PubMed

Biotechnol J. 2024 May;19(5):e2400039. doi: 10.1002/biot.202400039.ABSTRACTIndustrial production of bioactive compounds from actinobacteria, such as erythromycin and its derivatives, faces challenges in achieving optimal yields. To this end, the Design-Build-Test-Learn (DBTL) framework, a systematic metabolic engineering approach, was employed to enhance erythromycin production in Saccharopolyspora erythraea (S. erythraea) E3 strain. A genetically modified strain, S. erythraea E3-CymRP21-dcas9-sucC (S. erythraea CS), was developed by suppressing the sucC gene using an inducible promoter and dcas9 protein. The strain exhibited improved erythromycin synthesis, attributed to enhanced precursor synthesis and increased NADPH availability. Transcriptomic and metabolomic analyses revealed altered central carbon metabolism, amino acid metabolism, energy metabolism, and co-factor/vitamin metabolism in CS. Augmented amino acid metabolism led to nitrogen depletion, potentially causing cellular autolysis during later fermentation stages. By refining the fermentation process through ammonium sulfate supplementation, erythromycin yield reached 1125.66 mg L-1, a 43.5% increase. The results demonstrate the power of the DBTL methodology in optimizing erythromycin production, shedding light on its potential for revolutionizing antibiotic manufacturing in response to the global challenge of antibiotic resistance.PMID:38797723 | DOI:10.1002/biot.202400039

Zhonghua Fu Chan Ke Za Zhi. 2024 May 25;59(5):391-400. doi: 10.3760/cma.j.cn112141-20240116-00038.ABSTRACTObjective: To investigate the effect of rare ginsenosides (RGS) on reproductive injury induced by cyclophosphamide (CP) in female rats. Methods: Twenty-four female rats were divided into four groups [normal control (NC), RGS, CP, and CP+RGS group] with 6 rats in each group. CP group (the model group) and CP+RGS group (the treatment group) were intraperitoneally injected with CP 30 mg/kg for 5 days for modeling, and CP+RGS group was given RGS intragastric intervention. General growth status of rats in each group was observed, the organ index was calculated, and the pathological changes of ovary, uterus, liver and kidney were observed by hematoxylin-eosin staining. Serum levels of estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), pro-inflammatory factors interleukin (IL) 6, IL-1β, tumor necrosis factor-α were detected. The urine samples were collected after RGS treatment for metabonomics analysis. Metabolomic profiling based on ultra performance liquid chromatography (UPLC) coupled with mass spectrometry (MS) was used to analyze and determine the urine metabolites of rats in each group. Results: Compared with NC group, the ovary index of CP group [(0.054±0.015) %] was significantly decreased (P<0.05), the uterus index [(0.293±0.036) %] and estradiol level [(62.9±6.4) pmol/L] were significantly decreased (all P<0.01), serum levels of FSH, LH, IL-6 and IL-1β [(20.4±1.0) U/L, (29.0±3.0) U/L, (185.4±28.6) ng/L, (72.9±2.0) ng/L, respectively] were significantly increased (all P<0.01). Compared with CP group, the ovary index in CP+RGS group [(0.075±0.010) %] was significantly increased (P<0.05), serum estradiol level [(122.1±16.2) pmol/L] was significantly increased (P<0.01), serum FSH, IL-1β and IL-6 levels [(16.7±1.0) U/L, (111.8±17.4) ng/L, (60.1±2.2) ng/L, respectively] were significantly decreased (all P<0.01). Metabonomics analysis results showed that, a total of 352 metabolites were detected in urine, of which 12 were found to be potential markers associated with reproductive injury according to the screening standard. After treatment with RGS, differential metabolites were improved in the direction of NC group. Pathway enrichment suggests that the therapeutic effect of RGS was related to multiple metabolic pathways, including purine metabolism and taurine and hypotaurine metabolism. Conclusion: RGS might reduce inflammation and thus ameliorate the damage caused by CP to the reproductive system of female rats by affecting purine metabolism and other pathways.PMID:38797569 | DOI:10.3760/cma.j.cn112141-20240116-00038

Adv Biochem Eng Biotechnol. 2024 May 26. doi: 10.1007/10_2024_254. Online ahead of print.ABSTRACTPlant tissue culture has evolved in the last decades with several types of cultures being developed to promote a more sustainable food production system. Moreover, these cultures can be applied for the production of relevant metabolites with medicinal potential, thus contributing to nutrition and healthcare. Importantly, plant micropropagation has enabled agricultural expansion and tissue culture has emerged as a promising production alternative for several plants and their metabolites in the food, cosmetic, and pharmaceutical industries. Plant tissue cultures present several advantages over conventional propagation techniques as they are season independent, enabling a continuous supply of the plants/compounds of interest, with the guarantee of high phytosanitary quality. In addition, genetic uniformity is generally maintained, thus reducing chemical variability that can compromise safety and efficacy. Nevertheless, despite their undeniable potential, with many researchers focusing on new strategies to improve production yield in cell cultures, such as with the use of elicitors or resorting to metabolomics engineering, an effective and lucrative large-scale production has yet to be obtained. Indeed, only a few compounds with market value are produced in this regard and several limitations such as contaminations, low culture yield and production costs still need to be overcome in order to take advantage of the full potential of these techniques.PMID:38796640 | DOI:10.1007/10_2024_254

Metabolomics. 2024 May 25;20(3):62. doi: 10.1007/s11306-024-02125-y.ABSTRACTINTRODUCTION: The chemical classification of Cannabis is typically confined to the cannabinoid content, whilst Cannabis encompasses diverse chemical classes that vary in abundance among all its varieties. Hence, neglecting other chemical classes within Cannabis strains results in a restricted and biased comprehension of elements that may contribute to chemical intricacy and the resultant medicinal qualities of the plant.OBJECTIVES: Thus, herein, we report a computational metabolomics study to elucidate the Cannabis metabolic map beyond the cannabinoids.METHODS: Mass spectrometry-based computational tools were used to mine and evaluate the methanolic leaf and flower extracts of two Cannabis cultivars: Amnesia haze (AMNH) and Royal dutch cheese (RDC).RESULTS: The results revealed the presence of different chemical compound classes including cannabinoids, but extending it to flavonoids and phospholipids at varying distributions across the cultivar plant tissues, where the phenylpropnoid superclass was more abundant in the leaves than in the flowers. Therefore, the two cultivars were differentiated based on the overall chemical content of their plant tissues where AMNH was observed to be more dominant in the flavonoid content while RDC was more dominant in the lipid-like molecules. Additionally, in silico molecular docking studies in combination with biological assay studies indicated the potentially differing anti-cancer properties of the two cultivars resulting from the elucidated chemical profiles.CONCLUSION: These findings highlight distinctive chemical profiles beyond cannabinoids in Cannabis strains. This novel mapping of the metabolomic landscape of Cannabis provides actionable insights into plant biochemistry and justifies selecting certain varieties for medicinal use.PMID:38796627 | DOI:10.1007/s11306-024-02125-y

Metabolomics. 2024 May 25;20(3):63. doi: 10.1007/s11306-024-02124-z.ABSTRACTINTRODUCTION: Fighter pilots must support the effects of many stressors, including physical and psychological exertion, circadian disturbance, jet lag, and environmental stress. Despite the rigorous selection of military pilots, those factors predispose to failures in physiological compensatory mechanisms and metabolic flexibility.OBJECTIVES: We compared through NMR-based metabolomics the metabolic profile of Brazilian F5 fighter pilots with different flight experiences vs. the control group of non-pilots. We hypothesized that combat pilots have metabolic flexibility associated with combat flight time.METHODS: We evaluated for the first time 34 Brazilian fighter pilots from Santa Cruz Air Base (Rio de Janeiro, RJ) allocated into three groups: pilots with lower total accumulated flight experience < 1,100 h (PC1, n = 7); pilots with higher total accumulated flight experience ≥ 1,100 h (PC2, n = 6); military non-pilots (CONT, n = 21). Data collection included anthropometric measurements, total blood count, lipidogram, markers of oxidative stress, and serum NMR-based metabolomics.RESULTS: In comparison with controls (p < 0.05), pilots exhibited decreased levels of white blood cells (-13%), neutrophils (-15%), lymphocytes (-20%), alfa-glucose (-13%), lactate (-26%), glutamine (-11%), histidine (-20%), and tyrosine (-11%), but higher isobutyrate (+ 10%) concentrations. Significant correlations were found between lactate vs. amino acids in CONT (r = 0.55-0.68, p < 0.001), and vs. glutamine in PC2 (r = 0.94, p = 0.01).CONCLUSION: Fighter pilots with lower experience showed a dysregulation in immune-metabolic function in comparison with controls, which seemed to be counteracted by the accumulation of flight hours. Those findings might have implications for the health preservation and operational training of fighter pilots.PMID:38796596 | DOI:10.1007/s11306-024-02124-z

Nat Commun. 2024 May 25;15(1):4455. doi: 10.1038/s41467-024-48734-y.ABSTRACTLipids are the most abundant but poorly explored components of the human brain. Here, we present a lipidome map of the human brain comprising 75 regions, including 52 neocortical ones. The lipidome composition varies greatly among the brain regions, affecting 93% of the 419 analyzed lipids. These differences reflect the brain's structural characteristics, such as myelin content (345 lipids) and cell type composition (353 lipids), but also functional traits: functional connectivity (76 lipids) and information processing hierarchy (60 lipids). Combining lipid composition and mRNA expression data further enhances functional connectivity association. Biochemically, lipids linked with structural and functional brain features display distinct lipid class distribution, unsaturation extent, and prevalence of omega-3 and omega-6 fatty acid residues. We verified our conclusions by parallel analysis of three adult macaque brains, targeted analysis of 216 lipids, mass spectrometry imaging, and lipidome assessment of sorted murine neurons.PMID:38796479 | DOI:10.1038/s41467-024-48734-y

Lipids Health Dis. 2024 May 25;23(1):154. doi: 10.1186/s12944-024-02121-0.ABSTRACTCancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction, leveraging the distinct lipid profiles of cancer patient-derived specimens. This review aims to systematically summarize the application of MS-based lipidomic analysis in prognostic prediction for cancer patients. Our systematic review summarized 38 studies from the past decade that attempted prognostic prediction of cancer patients through lipidomics. Commonly analyzed cancers included colorectal, prostate, and breast cancers. Liquid (serum and urine) and tissue samples were equally used, with liquid chromatography-tandem MS being the most common analytical platform. The most frequently evaluated prognostic outcomes were overall survival, stage, and recurrence. Thirty-eight lipid markers (including phosphatidylcholine, ceramide, triglyceride, lysophosphatidylcholine, sphingomyelin, phosphatidylethanolamine, diacylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylethanolamine, lysophosphatidic acid, dihydroceramide, prostaglandin, sphingosine-1-phosphate, phosphatidylinosito, fatty acid, glucosylceramide and lactosylceramide) were identified as prognostic factors, demonstrating potential for clinical application. In conclusion, the potential for developing lipidomics in cancer prognostic prediction was demonstrated. However, the field is still nascent, necessitating future studies for validating and establishing lipid markers as reliable prognostic tools in clinical practice.PMID:38796445 | DOI:10.1186/s12944-024-02121-0

Food Chem Toxicol. 2024 May 23:114759. doi: 10.1016/j.fct.2024.114759. Online ahead of print.ABSTRACTT-2 toxin is a highly cardiotoxic environmental contaminant. Selenium can uphold the cardiovascular system's functionality. Selenium insufficiency is common. The aim of this study was to elucidate the effects of low selenium diet alone or in combination with T-2 toxin on myocardial tissue damage. Thirty-two Sprague-Dawley rats of 3 weeks of age were randomized into control, low selenium diet, low selenium diet combined with T-2 toxin groups (at doses of 10 ng/g and 100 ng/g body weight) for 12-weeks intervention. Pathohistology and ultrastructural changes in cardiac tissue were observed. Changes in cardiac metabolites were analyzed using untargeted metabolomics. The findings demonstrated that cardiac tissue abnormalities, interstitial bleeding, inflammatory cell infiltration, and mitochondrial damage can be brought on by low selenium diet alone or in combination with the T-2 toxin. A low selenium diet alone or in combination with the T-2 toxin affected cardiac metabolic profiles and resulted in aberrant modifications in many metabolic pathways, including the metabolism of amino acids, cholesterol, and thiamine. Accordingly, low selenium diet and T-2 toxin may have a synergistic effect. Our findings provide fresh insights into the processes of cardiac injury by revealing the effects of low selenium diet and T-2 toxin on cardiac metabolism.PMID:38796086 | DOI:10.1016/j.fct.2024.114759

J Lipid Res. 2024 May 23:100567. doi: 10.1016/j.jlr.2024.100567. Online ahead of print.ABSTRACTLipids play pivotal roles in an extensive range of metabolic and physiological processes. In recent years, the convergence of trapped ion mobility (TIMS) and mass spectrometry (MS) has enabled 4D-lipidomics, a highly promising technology for comprehensive lipid analysis. 4D-lipidomics assesses lipid annotations across four distinct dimensions-retention time, collisional cross section, m/z (mass-to-charge ratio), and MS/MS spectra-providing a heightened level of confidence in lipid annotation. These advantages prove particularly valuable when investigating complex disorders involving lipid metabolism, such as adrenoleukodystrophy (ALD). ALD is characterized by the accumulation of very-long-chain fatty acids (VLCFA) due to pathogenic variants in the ABCD1 gene. A comprehensive 4D-lipidomics strategy of ALD fibroblasts demonstrated significant elevations of various lipids from multiple classes. This indicates that the changes observed in ALD are not confined to a single lipid class and likely impacts a broad spectrum of lipid-mediated physiological processes. Our findings highlight the incorporation of mainly saturated and monounsaturated VLCFA variants into a range of lipid classes, encompassing phosphatidylcholines, triacylglycerols, and cholesterol esters. These include ultra-long-chain fatty acids with a length of up to thirty carbon atoms. Lipid species containing C26:0, C26:1 were the most frequently detected VLCFA lipids in our study. Furthermore, we report a panel of 121 new candidate biomarkers in fibroblasts, exhibiting significant differentiation between controls and individuals with ALD. In summary, this study demonstrates the capabilities of a 4D-lipid profiling workflow in unraveling novel insights into the intricate lipid modifications associated with metabolic disorders like ALD.PMID:38795862 | DOI:10.1016/j.jlr.2024.100567

Environ Pollut. 2024 May 23:124211. doi: 10.1016/j.envpol.2024.124211. Online ahead of print.ABSTRACTExposure to pesticide could contribute to neurodevelopmental and neurodegenerative disorders. Notably, research suggests that prenatal or early postnatal exposure to paraquat (PQ), an herbicide, might trigger neurodevelopmental toxicity in neural stem cells (NSCs) via oxidative stress. However, the molecular mechanisms of PQ-induced perturbations in NSCs, particularly at the metabolite level, are not fully understood. Using a dose-response metabolomics approach, we examined metabolic changes in murine NSCs exposed to different PQ doses (0, 10, 20, 40 μM) for 24h. At 20 μM, PQ treatment led to significant metabolic alterations, highlighting unique toxic mechanisms. Metabolic perturbations, mainly affecting amino acid metabolism pathways (e.g., phenylalanine, tyrosine, arginine, tryptophan, and pyrimidine metabolism), were associated with oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. Dose-response models were used to identify potential biomarkers (e.g., Putrescine, L-arginine, ornithine, L-histidine, N-acetyl-L-phenylalanine, thymidine) reflecting early damage from low-dose PQ exposure. These biomarkers could be used as points of departure (PoD) for characterizing PQ exposure hazard in risk assessment. Our study offers insights into mechanisms and risk assessment related to PQ-induced neurotoxicity in NSCs.PMID:38795820 | DOI:10.1016/j.envpol.2024.124211

Metabolism. 2024 May 23:155938. doi: 10.1016/j.metabol.2024.155938. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Hepatic lipogenesis is elevated in nutrient abundant conditions to convert the excess carbohydrate into triacylglycerol (TAG). Fatty acyl moiety of TAG is eventually transported into adipose tissues by very low density lipoprotein, leading to the accumulation of TAG as a preferred storage form of excess energy. Disruption of the balance between TAG clearance and synthesis leads to the accumulation of lipids in the liver, leading to the progression of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis. Protein arginine methyltransferase (PRMT) 6 has been linked to the various metabolic processes including hepatic gluconeogenesis, muscle atrophy and lipodystrophy in mouse models. However, the role of PRMT6 in the control of hepatic lipogenesis has not been elucidated to date.METHODS: We assessed the interaction between PRMT6 and LXR alpha by using co-immunoprecipitation assay. The specific arginine residue of LXR alpha that is methylated by PRMT6 was assessed by LC-MS/MS assay and the functional consequences of LXR alpha methylation was explored by mSREBP-1c luciferase assay. The effect of PRMT6 on hepatic lipogenesis was assessed by adenovirus-mediated ectopic expression of PRMT6 or knockdown of PRMT6 via shRNA in hepatocytes. Finally, the role of PRMT6 in hepatic lipid metabolism in vivo was explored by either ectopic expression of LXR alpha mutant that is defective in PRMT6-mediated arginine methylation or knockdown of PRMT6 in liver.RESULTS: We found that promoter activity of sterol regulatory element binding protein (SREBP) 1c is robustly activated by PRMT6. Interestingly, we demonstrated that PRMT6 binds to LXR alpha, a transcription factor for SREBP-1c, via its LXXLL motif, leading to the asymmetric dimethylation of an arginine residue and activation of this protein. Indeed, ectopic expression of PRMT6 in hepatocytes led to the enhanced expression of LXR alpha target genes in the lipogenic pathway. Conversely, genetic or pharmacological inhibition of PRMT6 diminished expression of lipogenic genes and the lipid accumulation in primary hepatocytes. Mechanistically, we found that asymmetric dimethylation of LXR alpha led to the dissociation of small heterodimer partner (SHP), a transcriptional co-inhibitor of this factor, resulting in the activation of LXR alpha-mediated transcriptional process. Finally, we showed that disruption of asymmetric dimethylation of LXR alpha in the liver led to the diminished expression of genes in the lipogenesis, resulting in the reduced hepatic lipid accumulation in high fat diet-fed mice in vivo.CONCLUSIONS: We showed that PRMT6 modulates LXR alpha activity by conferring asymmetric dimethylation of arginine 253, thus blocking SHP-mediated inhibition and promoting hepatic lipid accumulation. These results suggest that PRMT6 is critical in the control of lipid homeostasis by regulation of LXR alpha-mediated lipogenesis in the liver.PMID:38795769 | DOI:10.1016/j.metabol.2024.155938

J Mol Cell Cardiol. 2024 May 23:S0022-2828(24)00084-1. doi: 10.1016/j.yjmcc.2024.05.010. Online ahead of print.ABSTRACTBACKGROUND: Atherosclerosis is a chronic pathology, leading to acute coronary heart disease or stroke. MiR-127 has been found significantly upregulated in advanced atherosclerosis. But its function in atherosclerosis remains unexplored. We explored the role of miR-127-3p in regulating atherosclerosis development and its downstream mechanisms.METHODS: The expression profile of miR-127 in carotid atherosclerotic plaques of 23 patients with severe carotid stenosis was detected by RT-qPCR and in situ hybridization. Primary bone marrow-derived macrophages (BMDM) stimulated with oxidized low-density lipoprotein were used as an in vitro model. CCK-8, EdU, RT-qPCR, and flow cytometry were used to detect the proliferative capacity and polarization of BMDM, which were infected by lentivirus-carrying plasmid to upregulate or downregulate miR-127-3p expression, respectively. RNA sequencing combined with bioinformatic analysis and targeted fatty acid metabolomics approach were used to detect the transcriptome and lipid metabolites. The association between miR-127-3p and its target was verified by dual-luciferase activity reporting and Western blotting. Oxygen consumption rate of BMDM were detected using seahorse analysis. High-cholesterol-diet-fed low density lipoprotein deficient (LDLR-/-) mice, with-or-without carotid tandem-stenosis surgery, were treated with miR-127-3p agomir or antagomir to examine its effect on plaque development and stability.RESULTS: miR-127-3p, not -5p, is elevated in human advanced carotid atheroma and its expression is positively associated with macrophage accummulation in plaques. In vitro, miR-127-3p-overexpressed macrophage exhibites increased proliferation capacity and facilitates M1 polariztion whereas the contrary trend is present in miR-127-3p-inhibited macrophage. Stearoyl-CoA desaturase-1 (SCD1) is one potential target of miR-127-3p. miR-127-3p mimics decreases the activity of 3' untranslated regions of SCD-1. Furthermore, miR-127-3p downregulates SCD1 expression, and reversing the expression of SCD1 attenuates the increased proliferation induced by miR-127-3p overexpression in macrophage. miR-127-3p overexpression could also lead to decreased content of unsaturated fatty acids(UFAs), increased content of acetyl CoA and increased level of oxidative phosphorylation. In vivo, miR-127-3p agomir significantly increases atherosclerosis progression, macrophage proliferation and decreases SCD1 expression and the content of UFAs in aortic plaques of LDLR-/- mice. Conversely, miR-127-3p antagomir attenuated atherosclerosis, macrophage proliferation in LDLR-/- mice, and enhanced carotid plaque stability in mice with vulnerable plaque induced.CONCLUSION: MiR-127-3p enhances proliferation in macrophages through downregulating SCD-1 expression and decreasing the content of unsaturated fatty acid, thereby promoting atherosclerosis development and decreasing plaque stability. miR-127-3p/SCD1/UFAs might provide potential therapeutic target for anti-inflammation and atherosclerosis.PMID:38795767 | DOI:10.1016/j.yjmcc.2024.05.010

Am J Clin Nutr. 2024 May 23:S0002-9165(24)00482-9. doi: 10.1016/j.ajcnut.2024.05.017. Online ahead of print.ABSTRACTBACKGROUND: Our previous studies showed that curcumin prevented hepatic steatosis in animal models.OBJECTIVE: This study aimed to assess the effects of curcumin on hepatic fat content, body composition, and gut microbiota-dependent bile acid (BA) metabolism in patients with non-alcoholic simple fatty liver (NASFL).METHODS: In a 24-week double-blind randomized trial, 80 patients with NASFL received 500 mg/d curcumin or placebo. Hepatic fat content was measured using FibroTouch-based controlled attenuation parameters (CAP). Microbial composition and BA metabolites were analyzed using 16S rRNA sequencing and metabolomics.RESULTS: Curcumin consumption significantly reduced CAP value compared to placebo (-17.5 dB/m; 95%CI: -27.1, -7.8; P < 0.001). This corresponded to reduction in weight (-2.6 kg; 95%CI: -4.4, -0.8; P < 0.001) and BMI (-1.0 kg/m2; 95%CI: -2.0, -0.1; P = 0.032) compared to placebo group. Additionally, free fatty acid (-0.12 mmol/L; 95%CI: -0.20, -0.04; P = 0.004), triglycerides (-0.29 mmol/L; 95%CI: -0.41, -0.14; P < 0.001), fasting blood glucose (-0.06 mmol/L; 95%CI: -0.12, -0.01; P = 0.038), HbA1c (-0.06%; 95%CI: -0.33, -0.01; P = 0.019), and insulin (-4.94 μU/L; 95%CI: -9.73, -0.15; P = 0.043) showed significant reductions in the curcumin group compared to placebo group. Gut microbiota analysis indicated that curcumin significantly decreased Firmicutes to Bacteroidetes ratio and significantly increased Bacteroides abundance. Serum levels of deoxycholic acid, the most potent activator of Takeda G protein-coupled receptor 5 (TGR5), were significantly elevated after curcumin intervention (37.5 ng/mL; 95%CI: 6.7, 68.4; P = 0.018). Curcumin treatment also increased TGR5 expression in peripheral blood mononuclear cells and serum glucagon-like peptide-1levels (0.73 ng/mL; 95%CI: 0.16, 1.30; P = 0.012).CONCLUSION: Improvements in gut microbiota-dependent BA metabolism and TGR5 activation after 24-week curcumin intervention were associated with a reduction in hepatic fat content in patients with NASFL, providing evidence that curcumin is a potential nutritional therapy for NASFL. The trial was registered at www.chictr.org.cn THE URL OF REGISTRATION: https://www.chictr.org.cn/showproj.html?proj=155570 REGISTRATION ID: ChiCTR2200058052.PMID:38795741 | DOI:10.1016/j.ajcnut.2024.05.017

J Hazard Mater. 2024 May 23;473:134717. doi: 10.1016/j.jhazmat.2024.134717. Online ahead of print.ABSTRACTPrenatal exposure to benzotriazoles and benzothiazoles (collectively as BTs) was associated with pregnancy complications. Identifying the metabolites associated with prenatal BTs exposure may help elucidate the mechanism and characterize the exposure risk. In this prospective study of 158 pregnant women from Wuhan, China, urinary BTs were repeatedly measured across three trimesters to provide an accurate estimation of exposure during pregnancy. We conducted high-throughput targeted metabolomics with great coverage and high accuracy to characterize the urinary metabolic profile in late pregnancy. We first identified the perturbed metabolites of cocktail BTs exposure and then pinned down to the pairwise associations between individual BTs and the identified metabolites. A total of 44 metabolites were identified as perturbed biomarkers of cocktail BTs exposure based on the variable influence on projection (VIP > 1.2) score. Further pairwise associations analysis showed positive association of BTs with oxidative stress related biomarkers and negative association of BTs with neuronal function metabolites. The shared metabolic signatures among BTs in the co-occurrence network of pairwise association analysis may partially be attributed to the correlation among cocktail BTs exposure. The findings provide the potential mechanisms of BTs-associated pregnancy complications and offer insight into the health implications for prenatal BTs exposure. Furthermore, the framework we employed, which integrates both cocktail exposure and individual exposure, may illuminate future epidemiological research that seeks to incorporate exposure to mixtures and omics scale data.PMID:38795493 | DOI:10.1016/j.jhazmat.2024.134717

J Pharm Biomed Anal. 2024 May 23;246:116255. doi: 10.1016/j.jpba.2024.116255. Online ahead of print.ABSTRACTWilson disease (WD) is an inherited disorder characterized by abnormal copper metabolism with complex pathological features. Currently, this mechanism of copper overload-induced hepatic injury remains unclear. In this study, male toxic milk (TX) mice were selected as experimental subjects. Copper levels and biochemical indices were measured by atomic absorption spectroscopy (AAS) and kits. Liver tissue ultrastructure was observed by hematoxylin-eosin (H&E), sirius red staining and transmission electron microscopy. Plasma and liver metabolic profiles of TX mice were characterized by untargeted metabolomics. In addition, the expression of enzymes related to arachidonic acid metabolism in liver tissue was detected by Western blotting. The results showed the excessive copper content, concomitant oxidative stress, and hepatic tissue structural damage in TX mice. Seventy-eight metabolites were significantly different in WD, mainly involved in the metabolism of arachidonic acid, glycerophospholipids, sphingolipids, niacin and nicotinamide, and phenylalanine. Furthermore, the arachidonic acid metabolic pathway is an important pathway involved in WD metabolism. The level of arachidonic acid in the liver of TX mice was significantly lower (p < 0.01) compared to the control group. The expression of cytoplasmic phospholipase A2 (cPLA2) and arachidonic acid 12-lipoxygenase (ALOX12), related to the arachidonic acid metabolic pathway, was significantly different in the liver of TX mice (p < 0.01). Modulation of the arachidonic acid metabolic pathway could be a potential therapeutic strategy to alleviate WD symptoms.PMID:38795427 | DOI:10.1016/j.jpba.2024.116255

Ecotoxicol Environ Saf. 2024 May 24;279:116490. doi: 10.1016/j.ecoenv.2024.116490. Online ahead of print.ABSTRACTWith increasing plastic manufacture and consumption, microplastics/nanoplastics (MP/NP) pollution has become one of the world's pressing global environmental issues, which poses significant threats to ecosystems and human health. In recent years, sharp increasing researches have confirmed that MP/NP had direct or indirect effects on vegetative growth and sexual process of vascular plant. But the potential mechanisms remain ambiguous. MP/NP particles can be adsorbed and/or absorbed by plant roots or leaves and thus cause diverse effects on plant. This holistic review aims to discuss the direct effects of MP/NP on vascular plant, with special emphasis on the changes of metabolic and molecular levels. MP/NP can alter substance and energy metabolism, as well as shifts in gene expression patterns. Key aspects affected by MP/NP stress include carbon and nitrogen metabolism, amino acids biosynthesis and plant hormone signal transduction, expression of stress related genes, carbon and nitrogen metabolism related genes, as well as those involved in pathogen defense. Additionally, the review provides updated insights into the growth and physiological responses of plants exposed to MP/NP, encompassing phenomena such as seed/spore germination, photosynthesis, oxidative stress, cytotoxicity, and genotoxicity. By examining the direct impact of MP/NP from both physiological and molecular perspectives, this review sets the stage for future investigations into the complex interactions between plants and plastic pollutants.PMID:38795417 | DOI:10.1016/j.ecoenv.2024.116490

Endocr Rev. 2024 May 25:bnae016. doi: 10.1210/endrev/bnae016. Online ahead of print.ABSTRACTGlucocorticoid hormones (GC) are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels i.e. markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or non-specific. Current tools for assessing GC status, are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intra-individual variation, do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11βeta-hydroxysteroid dehydrogenase (11β-HSD) activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, miRNA, gene expression, epigenetic, and other novel biomarkers such as GDF-15 and osteocalcin, that could in future aid in the objective classification of GC status.PMID:38795365 | DOI:10.1210/endrev/bnae016

Metab Brain Dis. 2024 May 25. doi: 10.1007/s11011-024-01357-0. Online ahead of print.ABSTRACTAconitum coreanum (A. coreanum), a traditional Chinese medicine, has been proved to treat ischemic stroke (IS). However, the mechanisms of A. coreanum's anti-stroke is currently unknown. This study aimed to uncover the effect and mechanisms of A. coreanum. And study raw Aconitum coreanum (RA) and steamed Aconitum coreanum (SA) and Aconitum coreanum processed with ginger and Alumen (GA) on the mechanism of the pharmacological action of treating IS. Determining whether the efficacy is affected after processing. The right unilateral ligation of the carotid artery of gerbils was used to mimic IS. The neurological function score, infarct volume, oxidative stress level and inflammatory factor expression were measured in gerbils after IS. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins. Metabolomic analyzes IS-related metabolic pathways in urinary metabolites. RA, SA and GA significantly improved the infarct volume and behavioral score of IS gerbils, increased the expression of brain tissue superoxide dismutase (SOD), glutathione (GSH), nitric oxide (NO) and decreased the content of malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α). Western blot and immunofluorescence analysis results showed that RA, SA and GA significantly increased the expression of P-Akt, PI3K, HO-1 and KEAP1. Metabolomic studies identified 112 differential metabolites, including L-Proline, Riboflavin, Leukotriene D4, and 7-Methylxanthine, as potential biomarkers of stroke, involving 14 metabolic pathways including riboflavin metabolism, pyrimidine metabolism, and purine metabolism. Our findings indicated that A. coreanum protected against cerebral ischemia injury probably via the PI3K/Akt and KEAP1/NRF2 pathway. A. coreanum before and after processing both had a protective effect against IS brain injury in gerbils. The A. coreanum efficacy was not reduced after processing. Even compared to RA, SA had better efficacy.PMID:38795262 | DOI:10.1007/s11011-024-01357-0

J Appl Microbiol. 2024 May 24:lxae112. doi: 10.1093/jambio/lxae112. Online ahead of print.ABSTRACTAIMS: To develop antifungal lactic acid bacteria (LAB) and investigate their antifungal mechanisms against Aspergillus flavus in aflatoxin (AF) production.METHODS AND RESULTS: We isolated 179 LABs from cereal-based fermentation starters and investigated their antifungal mechanism against Aspergillus flavus through liquid chromatography-mass spectrometry and co-culture analysis techniques. Of the 179 isolates, antifungal activity was identified in Pediococcus pentosaceus, Lactobacillus crustorum, and Weissella paramesenteroides. These LABs reduced AF concentration by i) inhibiting mycelial growth, ii) binding AF to the cell wall, and iii) producing antifungal compounds. Species-specific activities were also observed, with P. pentosaceus inhibiting AF production and W. paramesenteroides showing AF B1 binding activity. In addition, crucial extracellular metabolites for selecting antifungal LAB were involved in the 2',3'-cAMP-adenosine and nucleoside pathways.CONCLUSIONS: This study demonstrates that P. pentosaceus, L. crustorum, and W. paramesenteroides are key LAB strains with distinct antifungal mechanisms against A. flavus, suggesting their potential as biological agents to reduce AF in food materials.PMID:38794887 | DOI:10.1093/jambio/lxae112

Exp Dermatol. 2024 May;33(5):e15103. doi: 10.1111/exd.15103.ABSTRACTErythrodermic psoriasis (EP) is a rare and life-threatening disease, the pathogenesis of which remains to be largely unknown. Metabolomics analysis can provide global information on disease pathophysiology, candidate biomarkers, and potential intervention strategies. To gain a better understanding of the mechanisms of EP and explore the serum metabolic signature of EP, we conducted an untargeted metabolomics analysis from 20 EP patients and 20 healthy controls. Furthermore, targeted metabolomics for focused metabolites were identified in the serum samples of 30 EP patients and 30 psoriasis vulgaris (PsV) patients. In the untargeted analysis, a total of 2992 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed significant difference between groups. After screening, 98 metabolites were found to be significantly dysregulated in EP, including 67 down-regulated and 31 up-regulated. EP patients had lower levels of L-tryptophan, L-isoleucine, retinol, lysophosphatidylcholine (LPC), and higher levels of betaine and uric acid. KEGG analysis showed differential metabolites were enriched in amino acid metabolism and glycerophospholipid metabolism. The targeted metabolomics showed lower L-tryptophan in EP than PsV with significant difference and L-tryptophan levels were negatively correlated with the PASI scores. The serum metabolic signature of EP was discovered. Amino acid and glycerophospholipid metabolism were dysregulated in EP. The metabolite differences provide clues for pathogenesis of EP and they may provide insights for therapeutic interventions.PMID:38794829 | DOI:10.1111/exd.15103