PubMed

J Oncol. 2023 Feb 14;2023:3591758. doi: 10.1155/2023/3591758. eCollection 2023.ABSTRACTOBJECTIVES: Indoleamine 2,3-dioxygenase 1 (IDO1) acts as the key rate-limiting enzyme that converts tryptophan (Trp) to kynurenine (Kyn). Its activity was primarily induced by interferon-γ (IFN-γ), which was reported to play a role in the development of acute radiation-induced pneumonitis. In this study, we aimed to investigate the correlation between IDO1 activity and radiation-induced lung toxicity (RILT) in stage III nonsmall cell lung cancer (NSCLC) patients who were treated with chemoradiotherapy (CRT).MATERIALS AND METHODS: Systemic IDO1 activity was reflected by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 stage III NSCLC patients were measured by high-performance liquid chromatography (HPLC) before the initiation of radiotherapy. Dynamic change of IDO1 activity was followed in 23 patients before, during, and after radiotherapy. We also used RNA sequencing (RNA-seq) data from the Cancer Genome Atlas Program (TCGA) database and performed gene set enrichment analysis (GSEA) to explore how IDO1 was involved in the development of RILT.RESULTS: 9.7% (11/113) of the whole group developed G3+ (greater than or equal to Grade 3) RILT. Preradiation IDO1 activity was significantly higher in patients who developed G3 + RILT than in nonG3 + RILT patients. (P = 0.029, AUC = 0.70). Univariate and multivariate analyses showed that high IDO1 activity was independently associated with the risk of G3 + RILT (P = 0.034). A predictive model combining both IDO1 activity and FEV1 was established for severe RILT and displayed a moderate predictive value (AUC = 0.83, P < 0.001). The incidence of G3 + RILT was 2.6% (1/38) in patients with an IDO activity ≤0.069 and FEV1 > 59.4%, and 50.0% (6/12) in those with an IDO activity >0.069 and FEV1 ≤ 59.4%. Of 23 patients with dynamic tracking, the IDO1 activity of postradiation was significantly lower than midradiation (P = 0.021), though no significant differences among the three time points were observed (P = 0.070). Bioinformatic analysis using RNA-seq data from 1014 NSCLC patients revealed that IDO mainly functioned in the inflammatory response instead of the late fibrosis process in NSCLC patients.CONCLUSION: High baseline IDO1 activity combined with unfavorable baseline FEV1 was predictive of severe RILT in unresectable stage III NSCLC patients. IDO1 might play a role in the acute inflammatory response. Finding effective interventions to alleviate RILT using IDO inhibitors is warranted in the future.PMID:36824664 | PMC:PMC9943611 | DOI:10.1155/2023/3591758

iScience. 2023 Jan 13;26(2):105965. doi: 10.1016/j.isci.2023.105965. eCollection 2023 Feb 17.ABSTRACTDespite the knowledge that protein translation and various metabolic reactions that create and sustain cellular life occur in the cytoplasm, the structural organization within the cytoplasm remains unclear. Recent models indicate that cytoplasm contains viscous fluid and elastic solid phases. We separated these viscous fluid and solid elastic compartments, which we call the cytosol and cytomatrix, respectively. The distinctive composition of the cytomatrix included structural proteins, ribosomes, and metabolome enzymes. High-throughput analysis revealed unique biosynthetic pathways within the cytomatrix. Enrichment of biosynthetic pathways in the cytomatrix indicated the presence of immobilized biocatalysis. Enzymatic immobilization and segregation can surmount spatial impediments, and the local pathway segregation may form cytoplasmic organelles. Protein translation was reprogrammed within the cytomatrix under the restriction of protein synthesis by drug treatment. The cytosol and cytomatrix are an elaborately interconnected network that promotes operational flexibility in healthy cells and the survival of malignant cells.PMID:36824274 | PMC:PMC9941065 | DOI:10.1016/j.isci.2023.105965

Front Nutr. 2023 Feb 7;10:1112497. doi: 10.3389/fnut.2023.1112497. eCollection 2023.ABSTRACTColored wheat has been recognized broadly for its nutritional value because of its natural content of the colorant anthocyanin. To investigate the reasons for the formation of the wheat grain color at maturity, metabolomic and transcriptomic analyses were performed on three different grain colors of wheat. Through metabolome analysis, 628 metabolites were identified. Of the 102 flavonoids, there are 9 kinds of anthocyanins related to color formation, mainly cyanidin and peonidin, and their metabolite content was the lowest in white-grain wheat. Among the genes associated with color formation, the structural gene TraesCS2D02G392900 in F3H with the bHLH transcription factor could elucidate the origin of wheat coloration. Multi-omics analysis showed that color formation is mainly influenced by the regulation of genes affecting anthocyanin and related synthesis. The results of this study may provide a theoretical basis for grain color formation at maturity and the nutritional and product development potential of colored wheat lines.PMID:36824168 | PMC:PMC9941320 | DOI:10.3389/fnut.2023.1112497

Allergy. 2023 Feb 23. doi: 10.1111/all.15690. Online ahead of print.ABSTRACTINTRODUCTION: Topical corticosteroids (TCS), used to treat atopic dermatitis (AD), have been associated with type 2 diabetes and osteoporosis in epidemiological studies, possibly explained by systemic absorption.OBJECTIVES: We examined whether intensive daily whole-body TCS treatment over two weeks followed by twice weekly application for four weeks could elicit insulin resistance and increase bone resorption in adults with AD.METHODS: A randomized parallel-group double-blind double-dummy non-corticosteroid-based active-comparator study design was completed in Copenhagen, Denmark. Thirty-six non-obese, non-diabetic adults with moderate-to-severe AD were randomized to whole-body treatment with betamethasone 17-valerate 0.1% plus a vehicle once daily or tacrolimus 0.1% twice daily after washout. Insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp combined with tracer infusions and biomarkers of bone formation (P1NP) and resorption (CTX) were evaluated at baseline, after two weeks of daily treatment and after further four weeks of twice-weekly maintenance treatment.RESULTS: AD severity improved with both treatments and systemic inflammation was reduced. After two weeks, we observed similar increase in peripheral insulin sensitivity with use of betamethasone (n=18) and tacrolimus (n=18). Bone resorption biomarker, CTX, was unchanged, while bone formation marker, P1NP, decreased after betamethasone treatment after both two and six weeks but remained unchanged in the tacrolimus arm.CONCLUSIONS: Whole-body treatment with TCS leads to systemic exposure but appears not to compromise glucose metabolism during short-term use, which may be a result of reduced systemic inflammatory activity. The negative impact on bone formation could be regarded an adverse effect of TCS.PMID:36824052 | DOI:10.1111/all.15690

BMC Cancer. 2023 Feb 23;23(1):183. doi: 10.1186/s12885-023-10656-1.ABSTRACTBACKGROUND: Breast cancer survivors face long-term sequelae compared to the general population, suggesting altered metabolic profiles after breast cancer. We used metabolomics approaches to investigate the metabolic differences between breast cancer patients and women in the general population, aiming to elaborate metabolic changes among breast cancer patients and identify potential targets for clinical interventions to mitigate long-term sequelae.METHODS: Serum samples were retrieved from 125 breast cancer cases recruited from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), and 125 healthy controls selected from Chicago Multiethnic Prevention and Surveillance Study (COMPASS). We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares discriminant analysis (PLS-DA) combined with fold change to select metabolic features associated with breast cancer. Pathway analyses were conducted using Mummichog to identify differentially enriched metabolic pathways among cancer patients. As potential confounders we included age, marital status, tobacco smoking, alcohol drinking, type 2 diabetes, and area deprivation index in our model. Random effects of residence for intercept was also included in the model. We further conducted subgroup analysis by treatment timing (chemotherapy/radiotherapy/surgery), lymph node status, and cancer stages.RESULTS: The entire study participants were African American. The average ages were 57.1 for cases and 58.0 for controls. We extracted 15,829 features in total, among which 507 features were eventually selected by our criteria. Pathway enrichment analysis of these 507 features identified three differentially enriched metabolic pathways related to prostaglandin, leukotriene, and glycerophospholipid. The three pathways demonstrated inconsistent patterns. Metabolic features in the prostaglandin and leukotriene pathways exhibited increased abundances among cancer patients. In contrast, metabolic intensity in the glycerolphospholipid pathway was deregulated among cancer patients. Subgroup analysis yielded consistent results. However, changes in these pathways were strengthened when only using cases with positive lymph nodes, and attenuated when only using cases with stage I disease.CONCLUSION: Breast cancer in African American women is associated with increase in serum metabolites involved in prostaglandin and leukotriene pathways, but with decrease in serum metabolites in glycerolphospholipid pathway. Positive lymph nodes and advanced cancer stage may strengthen changes in these pathways.PMID:36823587 | DOI:10.1186/s12885-023-10656-1

Arch Microbiol. 2023 Feb 24;205(3):97. doi: 10.1007/s00203-023-03439-6.ABSTRACTFor different breeds of dogs with acute diarrhea, the gut microbiota and metabolome profiles are unclear. This prospective observational study analyzed the gut microbiomes of poodles with acute diarrhea and Labrador retrievers with acute diarrhea based on 16S amplicon sequencing, with respective healthy dogs as controls. Fecal non-target metabolomics and metagenomics were performed on poodles with acute diarrhea. This study found that the diversity and structure of the microbial community differed significantly between the two breeds in cohorts of healthy dogs. Two breeds of dogs with acute diarrhea demonstrated different changes in microbial communities and metabolic functions. The metabolism of starch and sucrose was significantly decreased in dogs with acute diarrhea, which may be attributed to the reduced activity of dextran dextrinase. Non-targeted metabolomics identified 21 abnormal metabolic pathways exhibited by dogs with acute diarrhea, including starch, amino acid, bile acid metabolism, etc., and were closely related to specific intestinal flora. This study provided new insights into breed specificity and the development of dietary treatment strategy in canine gastrointestinal disease.PMID:36823480 | DOI:10.1007/s00203-023-03439-6

Environ Sci Pollut Res Int. 2023 Feb 24. doi: 10.1007/s11356-023-25965-y. Online ahead of print.ABSTRACTThe experiments were conducted in the Tibetan plateau environment, and the sewage treatment conditions were designed with ultraviolet (UV) irradiation for 5 min, 10 min, 30 min, and 180 min. The Illumina MiSeq high-throughput sequencing technology was used to analyze the microbiological and metabolomic patterns of the plateau sewage treatment at the experimental scale, and then the response mechanisms of microbial and nitrogen metabolism in sewage treatment were explored. The abundance of metabolism at the first level and global and overview maps at the second level were higher in the plateau environment than in other regions. The KEGG pathway shows the effect of UV on nitrogen metabolism and its aptitude to improving or inhibit it. The two main nitrogen removal processes are nitrification and dissimilatory nitrate reduction. This study reveals the response of activated sludge to UV radiation in a plateau environment from microbiological and metabolomic perspectives, providing ideas and perspectives for the study of water treatment system methods, as well as laying a valuable theoretical foundation for the enhancement of plateau sewage treatment capacity.PMID:36823464 | DOI:10.1007/s11356-023-25965-y

Nat Med. 2023 Feb 23. doi: 10.1038/s41591-023-02217-7. Online ahead of print.ABSTRACTFor decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its acetylation and inactivation by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we developed a multi-omics workflow combining gut microbiome metagenomics, metatranscriptomics and metabolomics from the longitudinal IBDMDB cohort of 132 controls and patients with IBD. This associated 12 previously uncharacterized microbial acetyltransferases with 5-ASA inactivation, belonging to two protein superfamilies: thiolases and acyl-CoA N-acyltransferases. In vitro characterization of representatives from both families confirmed the ability of these enzymes to acetylate 5-ASA. A cross-sectional analysis within the discovery cohort and subsequent prospective validation within the independent SPARC IBD cohort (n = 208) found three of these microbial thiolases and one acyl-CoA N-acyltransferase to be epidemiologically associated with an increased risk of treatment failure among 5-ASA users. Together, these data address a longstanding challenge in IBD management, outline a method for the discovery of previously uncharacterized gut microbial activities and advance the possibility of microbiome-based personalized medicine.PMID:36823301 | DOI:10.1038/s41591-023-02217-7

Int J Obes (Lond). 2023 Feb 23. doi: 10.1038/s41366-023-01281-w. Online ahead of print.ABSTRACTBACKGROUND/OBJECTIVE: This observational study dissects the complex temporal associations between body-mass index (BMI), waist-hip ratio (WHR) and circulating metabolomics using a combination of longitudinal and cross-sectional population-based datasets and new systems epidemiology tools.SUBJECTS/METHODS: Firstly, a data-driven subgrouping algorithm was employed to simplify high-dimensional metabolic profiling data into a single categorical variable: a self-organizing map (SOM) was created from 174 metabolic measures from cross-sectional surveys (FINRISK, n = 9708, ages 25-74) and a birth cohort (NFBC1966, n = 3117, age 31 at baseline, age 46 at follow-up) and an expert committee defined four subgroups of individuals based on visual inspection of the SOM. Secondly, the subgroups were compared regarding BMI and WHR trajectories in an independent longitudinal dataset: participants of the Young Finns Study (YFS, n = 1286, ages 24-39 at baseline, 10 years follow-up, three visits) were categorized into the four subgroups and subgroup-specific age-dependent trajectories of BMI, WHR and metabolic measures were modelled by linear regression.RESULTS: The four subgroups were characterised at age 39 by high BMI, WHR and dyslipidemia (designated TG-rich); low BMI, WHR and favourable lipids (TG-poor); low lipids in general (Low lipid) and high low-density-lipoprotein cholesterol (High LDL-C). Trajectory modelling of the YFS dataset revealed a dynamic BMI divergence pattern: despite overlapping starting points at age 24, the subgroups diverged in BMI, fasting insulin (three-fold difference at age 49 between TG-rich and TG-poor) and insulin-associated measures such as triglyceride-cholesterol ratio. Trajectories also revealed a WHR progression pattern: despite different starting points at the age of 24 in WHR, LDL-C and cholesterol-associated measures, all subgroups exhibited similar rates of change in these measures, i.e. WHR progression was uniform regardless of the cross-sectional metabolic profile.CONCLUSIONS: Age-associated weight variation in adults between 24 and 49 manifests as temporal divergence in BMI and uniform progression of WHR across metabolic health strata.PMID:36823293 | DOI:10.1038/s41366-023-01281-w

Nat Commun. 2023 Feb 23;14(1):1011. doi: 10.1038/s41467-023-36708-5.ABSTRACTSerine synthesis is crucial for tumor growth and survival, but its regulatory mechanism in cancer remains elusive. Here, using integrative metabolomics and transcriptomics analyses, we show a heterogeneity between metabolite and transcript profiles. Specifically, the level of serine in hepatocellular carcinoma (HCC) tissues is increased, whereas the expression of phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in serine biosynthesis pathway, is markedly downregulated. Interestingly, the increased serine level is obtained by enhanced PHGDH catalytic activity due to protein arginine methyltransferase 1 (PRMT1)-mediated methylation of PHGDH at arginine 236. PRMT1-mediated PHGDH methylation and activation potentiates serine synthesis, ameliorates oxidative stress, and promotes HCC growth in vitro and in vivo. Furthermore, PRMT1-mediated PHGDH methylation correlates with PHGDH hyperactivation and serine accumulation in human HCC tissues, and is predictive of poor prognosis of HCC patients. Notably, blocking PHGDH methylation with a TAT-tagged nonmethylated peptide inhibits serine synthesis and restrains HCC growth in an HCC patient-derived xenograft (PDX) model and subcutaneous HCC cell-derived xenograft model. Overall, our findings reveal a regulatory mechanism of PHGDH activity and serine synthesis, and suggest PHGDH methylation as a potential therapeutic vulnerability in HCC.PMID:36823188 | DOI:10.1038/s41467-023-36708-5

Nat Rev Rheumatol. 2023 Feb 23. doi: 10.1038/s41584-023-00922-8. Online ahead of print.NO ABSTRACTPMID:36823186 | DOI:10.1038/s41584-023-00922-8

Sci Rep. 2023 Feb 23;13(1):3177. doi: 10.1038/s41598-023-27603-6.ABSTRACTIt is difficult to directly obtain pathological diagnosis of perihilar cholangiocarcinoma (pCCA). Analysis of bile in the pCCA microenvironment, based on metabolomics and statistical methods, can help in clinical diagnosis. Clinical information, bile samples, blood liver function, blood CA199, CEA, and other indicators were collected from 33 patients with pCCA and 16 patients with gallstones. Bile samples were analyzed using untargeted metabolomics methods. A combination of multivariate and univariate analyses were used to screen for potential differential metabolites Through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and differential metabolite remodeling, we explored changes in the pCCA pathway and potential therapeutic targets. There were significant differences in patient blood TBIL, ALT, AST, TBA, CA19-9, and CEA indices (p < 0.05, |log2(fc)| ≥ 1) between two groups. A significant correlation was found between these different indicators by Spearman's analysis. The clinical parameters were correlated with mass-to-charge ratios of 305 (Positive Ion Mode, POS) and 246 (Negative Ion Mode, NEG) in the metabolic group (|r| ≥ 0.7, P ≤ 10-7). The result of this study indicated that bile untargeted metabolomics combined with statistical analysis techniques may be used for diagnose and treatment of pCCA.PMID:36823159 | DOI:10.1038/s41598-023-27603-6

J Hepatol. 2023 Feb 21:S0168-8278(23)00098-3. doi: 10.1016/j.jhep.2023.02.010. Online ahead of print.ABSTRACTBACKGROUND & AIMS: The consumption of sugar and high-fat diet (HFD) promotes the development of obesity and metabolic dysfunction. Despite their well-known synergy, the mechanisms by which sugar worsens the outcomes associated with a HFD intake is largely elusive.METHODS: Six week-old, male, C57 B l/6 J mice were fed either chow or HFD provided with regular, fructose- or glucose-sweetened water. Moreover, cultured AML12 hepatocytes were engineered to overexpress ketohexokinase C (KHK-C) using lentivirus or to knockdown CPT1α using CRISPR-Cas9. The cell culture experiments were complimented with in-vivo studies using mice with hepatic overexpression of KHK-C and in mice with liver-specific CPT1α knockout. We used comprehensive metabolomics, electron microscopy, mitochondrial substrate phenotyping, proteomics and acetylome analysis to investigate the underlying mechanism.RESULTS: Fructose supplementation of mice on normal chow, and fructose or glucose supplementation of mice on HFD increase KHK-C, an enzyme that catalyzes the first step of fructolysis. Elevated KHK-C is associated with an increase in lipogenic proteins, such as ACLY, without affecting their mRNA expression. An increase in KHK-C also correlates with acetylation of CPT1α at K508, and lower CPT1α protein in vivo. In vitro, KHK-C overexpression lowers CPT1α and increases triglyceride accumulation. The effects of KHK-C are, in part, replicated by a knockdown of CPT1α. An increase in KHK-C correlates negatively with CPT1α protein in mice fed sugar and HFD, but also in genetically obese db/db and lipodystrophic FIRKO mice. Mechanistically, overexpression of KHK-C in vitro increases global protein acetylation and decreases the major cytoplasmic deacetylase, SIRT2.CONCLUSIONS: KHK-C-induced acetylation is a novel mechanism by which dietary fructose augments lipogenesis and decreases fatty acid oxidation to support the development of metabolic complications.IMPACT AND IMPLICATIONS: Fructose is a highly lipogenic nutrient whose negative consequences have been largely attributed to increased de novo lipogenesis. Here we show that fructose upregulates ketohexokinase, which in turn modifies global protein acetylation, including acetylation of CPT1a, to decrease fatty acid oxidation. Our findings broaden the impact of dietary sugar beyond its lipogenic role and have implications on drug development aimed at reducing the harmful effects attributed to sugar metabolism.PMID:36822479 | DOI:10.1016/j.jhep.2023.02.010

J Nutr. 2023 Feb 21:S0022-3166(23)12678-2. doi: 10.1016/j.tjnut.2023.02.021. Online ahead of print.ABSTRACTBACKGROUND: Metabolomics approaches have been widely used to define consumption of foods but have less often been used to study exposure to dietary supplements.OBJECTIVE: To identify dietary supplements associated with metabolite levels, and to examine whether those metabolites predicted incident diabetes risk.METHODS: We studied 3972 participants from a prospective cohort study of 18 to 74 year old Hispanic/Latino adults. At a baseline examination we ascertained use of dietary supplements using recall methods and concurrently, a serum metabolomic panel. After adjustment for potential confounders, we identified dietary supplements associated with metabolites. We then examined the association of these metabolites with incident diabetes at the six-year study examination.RESULTS: We observed a total of 110 dietary supplement - metabolite associations that met criteria for statistical significance adjusted for age, sex, field center, Hispanic/Latino background, body mass index, diet, smoking, physical activity and number of medications (adjusted P < 0.05). This included 13 metabolites uniquely associated with only one dietary supplement ingredient. Vitamin C had the most associated metabolites (n=15), including positive associations with oxalate, tartronate, threonate and isocitrate which were each in turn protective for risk of incident diabetes. Vitamin C also was associated with higher N-acetylvaline level, which was an unfavorable diabetes risk factor. Other findings related to branched chain amino acid (BCAA) related compounds including alpha-hydroxyisovalerate and 2-hydroxy-3-methylvalerate, which were inversely associated with thiamin or riboflavin intake and also predicted higher diabetes risk. Vitamin B12 had an inverse association with gamma-glutamylvaline, levels of which were inversely associated with risk of diabetes.CONCLUSIONS: Our data point to potential metabolite changes associated with Vitamin C and B vitamins which may have favorable metabolic effects. Knowledge of blood metabolites that can be modified by dietary supplement intake may aid understanding of health effects of dietary supplements and identify potential biological mediators.PMID:36822396 | DOI:10.1016/j.tjnut.2023.02.021

Comp Biochem Physiol C Toxicol Pharmacol. 2023 Feb 21:109584. doi: 10.1016/j.cbpc.2023.109584. Online ahead of print.ABSTRACTIn our study, the antioxidant capacity of carob pods water extract (CPWE) against deltamethrin (DM)-induced oxidative stress, a widely used pesticide around the world, was investigated in vitro and in vivo in a zebrafish model. The in vitro antioxidant capacity of the obtained extract was evaluated with different methods using trolox, BHA and BHT standard antioxidants. For in vivo experiments, 4hpf zebrafish embryos were exposed to 10 ppb and 25 ppb DM for 120 h and the larvae were treated with 1-10 and 100 ppm CPWE for 4 h at 72th hours. According to the results obtained, it has been determined that the exposure of zebrafish to DM during the developmental period causes important body malformations, decrease in survival rate, reduction in eye size, shortening in body length and decrease in locomotor activity in the dark period. In addition, according to the results of whole-mount staining, it was determined that DM caused a significant increase in the amount of free oxygen radicals and apoptotic cells. It was also confirmed by metabolome analysis that CPWE application for 4 h reduced DM-induced toxicity and oxidative stress. As a result, it can be said that CPWE has an important antioxidant capacity in eliminating DM-induced oxidative stress.PMID:36822298 | DOI:10.1016/j.cbpc.2023.109584

J Leukoc Biol. 2023 Jan 10;113(1):41-57. doi: 10.1093/jleuko/qiac002.ABSTRACTSystemic lupus erythematosus development is influenced by both sex and the gut microbiota. Metabolite production is a major mechanism by which the gut microbiota influences the immune system, and we have previously found differences in the fecal metabolomic profiles of lupus-prone female and lupus-resistant male BWF1 mice. Here we determine how sex and microbiota metabolite production may interact to affect lupus. Transcriptomic analysis of female and male splenocytes showed genes that promote phagocytosis were upregulated in BWF1 male mice. Because patients with systemic lupus erythematosus exhibit defects in macrophage-mediated phagocytosis of apoptotic cells (efferocytosis), we compared splenic macrophage efferocytosis in vitro between female and male BWF1 mice. Macrophage efferocytosis was deficient in female compared to male BWF1 mice but could be restored by feeding male microbiota. Further transcriptomic analysis of the genes upregulated in male BWF1 mice revealed enrichment of genes stimulated by PPARγ and LXR signaling. Our previous fecal metabolomics analyses identified metabolites in male BWF1 mice that can activate PPARγ and LXR signaling and identified one in particular, phytanic acid, that is a very potent agonist. We show here that treatment of female BWF1 splenic macrophages with phytanic acid restores efferocytic activity via activation of the PPARγ and LXR signaling pathways. Furthermore, we found phytanic acid may restore female BWF1 macrophage efferocytosis through upregulation of the proefferocytic gene CD36. Taken together, our data indicate that metabolites produced by BWF1 male microbiota can enhance macrophage efferocytosis and, through this mechanism, could potentially influence lupus progression.PMID:36822162 | DOI:10.1093/jleuko/qiac002

Biomed Pharmacother. 2023 Feb 21;161:114409. doi: 10.1016/j.biopha.2023.114409. Online ahead of print.ABSTRACTThis study aimed to investigate the protective effect of Herba Origani, the dried whole herb of Origanum vulgare L., on dextran sodium sulfate (DSS)-induced ulcerative colitis in mice and explore its mechanisms of action through analyzing the intestinal microbiota in cecum contents and metabolites in colonic tissues. HOEP alleviated colitis symptoms, colonic inflammation and pathological injury as well as repaired intestinal barrier function in DSS-induced UC mice. The intestinal microbiota analysis showed that HOEP restored the gut microbiota dysbiosis in DSS-treated mice by increasing the alpha diversity of the intestinal microbiota, increasing the abundance of the Bacteroidota community and adjusting short-chain fatty acids (SCFAs), which maintain mucosal immunity and intestinal barrier. Metabolomic analysis revealed that HOEP promoted bile acids absorption and regulated bile acids metabolism in the intestine, thereby maintaining intestinal mucosal immune homeostasis. In addition, HOEP might also regulate the intestinal immune system through the phosphatidylinositol signaling system. These findings suggested that HOEP exerted promising protection against DSS-induced ulcerative mice through remolding gut microbiota to regulate bile acid and SCFA metabolism, and that HOEP have a potential to be utilized for the treatment of inflammatory intestinal diseases.PMID:36822021 | DOI:10.1016/j.biopha.2023.114409

Environ Int. 2023 Feb 13;173:107817. doi: 10.1016/j.envint.2023.107817. Online ahead of print.ABSTRACTEnvironmental exposure increases the risk of dyslipidemia, which affects human health. Research has shown that persistent organic pollutants (POPs), including per- and polyfluoroalkyl substances (PFASs), polychlorinated biphenyls, polybrominated diphenyl ethers, and phthalate metabolites, are associated with a higher risk of abnormal blood lipid levels in humans. However, the key molecules involved in dyslipidemia and the mechanisms are not fully understood. This study aims to investigate the biomarkers that mediate the relationships between blood lipids and four groups of POPs and revealed their potential mechanisms. Specifically, in 278 male blood samples, blood lipid and POPs levels were measured and metabolites were detected using untargeted metabolomics. Spearman's correlation analysis and binary logistic regression were employed to assess the relationship between POPs and lipid indexes. We observed that PFASs were associated with a higher risk of abnormal total cholesterol (TC) and low-density lipoprotein (LDL), while other POPs displayed little association with abnormal lipid indexes. Among all the PFASs, 6:2Cl-PFESA was associated with the fewest metabolites. A metabolome-wide association study combined with a meet-in-the-middle approach was used to identify potential biomarkers that mediate the association between POPs and abnormal blood lipids. The mediation analysis pointed to 105 significant mediators as potential biomarkers mediating the association between PFASs and TC, and 82 significant mediators were potential biomarkers that mediated the association between PFASs and LDL. 24-Hydroxycholesterol, 3alpha,7alpha-dihydroxy-5beta-cholestan-26-al, PC(18:0/0:0), PC(22:5/0:0), GPCho(18:1/18:1), LysoPC(22:2(13Z,16Z)), LysoPC(16:0), 9(S)-HODE, 9,10-DHOME, l-glutamate, 4-hydroxybutyric acid, cytosine, PC(14:1(9Z)/18:0), sphinganine, and (S)-beta-aminoisobutyrate were identified as important biomarkers. The mechanism may mainly involves glycerophospholipid metabolism, primary bile acid biosynthesis, and linoleic acid metabolism. PPARγ likely plays a role in the associations between PFASs and abnormal cholesterol metabolism. Overall, our study provides clues for the early detection of PFAS-induced dyslipidemia and brings forth a theoretical framework for further research into this mechanism.PMID:36822003 | DOI:10.1016/j.envint.2023.107817

J Hazard Mater. 2023 Feb 20;449:131050. doi: 10.1016/j.jhazmat.2023.131050. Online ahead of print.ABSTRACTMixed bromine/chlorine transformation products of tetrabromobisphenol A (ClyBrxBPAs) are mixed halogenated-type compounds recently identified in electronic waste dismantling sites. There are a lack of toxicity data on these compounds. To study their development toxicity, the proliferation toxicity was investigated using human embryonic stem cells (hESC) exposed to the lowest effective dose of two ClyBrxBPA analogues (2-chloro-2',6-dibromobisphenol A and 2,2'-dichloro-6-monobromobisphenol A). For comparison, tetrabromobisphenol A, 2,2',6-tribromobisphenol A, and bisphenol A were also assessed. It was observed that ClyBrxBPAs inhibited hESCs proliferation in a concentration-dependent manner. The cell bioaccumulation efficiency of ClyBrxBPAs was higher than that of tetrabromobisphenol A. Also, ClyBrxBPAs were more toxic than tetrabromobisphenol A, with 2,2'-dichloro-6-monobromobisphenol A exhibiting the most potent toxicity. Furthermore, flow cytometry and oxidative stress results showed that increased reactive oxygen species raised the degree of apoptosis and reduced DNA synthesis. Metabolomics analysis on the effect of ClyBrxBPAs on metabolic pathway alteration showed that ClyBrxBPAs mainly interfered with four metabolic pathways related to amino acid metabolism and biosynthesis. These results provide an initial perspective on the proliferation toxicity of ClyBrxBPAs, indicating development toxicity in children.PMID:36821903 | DOI:10.1016/j.jhazmat.2023.131050

J Pharm Pharmacol. 2023 Feb 23:rgad001. doi: 10.1093/jpp/rgad001. Online ahead of print.ABSTRACTOBJECTIVES: Corni Fructus is one of the most famous traditional Chinese medicines (TCMs) for the treatment of various chronic kidney diseases. Wine-processed Corni Fructus (WCF) is the main processed form of Crude Corni Fructus (CCF). In this study, potential mechanisms of action of CCF and WCF on chronic renal failure (CRF) model were developed to explore wine-processed mechanism of Corni Fructus.METHODS: An integrated strategy combining metabolomics, network analysis and bioinformatics analysis has been established to investigate the therapeutic mechanisms of WCF and CCF in rats with CRF.KEY FINDINGS: The histopathological results showed that both WCF and CCF improved kidney injury and dysfunction of CRF rats, but WCF was more effective than CCF. Metabolic pathway analysis indicated that 24 metabolites and 5 major disturbed pathways associated with CCF, while WCF regulated 27 metabolites and 2 metabolic pathways. Bioinformatic analysis and network analysis revealed that 8 genes and 7 genes were regulated by CCF and WCF on CRF rats, respectively. The quantitative real-time polymerase chain reaction experiments verified the regulatory ability of CCF and WCF on the expression of 4 genes.CONCLUSIONS: An integrated strategy combined metabolomics, network analysis and bioinformatics was established to provide valuable holistic insight to explore the processing mechanism of TCMs.PMID:36821628 | DOI:10.1093/jpp/rgad001