathways related to MetS. Four machine learning algorithms, including support vector machine (SVM), random forest (RF), k-nearest neighbor (KNN), and logistic regression were used to build diagnostic models for MetS.RESULTS: Thirteen significantly differential metabolites were identified and pathway enrichment revealed that arginine, proline, and glutathione metabolism are disturbed metabolic pathways related to MetS. The protein-metabolite-disease interaction network identified 38 proteins and 23 diseases are associated with 10 MetS-related metabolites. The areas under the receiver operating characteristic curve of the SVM, RF, KNN, and logistic regression models based on metabolic biomarkers were 0.887, 0.993, 0.914, and 0.755, respectively.CONCLUSIONS: The plasma metabolome provides a promising resource of biomarkers for the predictive diagnosis and targeted prevention of MetS. Alterations in amino acid metabolism play significant roles in the pathophysiology of MetS. The biomarker panels and metabolic pathways could be used as preventive targets in dealing with cardiometabolic diseases related to MetS.PMID:36564831 | DOI:10.1186/s12933-022-01716-0