PubMed

mSystems. 2023 Jan 23:e0130022. doi: 10.1128/msystems.01300-22. Online ahead of print.ABSTRACTMetformin is a common drug for the management of type 2 diabetes mellitus; however, it causes various adverse gastrointestinal effects, especially after prolonged treatment. It is thus of interest to identify an adjuvant treatment that synergizes with the efficacy of metformin while mitigating its adverse effects. Since previous evidence supports that the gut microbiota is a target of metformin, this study investigated the beneficial effect and mechanism of the coadministration of probiotics with metformin in the management of type 2 diabetes mellitus by conducting a 3-month randomized, double-blind, placebo-controlled clinical trial (n = 27 and 21 in the probiotic and placebo groups, respectively, who completed the trial). Clinical results showed that the coadministration of probiotics with metformin significantly reduced glycated hemoglobin compared with metformin taken alone (P < 0.05). Metagenomic and metabolomic analyses showed that the coadministration of probiotics increased the abundance of gut short-chain fatty acid (SCFA)-producing bacteria and bile acids. Significantly or marginally more bile acids and related metabolites were detected in the probiotic group than in the placebo group postintervention. Taken together, the results of our study showed that the coadministration of probiotics with metformin synergized with the hypoglycemic effect in patients with type 2 diabetes mellitus, which was likely through modulating the gut microbiome and, subsequently, SCFA and bile acid metabolism. Our findings support that cotreatment with probiotics and metformin is beneficial to patients with type 2 diabetes mellitus. IMPORTANCE Metformin causes variable adverse gastrointestinal effects, especially after prolonged treatment. We found that cotreatment with Probio-X and metformin for the management of type 2 diabetes mellitus may promote gut SCFA-producing bacteria and the levels of specific bile acids, thus increasing the secretion of related gastrointestinal hormones and ultimately improving glucose homeostasis.PMID:36688679 | DOI:10.1128/msystems.01300-22

J Virol. 2023 Jan 23:e0136322. doi: 10.1128/jvi.01363-22. Online ahead of print.ABSTRACTViral infections alter host cell metabolism and homeostasis; however, the mechanisms that regulate these processes have only begun to be elucidated. We report here that Zika virus (ZIKV) infection activates the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2), which precedes oxidative stress. Downregulation of Nrf2 or inhibition of glutathione (GSH) synthesis resulted in significantly increased viral replication. Interestingly, 6-amino-nicotinamide (6-AN), a nicotinamide analog commonly used as an inhibitor of the pentose phosphate pathway (PPP), decreased viral replication by over 1,000-fold. This inhibition was neither recapitulated by the knockdown of PPP enzymes, glucose 6-phosphate dehydrogenase (G6PD), or 6-phosphogluconate dehydrogenase (6PGD), nor prevented by supplementation with ribose 5-phosphate. Instead, our metabolomics and metabolic phenotype studies support a mechanism in which 6-AN depletes cells of NAD(H) and impairs NAD(H)-dependent glycolytic steps resulting in inhibition of viral replication. The inhibitory effect of 6-AN was rescued with precursors of the salvage pathway but not with those of other NAD+ biosynthesis pathways. Inhibition of glycolysis reduced viral protein levels, which were recovered transiently. This transient recovery in viral protein synthesis was prevented when oxidative metabolism was inhibited by blockage of the mitochondrial pyruvate carrier, fatty acid oxidation, or glutaminolysis, demonstrating a compensatory role of mitochondrial metabolism in ZIKV replication. These results establish an antagonistic role for the host cell Nrf2/GSH/NADPH-dependent antioxidant response against ZIKV and demonstrate the dependency of ZIKV replication on NAD(H). Importantly, our work suggests the potential use of NAD(H) antimetabolite therapy against the viral infection. IMPORTANCE Zika virus (ZIKV) is a major public health concern of international proportions. While the incidence of ZIKV infections has declined substantially in recent years, the potential for the reemergence or reintroduction remains high. Although viral infection alters host cell metabolism and homeostasis to promote its replication, deciphering the mechanism(s) involved in these processes is important for identifying therapeutic targets. The present work reveals the complexities of host cell redox regulation and metabolic dependency of ZIKV replication. An antagonistic effect of the Nrf2/GSH/NADP(H)-dependent antioxidant response against ZIKV infection and an essential role of NAD(H) metabolism and glycolysis for viral replication are established for the first time. These findings highlight the potential use of NAD(H) antimetabolites to counter ZIKV infection and pathogenesis.PMID:36688653 | DOI:10.1128/jvi.01363-22

J Proteome Res. 2023 Jan 23. doi: 10.1021/acs.jproteome.2c00632. Online ahead of print.ABSTRACTspectrum_utils is a Python package for mass spectrometry data processing and visualization. Since its introduction, spectrum_utils has grown into a fundamental software solution that powers various applications in proteomics and metabolomics, ranging from spectrum preprocessing prior to spectrum identification and machine learning applications to spectrum plotting from online data repositories and assisting data analysis tasks for dozens of other projects. Here, we present updates to spectrum_utils, which include new functionality to integrate mass spectrometry community data standards, enhanced mass spectral data processing, and unified mass spectral data visualization in Python. spectrum_utils is freely available as open source at https://github.com/bittremieux/spectrum_utils.PMID:36688502 | DOI:10.1021/acs.jproteome.2c00632

Nutr Cancer. 2023 Jan 23:1-14. doi: 10.1080/01635581.2023.2165692. Online ahead of print.ABSTRACTEpidemiologic studies of diabetic patients treated with metformin identified significantly lower incidences of cancer. From this, there is growing interest in the use of metformin to treat and prevent cancer. Studies have investigated chemopreventive mechanisms including alterations in calorie intake, cancer metabolism, and cell signaling. Repurposing the drug is challenging due to its metabolic effects and non-uniform effects on different types of cancer. In our previously published studies, we observed that benzo[a]pyrene treated mice receiving metformin significantly reduced lung adenomas; however, mice had reduced weight gain. In this study, we compared chemoprevention diets with and without metformin to evaluate the effects of diet vs. effects of metformin. We also performed tandem mass spectrometry on mouse serum to assess metabolomic alterations associated with metformin treatment. In metformin cohorts, the rate of weight gain was reduced, but weights did not vary between diets. There was no weight difference between diets without metformin. Interestingly, caloric intake was increased in metformin treated mice. Metabolomic analysis revealed metabolite alterations consistent with metformin treatment. Based on these results, we conclude that previous reductions in lung adenomas may have been occurred from anticancer effects of metformin rather than a potentially toxic effect such as calorie restriction.PMID:36688306 | DOI:10.1080/01635581.2023.2165692

Front Aging Neurosci. 2023 Jan 5;14:1105019. doi: 10.3389/fnagi.2022.1105019. eCollection 2022.ABSTRACTAIM: There is increasing evidence suggesting that vitamins may play important roles in the pathogenesis of multiple system atrophy (MSA). The purpose of this study was to detect the changes of serum vitamin levels and investigate their correlation with disease severity in MSA patients.METHODS: In this cross-sectional study, 244 MSA patients, 200 Parkinson's disease (PD) patients and 244 age-gender matched healthy controls were recruited. Serum vitamin levels were measured, including vitamin A, B1, B2, B9 (folate), B12, C, D, and E. Relevant clinical scales were used to assess the disease severity of MSA patients.RESULTS: Compared with the healthy controls, decreased serum folate levels and increased serum vitamin A and C levels were detected in MSA patients. Similar differences were also observed in the gender-based subgroup analysis. There were no differences detected between MSA and PD patients. In MSA patients, significant correlation was found between vitamin A, folate, or vitamin C and relevant clinical scales or laboratory findings. In addition, ROC analysis showed potential diagnostic value of the combination of vitamin A, folate, and vitamin C in distinguishing MSA patients from healthy controls.CONCLUSION: There were significant changes in the blood vitamin spectrums of MSA patients, suggesting that dysregulation of vitamins homeostasis might play an important role in the pathogenesis of MSA.PMID:36688152 | PMC:PMC9849558 | DOI:10.3389/fnagi.2022.1105019

Front Aging Neurosci. 2023 Jan 6;14:1059017. doi: 10.3389/fnagi.2022.1059017. eCollection 2022.ABSTRACTWith age the apolipoprotein E (APOE) E4 allele (involved in lipid homeostasis) is associated with perturbation of bioenergetics pathways in Alzheimer's disease (AD). We therefore hypothesized that in aging mice APOE genotype would affect the L-carnitine system (central to lipid bioenergetics), in the brain and in the periphery. Using liquid chromatography-mass spectrometry, levels of L-carnitine and associated metabolites: γ-butyrobetaine (GBB), crotonobetaine, as well as acylcarnitines, were evaluated at 10-, 25-, and 50-weeks, in the brain and the periphery, in a targeted replacement mouse model of human APOE (APOE-TR). Aged APOE-TR mice were also orally administered 125 mg/kg of L-carnitine daily for 7 days followed by evaluation of brain, liver, and plasma L-carnitine system metabolites. Compared to E4-TR, an age-dependent increase among E2- and E3-TR mice was detected for medium- and long-chain acylcarnitines (MCA and LCA, respectively) within the cerebrovasculature and brain parenchyma. While following L-carnitine oral challenge, E4-TR mice had higher increases in the L-carnitine metabolites, GBB and crotonobetaine in the brain and a reduction of plasma to brain total acylcarnitine ratios compared to other genotypes. These studies suggest that with aging, the presence of the E4 allele may contribute to alterations in the L-carnitine bioenergetic system and to the generation of L-carnitine metabolites that could have detrimental effects on the vascular system. Collectively the E4 allele and aging may therefore contribute to AD pathogenesis through aging-related lipid bioenergetics as well as cerebrovascular dysfunctions.PMID:36688151 | PMC:PMC9853982 | DOI:10.3389/fnagi.2022.1059017

Front Med Technol. 2023 Jan 4;4:1065506. doi: 10.3389/fmedt.2022.1065506. eCollection 2022.ABSTRACTHepatocellular carcinoma (HCC) remains a global health burden, and is mostly diagnosed at late and advanced stages. Currently, limited and insensitive diagnostic modalities continue to be the bottleneck of effective and tailored therapy for HCC patients. Moreover, the complex reprogramming of metabolic patterns during HCC initiation and progression has been obstructing the precision medicine in clinical practice. As a noninvasive and global screening approach, metabolomics serves as a powerful tool to dynamically monitor metabolic patterns and identify promising metabolite biomarkers, therefore holds a great potential for the development of tailored therapy for HCC patients. In this review, we summarize the recent advances in HCC metabolomics studies, including metabolic alterations associated with HCC progression, as well as novel metabolite biomarkers for HCC diagnosis, monitor, and prognostic evaluation. Moreover, we highlight the application of multi-omics strategies containing metabolomics in biomarker discovery for HCC. Notably, we also discuss the opportunities and challenges of metabolomics in nowadays HCC precision medicine. As technologies improving and metabolite biomarkers discovering, metabolomics has made a major step toward more timely and effective precision medicine for HCC patients.PMID:36688143 | PMC:PMC9845953 | DOI:10.3389/fmedt.2022.1065506

Front Nutr. 2023 Jan 4;9:945356. doi: 10.3389/fnut.2022.945356. eCollection 2022.ABSTRACTINTRODUCTION: Parkinson's disease is a neurodegenerative disorder involving loss of dopaminergic neurons. Multiple studies implicate the microbiota-gut-brain axis in Parkinson's disease pathophysiology. Ping-wei-san plus Herbal Decoction, a traditional Chinese medicine composition with beneficial effects in Parkinson's disease, may have a complex array of actions. Here we sought to determine whether gut microbiota and metabolic pathways are involved in Ping-wei-san plus herbal therapy for Parkinson's disease and to identify functional pathways to guide research.METHODS AND RESULTS: The model of Parkinson's disease were induced with the rotenone. The Ping-wei-san plus group received the PWP herbal decoction for 90 days, after which all groups were analyzed experimentally. PWP herbal treatment improved motor behavior and emotional performance, balanced gut microbiota, and benefited dietary metabolism. Tandem Mass Tags mass spectrometry identified many differentially expressed proteins (DEPs) in the substantia nigra and duodenum in the PWP group, and these DEPs were enriched in pathways such as those involving cAMP signaling, glutamatergic synapses, dopaminergic synapses, and ribosome-rich functions in the gut. The PWP group showed increases in recombinant tissue inhibitors of metalloproteinase 3, and nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain containing proteins 6 in the substantia nigra and decreased parkin, gasdermin D, recombinant tissue inhibitors of metalloproteinase 3, and nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing proteins 6 in the duodenum.DISCUSSION: In conclusion, this study combined gut microbiota, metabolomics, and proteomics to evaluate the mechanism of action of Ping-wei-san plus on Parkinson's disease and revealed that PWP herbal treatment modulated gut microbiota, altered metabolite biological pathways, and affected functional pathway protein expression in Parkinson's disease mice, resulting in therapeutic effects.PMID:36687704 | PMC:PMC9845696 | DOI:10.3389/fnut.2022.945356

Front Nutr. 2023 Jan 6;9:1079325. doi: 10.3389/fnut.2022.1079325. eCollection 2022.ABSTRACTINTRODUCTION: Harvest time represents one of the crucial factors concerning the quality of alpine green tea. At present, the mechanisms of the tea quality changing with harvest time have been unrevealed.METHODS: In the current study, fresh tea leaves (qmlc and gylc) and processed leaves (qmgc and gygc) picked during Qingming Festival and Guyu Festival were analyzed by means of sensory evaluation, metabolomics, transcriptomic analysis, and high-throughput sequencing, as well as their endophytic bacteria (qm16s and gy16s).RESULTS: The results indicated qmgc possessed higher sensory quality than gygc which reflected from higher relative contents of amino acids, and soluble sugars but lower relative contents of catechins, theaflavins, and flavonols. These differential metabolites created features of light green color, prominent freshness, sweet aftertaste, and mild bitterness for qmgc.DISCUSSION: Flavone and flavonol biosynthesis and phenylalanine metabolism were uncovered as the key pathways to differentiate the quality of qmgc and gygc. Endophytic bacteria in leaves further influence the quality by regulating the growth of tea trees and enhancing their disease resistance. Our findings threw some new clues on the tea leaves picking to pursue the balance when facing the conflicts of product quality and economic benefits.PMID:36687681 | PMC:PMC9854344 | DOI:10.3389/fnut.2022.1079325

Front Microbiol. 2023 Jan 6;13:1084010. doi: 10.3389/fmicb.2022.1084010. eCollection 2022.ABSTRACTRoot-knot nematodes especially Meloidogyne spp. are considered as most destructive obligate parasites that substantially reduce crop yield and quality. Fosthiazate is an efficient organothiophosphate chemical with nematicidal activity against Meloidogyne spp. The present study aimed to analyze the efficacy of fosthiazate against root-knot disease in Cucumis melo var. saccharinus and its potential effects on rhizosphere microbiome and metabolites. The fosthiazate (40%) was applied two times by spraying on the day of transplanting and during the pollination period (after 31 days). Samples from treatment (fosthiazate 40%: MF) and control groups (untreated plants; MCK) were analysed through metagenomic and metabolomic profiling of rhizospheres. Results revealed that root-knot index of the MF group (9.26 ± 1.28) was significantly (p < 0.05) lower than the MCK group (22.06 ± 0.71) with a control effect of 57.85% after 31 days of the first spray, whereas fosthiazate efficacy reduced to 31.87% after 38 days of second application with significantly (p < 0.05) different root-knot index values (MF: 56 ± 1.43 and; MCK: 82.26 ± 3.87). However, Cucumis melo var. saccharinus fruit yield in both groups (MCK: 21.1 ± 0.9 and MF: 21.53 ± 0.85) showed no differences (p > 0.05). Metagenomic profiling revealed Proteobacteria, Acidobacteriota, and Firmicutes as predominant phyla and Bacillus, Sphingomonas, and Acidibacter as predominant genera in rhizosphere soil samples of both MF and MCK groups. Further, a t-test revealed higher differential enrichment of Firmicutes at phylum level and Bacillus at genus level in MF than MCK. Metabolomic profiling of rhizospheric soil revealed a total of six differential metabolites (p < 0.05), four of them (Sucrose, Hexaonic acid 1, (Z)-9-Octadecenamide 1, and Hexadecanamide) were up-regulated in MF group, whereas two of them (2,3,4-Trihydroxy-3-(Hydroxymethyl) Butanol and Sulfurous acid, 2, ethylhexylundecyl ester) were down-regulated in CK group. Our study concluded that fosthiazate exhibits a better control over the rook-knot disease in the short term and resulted in trackable changes in rhizosphere microbiome and metabolome.PMID:36687623 | PMC:PMC9853079 | DOI:10.3389/fmicb.2022.1084010

Front Microbiol. 2023 Jan 4;13:1068825. doi: 10.3389/fmicb.2022.1068825. eCollection 2022.ABSTRACTBACKGROUND: Growing evidence suggests the gut microbiota and metabolites in serum or fecal may play a key role in the process of alcohol use disorder (AUD). However, the correlations of gut microbiota and metabolites in both feces and serum in AUD subjects are not well understood.METHODS: We established a rat model of AUD by a chronic intermittent ethanol voluntary drinking procedure, then the AUD syndromes, the gut microbiota, metabolomic profiling in feces and serum of the rats were examined, and correlations between gut microbiota and metabolites were analyzed.RESULTS: Ethanol intake preference increased and maintained at a high level in experimental rats. Anxiety-like behaviors was observed by open field test and elevated plus maze test after ethanol withdraw, indicating that the AUD rat model was successfully developed. The full length 16S rRNA gene sequencing showed AUD significantly changed the β-diversity of gut microbial communities, and significantly decreased the microbial diversity but did not distinctly impact the microbial richness. Microbiota composition significantly changed in AUD rats, such as the abundance of Romboutsia and Turicibacter were significantly increased, whereas uncultured_bacterium_o_Mollicutes_RF39 was decreased. In addition, the untargeted metabolome analysis revealed that many metabolites in both feces and serum were altered in the AUD rats, especially involved in sphingolipid metabolism and glycerophospholipid metabolism pathways. Finally, multiple correlations among AUD behavior, gut microbiota and co-changed metabolites were identified, and the metabolites were directly correlated with the gut microbiota and alcohol preference.CONCLUSION: The altered metabolites in feces and serum are important links between the gut microbiota dysbiosis and alcohol preference in AUD rats, and the altered gut microbiota and metabolites can be potentially new targets for treating AUD.PMID:36687619 | PMC:PMC9846065 | DOI:10.3389/fmicb.2022.1068825

Front Microbiol. 2023 Jan 6;13:1076675. doi: 10.3389/fmicb.2022.1076675. eCollection 2022.ABSTRACTINTRODUCTION: Black Tibetan sheep is one of the primitive sheep breeds in China that is famous for its great eating quality and nutrient value but with little attention to the relationship between feeding regimes and rumen metabolome along with its impact on the muscle metabolism and meat quality.METHODS: This study applies metabolomics-based analyses of muscles and 16S rDNA-based sequencing of rumen fluid to examine how feeding regimes influence the composition of rumen microbiota, muscle metabolism and ultimately the quality of meat from Black Tibetan sheep. Twenty-seven rams were randomly assigned to either indoor feeding conditions (SG, n = 9), pasture grazing with indoor feeding conditions (BG, n = 9) or pasture grazing conditions (CG, n = 9) for 120 days.RESULTS: The results showed that, compared with BG and CG, SG improved the quality of Black Tibetan sheep mutton by preventing a decline in pH and increasing fat deposition to enhance the color, tenderness and water holding capacity (WHC) of the Longissimus lumborum (LL). Metabolomics and correlation analyses further indicated that the feeding regimes primarily altered amino acid, lipid and carbohydrate metabolism in muscles, thereby influencing the amino acid (AA) and fatty acid (FA) levels as well as the color, tenderness and WHC of the LL. Furthermore, SG increased the abundance of Christensenellaceae R-7 group, [Eubacterium] coprostanoligenes group, Methanobrevibacter, Ruminococcus 2 and Quinella, decreased the abundance of Lactobacillus, Prevotella 1 and Rikenellaceae RC9 gut group, and showed a tendency to decrease the abundance of Succinivibrio and Selenomonas 1. Interestingly, all of these microorganisms participated in the deposition of AAs and FAs and modified the levels of different metabolites involved in the regulation of meat quality (maltotriose, pyruvate, L-ascorbic acid, chenodeoxycholate, D-glucose 6-phosphate, glutathione, etc.).DISCUSSION: Overall, the results suggest that feeding Black Tibetan sheep indoors with composite forage diet was beneficial to improve the mouthfeel of meat, its color and its nutritional value by altering the abundance of rumen bacteria which influenced muscle metabolism.PMID:36687606 | PMC:PMC9854131 | DOI:10.3389/fmicb.2022.1076675

Front Microbiol. 2023 Jan 4;13:1112456. doi: 10.3389/fmicb.2022.1112456. eCollection 2022.NO ABSTRACTPMID:36687589 | PMC:PMC9846801 | DOI:10.3389/fmicb.2022.1112456

Front Cell Neurosci. 2023 Jan 4;16:1057887. doi: 10.3389/fncel.2022.1057887. eCollection 2022.ABSTRACTDeep brain stimulation (DBS) of the nucleus accumbens (NAc) (NAc-DBS) is an effective solution to refractory obsessive-compulsive disorder (OCD). However, evidence for the neurobiological mechanisms of OCD and the effect of NAc-DBS is still lacking. One hypothesis is that the electrophysiological activities in the NAc are modulated by DBS, and another hypothesis is that the activities of neurotransmitters in the NAc are influenced by DBS. To investigate these potential alterations, rats with quinpirole (QNP)- induced OCD were treated with DBS of the core part of NAc. Then, extracellular spikes (SPK) and local field potentials (LFP) in the NAc were recorded, and the levels of relevant neurotransmitters and related proteins were measured. Analysis of SPK revealed that the firing rate was decreased and the firing pattern was changed after NAc-DBS, and analysis of LFP showed that overall power spectral density (PSD) levels were reduced after NAc-DBS. Additionally, we found that the relative powers of the theta band, alpha band and beta band were increased in OCD status, while the relative powers of the delta band and gamma band were decreased. This pathological pattern of power distribution was reformed by NAc-DBS. Furthermore, we found that the local levels of monoamines [dopamine (DA) and serotonin (5-HT)] and amino acids [glutamate (Glu) and gamma-aminobutyric acid (GABA)] in the NAc were increased in OCD status, and that the expression of the two types of DA receptors in the NAc exhibited an opposite change. These abnormalities could be reversed by NAc-DBS. These findings provide a more comprehensive understanding about the function of the NAc in the pathophysiology of OCD and provide more detailed evidence for the potential effect of NAc-DBS.PMID:36687525 | PMC:PMC9845878 | DOI:10.3389/fncel.2022.1057887

Mediators Inflamm. 2023 Jan 12;2023:6051946. doi: 10.1155/2023/6051946. eCollection 2023.ABSTRACTBased on the multiomics analysis, this study is aimed at investigating the underlying mechanism of didymin against acute liver injury (ALI). The mice were administrated with didymin for 2 weeks, followed by injection with lipopolysaccharide (LPS) plus D-galactosamine (D-Gal) to induce ALI. The pathological examination revealed that didymin significantly ameliorated LPS/D-Gal-induced hepatic damage. Also, it markedly reduced proinflammatory cytokines release by inhibiting the TLR4/NF-κB pathway activation, alleviating inflammatory injury. A transcriptome analysis proved 2680 differently expressed genes (DEGs) between the model and didymin groups and suggested that the PI3K/Akt and metabolic pathways might be the most relevant targets. Meanwhile, the metabolome analysis revealed 67 differently expressed metabolites (DEMs) between the didymin and model groups that were mainly clustered into the glycerophospholipid metabolism, which was consistent with the transcriptome study. Importantly, a comprehensive analysis of both the omics indicated a strong correlation between the DEGs and DEMs, and an in-depth study demonstrated that didymin alleviated metabolic disorder and hepatocyte injury likely by inhibiting the glycerophospholipid metabolism pathway through the regulation of PLA2G4B, LPCAT3, and CEPT1 expression. In conclusion, this study demonstrates that didymin can ameliorate LPS/D-Gal-induced ALI by inhibiting the glycerophospholipid metabolism and PI3K/Akt and TLR4/NF-κB pathways.PMID:36687218 | PMC:PMC9851790 | DOI:10.1155/2023/6051946

Exposome. 2023 Jan 5;3(1):osac011. doi: 10.1093/exposome/osac011. eCollection 2023.ABSTRACTPrimary sclerosing cholangitis (PSC) is a complex bile duct disorder. Its etiology is incompletely understood, but environmental chemicals likely contribute to risk. Patients with PSC have an altered bile metabolome, which may be influenced by environmental chemicals. This novel study utilized state-of-the-art high-resolution mass spectrometry (HRMS) with bile samples to provide the first characterization of environmental chemicals and metabolomics (collectively, the exposome) in PSC patients located in the United States of America (USA) (n = 24) and Norway (n = 30). First, environmental chemical- and metabolome-wide association studies were conducted to assess geographic-based similarities and differences in the bile of PSC patients. Nine environmental chemicals (false discovery rate, FDR < 0.20) and 3143 metabolic features (FDR < 0.05) differed by site. Next, pathway analysis was performed to identify metabolomic pathways that were similarly and differentially enriched by the site. Fifteen pathways were differentially enriched (P < .05) in the categories of amino acid, glycan, carbohydrate, energy, and vitamin/cofactor metabolism. Finally, chemicals and pathways were integrated to derive exposure-effect correlation networks by site. These networks demonstrate the shared and differential chemical-metabolome associations by site and highlight important pathways that are likely relevant to PSC. The USA patients demonstrated higher environmental chemical bile content and increased associations between chemicals and metabolic pathways than those in Norway. Polychlorinated biphenyl (PCB)-118 and PCB-101 were identified as chemicals of interest for additional investigation in PSC given broad associations with metabolomic pathways in both the USA and Norway patients. Associated pathways include glycan degradation pathways, which play a key role in microbiome regulation and thus may be implicated in PSC pathophysiology.PMID:36687160 | PMC:PMC9853141 | DOI:10.1093/exposome/osac011

ACS Omega. 2023 Jan 5;8(2):2306-2314. doi: 10.1021/acsomega.2c06625. eCollection 2023 Jan 17.ABSTRACTThe extract of Tribulus terrestris (TT) has been used as a component of several nutritional supplements for enhancing human vitality. However, its protective effect on ischemic stroke has yet to be fully investigated. In this study, the middle cerebral artery occlusion (MCAO) rat model was established and treated with gross saponin of TT fruit (GSTTF) by gavage to explore its anti-ischemic stroke efficacy. Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was applied to profile the brain tissue metabolite changes and further obtain the metabolic pathways that were greatly involved in the efficacy of GSTTF. Subsequent molecular biology experiments were applied to validate the findings from metabolomics analysis. The results showed that GSTTF administration remarkably decreased the infarction volume of brain tissue and improved the neurobehavioral scores of MCAO rats. Metabolomics analysis revealed that pathways, including glycerophospholipid metabolism, sphingolipid metabolism, and arachidonic acid metabolism, were considered associated with the protective effect of GSTTF against MCAO, which were greatly involved in the inflammatory responses. The results of the biochemistry analysis showed that GSTTF treatment significantly reduced the levels of TNF-α and IL-6 in brain tissue after MCAO. The anti-inflammatory mechanism of GSTTF was further investigated, which revealed that GSTTF could inhibit the TLR4/MyD88/NF-κB signaling pathway to exert protective effects on MCAO. This study provides the underlying anti-inflammatory mechanism of GSTTF for ischemic stroke protection, which has important implications for the development of GSTTF-related functional foods or food supplements.PMID:36687021 | PMC:PMC9851020 | DOI:10.1021/acsomega.2c06625

Front Oncol. 2023 Jan 6;12:1054233. doi: 10.3389/fonc.2022.1054233. eCollection 2022.ABSTRACTResistance to drug treatment is a critical barrier in cancer therapy. There is an unmet need to explore cancer hallmarks that can be targeted to overcome this resistance for therapeutic gain. Over time, metabolic reprogramming has been recognised as one hallmark that can be used to prevent therapeutic resistance. With the advent of metabolomics, targeting metabolic alterations in cancer cells and host patients represents an emerging therapeutic strategy for overcoming cancer drug resistance. Driven by technological and methodological advances in mass spectrometry imaging, spatial metabolomics involves the profiling of all the metabolites (metabolomics) so that the spatial information is captured bona fide within the sample. Spatial metabolomics offers an opportunity to demonstrate the drug-resistant tumor profile with metabolic heterogeneity, and also poses a data-mining challenge to reveal meaningful insights from high-dimensional spatial information. In this review, we discuss the latest progress, with the focus on currently available bulk, single-cell and spatial metabolomics technologies and their successful applications in pre-clinical and translational studies on cancer drug resistance. We provide a summary of metabolic mechanisms underlying cancer drug resistance from different aspects; these include the Warburg effect, altered amino acid/lipid/drug metabolism, generation of drug-resistant cancer stem cells, and immunosuppressive metabolism. Furthermore, we propose solutions describing how to overcome cancer drug resistance; these include early detection during cancer initiation, monitoring of clinical drug response, novel anticancer drug and target metabolism, immunotherapy, and the emergence of spatial metabolomics. We conclude by describing the perspectives on how spatial omics approaches (integrating spatial metabolomics) could be further developed to improve the management of drug resistance in cancer patients.PMID:36686803 | PMC:PMC9854130 | DOI:10.3389/fonc.2022.1054233

Front Oncol. 2023 Jan 4;12:959454. doi: 10.3389/fonc.2022.959454. eCollection 2022.ABSTRACTBACKGROUND: Breast cancer (BC) has recently become the most prevalent malignancy in women. There are many alternative treatments for BC, and for aesthetic and postoperative quality of life concerns, breast-conserving surgery and corresponding adjuvant therapy have become the predominant treatment for early invasive BC. Currently, the main method used to assess the margins for breast-conserving surgery is intraoperative pathological diagnosis. However, the designation of surgical margins is controversial, and metabolomics may be a novel approach to evaluate surgical margins.METHODS: We collected specimens from 10 breast cancer patients and samples from its surrounding tissues and divided them into cancerous tissue and 1 mm, 2 mm, 3 mm, 5 mm and 10 mm cutting edge tissues, with a total of 60 samples. The samples were analyzed by mass spectrometry on an ultra-performance liquid chromatography-quadrupole/Orbitrap high resolution platform. The data were then statistically analyzed to detect metabolic changes in the different cutting edges and to identify possible surgical cutting edges with statistically significant findings. Abnormal metabolic pathways were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG), which elucidated potential markers.RESULTS: Statistical analysis indicated that there were substantial differences between the 1 mm margin tissue and the cancer tissue, while there were no statistically significant differences between the 1 mm tissue and tissues from the other margins. The levels of 6 metabolites in the 1 mm tissue were significantly different from those in the cancer tissue and were not significantly different from those in the 2 mm tissue. The six metabolites were pyruvate, N-acetyl-L-aspartate, glutamic acid, γ-aminobutyric acid, fumaric acid, and citric acid. Metabolic pathways such as amino acid metabolism and amino t-RNA synthesis in the margin tissue were significantly distinct from those in cancer tissues based on KEGG analysis.CONCLUSION: There was a significant difference between the 1 mm margin tissue and the cancerous tissue. Based on metabolomic analysis, the 1 mm negative margin is sufficient for surgery, and the six metabolites that we identified as abnormal, including pyruvic acid, N-acetyl-L-aspartic acid, glutamic acid, gamma-aminobutyric acid, fumaric acid and citric acid, may serve as biomarkers for a negative margin and help surgeons select an appropriate surgical margin.PMID:36686765 | PMC:PMC9846322 | DOI:10.3389/fonc.2022.959454

Front Pharmacol. 2023 Jan 5;13:1104280. doi: 10.3389/fphar.2022.1104280. eCollection 2022.ABSTRACTAcute respiratory distress syndrome (ARDS) is an acute and diffuse pulmonary inflammation, characterized by severe hypoxic respiratory failure caused by inflammatory tissue damage, which is a common cause of respiratory failure. Currently, there is no treatment available that can prevent or reverse the devastating effects caused by these conditions. The purpose of this study was to determine the effects of WRS on gut microbiota and the potential effect of gut microbiota on the treatment of lung disease by using a staphylococcal enterotoxin B (SEB)-induced ARDS model. The results showed that WRS could significantly reduce the pathological damage to lung and colon tissues and improve the lung and intestinal functions of ARDS mice. WRS was able to improve the level of cytokines in serum and lung tissue. Additionally, WRS could reverse the gut microbiota dysbiosis caused by SEB in ARDS mice. WRS increases the production of short-chain fatty acids (SCFAs) in the gut. This increase in SCFAs may lead to increased migration of SCFAs to the lungs and activation of free fatty acid receptors (FFAR) three and FFAR2 in lung epithelial cells, alleviating the symptoms of ARDS. Interestingly, WRS improves the faecal metabolite profiles in SEB-induced ARDS mice via tryptophan metabolism. On the basis of the component-target-metabolism strategy, baicalin, oroxylin A-7-O-glucuronide and skullcapflavon II were identified as the potential bioactive markers in WRS for the treatment of ARDS. Our study showed that WRS could ameliorate SEB-induced ARDS by regulating the structure of gut microbiota, increasing the production of SCFAs and modifying the faecal metabolite profiles through the lung-gut axis, and providing alternative treatment strategies for lung disease.PMID:36686672 | PMC:PMC9849372 | DOI:10.3389/fphar.2022.1104280