PubMed

Environ Pollut. 2023 Jan 7:121046. doi: 10.1016/j.envpol.2023.121046. Online ahead of print.ABSTRACTChromium (Cr) is a highly toxic element adversely affecting the environment, cultivable lands, and human populations. The present study investigated the effects of Cr (VI) (100-400 μM) on plant morphology and growth, photosynthetic pigments, organic osmolytes, ionomics, and metabolomic dynamics of the halophyte Suaeda maritima to decipher the Cr tolerance mechanisms. Cr exposure reduced the growth and biomass in S. maritima. The photosynthetic pigments content significantly declined at higher Cr concentrations (400 μM). However, at lower Cr concentrations (100-300 μM), the photosynthetic pigments remained unaffected or increased. The results suggest that a high concentration of Cr exposure might have adverse effects on PS II in S. maritima. The enhanced uptake of Na+ in S. maritima imposed to Cr stress indicates that Na + might have a pivotal role in osmotic adjustment, thereby maintaining water status under Cr stress. The proline content was significantly upregulated in Cr-treated plants suggesting its role in maintaining osmotic balance and scavenging ROS. The metabolomic analysis of control and 400 μM Cr treated plants led to the identification of 62 metabolites. The fold chain analysis indicated the upregulation of several metabolites, including phytohormones (SA and GA3), polyphenols (cinnamic acid, sinapic acid, coumaric acid, vanillic acid, and syringic acid), and amino acids (alanine, leucine, proline, methionine, and cysteine) under Cr stress. The upregulation of these metabolites suggests the enhanced metal chelation and sequestration in vacuoles, reducing oxidative stress by scavenging ROS and promoting photosynthesis by maintaining the chloroplast membrane structure and photosynthetic pigments. Furthermore, in S. maritima, Cr tolerance index (Ti) was more than 60% in all the treatments, and Cr bio-concentration factor (BCF) and translocation factor (Tf) values were all greater than 1.0, which clearly indicates the Cr-hyperaccumulator characteristics of this halophyte.PMID:36627045 | DOI:10.1016/j.envpol.2023.121046

Anal Biochem. 2023 Jan 7:115036. doi: 10.1016/j.ab.2023.115036. Online ahead of print.ABSTRACTFlow-injection mass spectrometry (FI-MS) enables metabolomics studies with a very high sample-throughput. However, FI-MS is prone to in-source modifications of analytes because samples are directly injected into the electrospray ionization source of a mass spectrometer without prior chromatographic separation. Here, we spiked authentic standards of 160 primary metabolites individually into an Escherichia coli metabolite extract and measured the thus derived 160 spike-in samples by FI-MS. Our results demonstrate that FI-MS can capture a wide range of chemically diverse analytes within 30 seconds measurement time. However, the data also revealed extensive in-source modifications. Across all 160 spike-in samples, we identified significant increases of 11,013 ion peaks in positive and negative mode combined. To explain these unknown m/z features, we connected them to the m/z feature of the (de-)protonated metabolite using information about mass differences and MS2 spectra. This resulted in networks that explained on average 49% of all significant features. The networks showed that a single metabolite undergoes compound specific and often sequential in-source modifications like adductions, chemical reactions, and fragmentations. Our results show that FI-MS generates complex MS1 spectra, which leads to an overestimation of significant features, but neutral losses and MS2 spectra explain many of these features.PMID:36627043 | DOI:10.1016/j.ab.2023.115036

J Appl Microbiol. 2022 Dec 14:lxac035. doi: 10.1093/jambio/lxac035. Online ahead of print.ABSTRACTAIMS: To evaluate the effects of the Qingwen Gupi decoction (QGT) in a rat model of bleomycin-induced pulmonary fibrosis (PF), and explore the underlying mechanisms by integrating UPLC-Q-TOF/MS metabolomics and 16S rDNA sequencing of gut microbiota.METHODS AND RESULTS: The animals were randomly divided into the control, PF model, pirfenidone-treated, and low-, medium-, and high-dose QGT groups. The lung tissues were examined and the expression of TGF-β, SMAD-3, and SMAD-7 mRNAs in the lung tissues were analyzed. Metabolomic profiles were analyzed by UPLC-QTOF/MS, and the intestinal flora were examined by prokaryotic 16 rDNA sequencing. Pathological examination and biochemical indices revealed that QGT treatment improved the symptoms of PF by varying degrees. Furthermore, QGT significantly downregulated TGF-β1 and Smad-3 mRNAs and increased the expression levels of Smad-7. QGT-L in particular increased the levels of 18 key metabolic biomarkers that were associated with nine gut microbial species and may exert antifibrosis effects through arachidonic acid metabolism, glycerophospholipid metabolism, and phenylalanine metabolism.CONCLUSIONS: QGT alleviated PF in a rat model through its anti-inflammatory, antioxidant, and anti-fibrotic effects, and by reversing bleomycin-induced gut dysbiosis.This study lays the foundation for further research on the pathological mechanisms of PF and the development of new drug candidates.PMID:36626779 | DOI:10.1093/jambio/lxac035

ACS Chem Biol. 2023 Jan 10. doi: 10.1021/acschembio.2c00784. Online ahead of print.ABSTRACTAltered cellular metabolism is a hallmark of cancer pathogenesis and progression; for example, a near-universal feature of cancer is increased metabolic flux through the hexosamine biosynthetic pathway (HBP). This pathway produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a potent oncometabolite that drives multiple facets of cancer progression. In this study, we synthesized and evaluated peracetylated hexosamine analogs designed to reduce flux through the HBP. By screening a panel of analogs in pancreatic cancer and glioblastoma multiform (GBM) cells, we identified Ac4Glc2Bz─a benzyl-modified GlcNAc mimetic─as an antiproliferative cancer drug candidate that down-regulated oncogenic metabolites and reduced GBM cell motility at concentrations non-toxic to non-neoplastic cells. More specifically, the growth inhibitory effects of Ac4Glc2Bz were linked to reduced levels of UDP-GlcNAc and concomitant decreases in protein O-GlcNAc modification in both pancreatic cancer and GBM cells. Targeted metabolomics analysis in GBM cells showed that Ac4Glc2Bz disturbed glucose metabolism, amino acid pools, and nucleotide precursor biosynthesis, consistent with reduced proliferation and other anti-oncogenic properties of this analog. Furthermore, Ac4Glc2Bz reduced the invasion, migration, and stemness of GBM cells. Importantly, normal metabolic functions mediated by UDP-GlcNAc were not disrupted in non-neoplastic cells, including maintenance of endogenous levels of O-GlcNAcylation with no global disruption of N-glycan production. Finally, a pilot in vivo study showed that a potential therapeutic window exists where animals tolerated 5- to 10-fold higher levels of Ac4Glc2Bz than projected for in vivo efficacy. Together, these results establish GlcNAc analogs targeting the HBP through salvage mechanisms as a new therapeutic approach to safely normalize an important facet of aberrant glucose metabolism associated with cancer.PMID:36626752 | DOI:10.1021/acschembio.2c00784

Hepatology. 2023 Jan 3. doi: 10.1097/HEP.0000000000000025. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a malignant disease. Compared with tyrosine kinase inhibitors (the classical therapy), immune checkpoint inhibitors are more effective in the treatment of HCC, despite their limited efficacy. Among these restricted factors, exhaustion of tumor-infiltrated lymphocytes (TILs), especially CD8+ T cells, is a core event. We aimed to determine the key factors contributing to CD8+ T cell infiltration in HCC and investigate the underlying mechanisms.APPROACH AND RESULTS: Using machine learning and multiplex immunohistochemistry analysis, we showed that dedicator of cytokinesis protein 2 (DOCK2) was a potential indicator of infiltrated CD8+ T cells in HCC. Using RNA sequencing, flow cytometry analysis, and mouse HCC models, we demonstrated that DOCK2 inactivation accounted for infiltrated CD8+ T cell exhaustion in tumors. Using quasi-targeted metabolomics, mass spectrum, and mass cytometry by time of flight analysis, we found that cholesterol sulfate (CS) synthesized by sulfotransferase 2B1 (SULT2B1) in tumor cells suppressed DOCK2 enzymatic activity of T cells. Through virtual screening, molecular docking simulation, and experiments validation, we demonstrated that tolazamide reversed DOCK2 inactivation-mediated CD8+ T cell exhaustion and enhanced anti-PDL1 antibody + Apatinib immunotherapeutic effects on HCC.CONCLUSIONS: This study indicates that DOCK2 controls CD8+ T cell infiltration in HCC, and CS synthesized by SULT2B1 in tumor cells promotes effector T cell exhaustion. The findings suggest that the usage of conventional drugs affects immunotherapy efficacy in HCC patients.PMID:36626623 | DOI:10.1097/HEP.0000000000000025

Amino Acids. 2023 Jan 10. doi: 10.1007/s00726-023-03233-0. Online ahead of print.ABSTRACTInflammatory bowel disease (IBD), which mainly comprises ulcerative colitis (UC) and Crohn's disease (CD), is a common chronic intestinal inflammatory disease that affects the ileum, rectum, and colon. Currently, the diagnosis of IBD is based on clinical history, physical examination and complementary diagnostic tests. It is challenging for physicians to make a definitive diagnosis. This study aimed to analyze the variation in amino acid metabolites in IBD serum and to identify potential predictive biomarkers of IBD diagnosis and progression. Serum samples were collected from 158 UC patients, 130 CD patients and 138 healthy controls (HCs). The 37 amino acids in serum were determined by ultra-high-pressure liquid chromatography coupled to a mass spectrometer. A panel of three-amino-acid metabolites (taurine, homocitrulline and kynurenine) was identified as a specific biomarker panel of IBD. Receiver operating characteristic analysis (ROC) showed that the panel had a sensitivity of 88.4% with a specificity of 84.6% for discriminating CD patients from UC patients. The biomarkers identified are increased in CD compared to UC. Our approach demonstrated a strong relationship between serum amino acid levels and IBD. We successfully identified serum amino acid biomarkers associated with CD and UC. The biomarker panel has potential in clinical practice for IBD diagnosis and will provide new insights into IBD pathogenesis.PMID:36625991 | DOI:10.1007/s00726-023-03233-0

Microbiol Spectr. 2023 Jan 10:e0251722. doi: 10.1128/spectrum.02517-22. Online ahead of print.ABSTRACTHyperlipidemia is a risk factor and key indicator for cardiovascular diseases, and the gut microbiota is highly associated with hyperlipidemia. Bacteroides vulgatus is a prevalent mutualist across human populations and confers multiple health benefits such as immunoregulation, antiobesity, and coronary artery disease intervention. However, its role in antihyperlipidemia has not been systematically characterized. This study sought to identify the effect of B. vulgatus Bv46 on hyperlipidemia. Hyperlipidemic rats were modeled by feeding them a high-fat diet for 6 weeks. The effect of B. vulgatus Bv46 supplementation was evaluated by measuring anthropometric parameters, lipid and inflammation markers, and the liver pathology. Multi-omics was used to explore the underlying mechanisms. The ability of B. vulgatus Bv46 to produce bile salt hydrolase was confirmed by gene annotation and in vitro experiments. Oral administration of B. vulgatus Bv46 in hyperlipidemic rats significantly reduced the body weight gain, food efficiency, and liver index, improved the serum lipid profile, lowered the levels of serum inflammatory cytokines, promoted the loss of fecal bile acids (BAs), and extended the fecal pool of short-chain fatty acids (SCFAs), especially propionate and butyrate. B. vulgatus Bv46 induced compositional shifts of the gut microbial community of hyperlipidemic rats, characterized by a lower ratio of Firmicutes to Bacteroidetes with an increase of genera Bacteroides and Parabacteroides. After intervention, serum metabolite profiling exhibited an adaptation in amino acids and glycerophospholipid metabolism. Transcriptomics further detected altered biological processes, including primary bile acid biosynthesis and fatty acid metabolic process. Taken together, the findings suggest that B. vulgatus Bv46 could be a promising candidate for interventions against hyperlipidemia. IMPORTANCE As a core microbe of the human gut ecosystem, Bacteroides vulgatus has been linked to multiple aspects of metabolic disorders in a collection of associative studies, which, while indicative, warrants more direct experimental evidence to verify. In this study, we experimentally demonstrated that oral administration of B. vulgatus Bv46 ameliorated the serum lipid profile and systemic inflammation of high-fat diet-induced hyperlipidemic rats in a microbiome-regulated manner, which appears to be associated with changes of bile acid metabolism, short-chain fatty acid biosynthesis, and serum metabolomic profile. This finding supports the causal contribution of B. vulgatus in host metabolism and helps to form the basis of novel therapies for the treatment of hyperlipidemia.PMID:36625637 | DOI:10.1128/spectrum.02517-22

Microbiol Spectr. 2023 Jan 10:e0379622. doi: 10.1128/spectrum.03796-22. Online ahead of print.ABSTRACTSeveral previous studies have shown that oral microbial disorders may be closely related to the occurrence and development of type 2 diabetes mellitus (T2DM). However, whether the function of oral microorganisms and their metabolites have changed in patients with T2DM who have not suffered from any oral diseases has not been reported. We performed metagenomic analyses and nontargeted metabolic analysis of saliva and supragingival plaque samples from patients with T2DM who have not suffered any oral diseases and normal controls. We found that periodontal pathogens such as Porphyromonas gingivalis and Prevotella melaninogenica were significantly enriched, while the abundances of dental caries pathogens such as Streptococcus mutans and Streptococcus sobrinus were not significantly different in patients with T2DM compared to those in normal controls. Metabolomic analyses showed that the salivary levels of cadaverine and L-(+)-leucine of patients with T2DM were significantly higher than those of normal controls, while the supragingival plaque levels of N-acetyldopamine and 3,4-dimethylbenzoic acid in patients with T2DM were significantly higher than those in the normal controls. Additionally, we identified the types of oral microorganisms related to the changes in the levels of circulating metabolites, and the oral microorganisms were involved in the dysregulation of harmful metabolites such as cadaverine and n, n-dimethylarginine. Overall, our study first described the changes in the composition of oral microorganisms and their metabolites in patients with T2DM who have not suffered any oral diseases, which will provide a direct basis for finding oral biomarkers for early warning of oral diseases in T2DM. IMPORTANCE The incidence of oral diseases in type 2 diabetic patients might increase, and the severity might also be more serious. At present, the relationship between oral microorganisms and type 2 diabetes mellitus (T2DM) has become a hot topic in systemic health research. However, whether the function of oral microorganisms and their metabolites have changed in patients with T2DM who have not suffered from any oral diseases has not been reported. We found that even if the oral condition of T2DM is healthy, their oral microbes and metabolites have changed, thus increasing the risk of periodontal disease. Our study first described the changes in the composition of oral microorganisms and their metabolites in T2DM who have not suffered any oral diseases and revealed the correlation between oral microorganisms and their metabolites, which will provide a direct basis for finding oral biomarkers for early warning of oral diseases in patients with T2DM.PMID:36625596 | DOI:10.1128/spectrum.03796-22

Anal Chem. 2023 Jan 10;95(1):83-99. doi: 10.1021/acs.analchem.2c04606.NO ABSTRACTPMID:36625102 | DOI:10.1021/acs.analchem.2c04606

Curr Hypertens Rev. 2023 Jan 9. doi: 10.2174/1573402119666230109142156. Online ahead of print.ABSTRACTCardiac circadian rhythms are an important regulator of body functions, including cardiac activities and blood pressure. Disturbance of circadian rhythm is known to trigger and aggravate various cardiovascular diseases. Thus, modulating the circadian rhythm can be used as a therapeutic approach to cardiovascular diseases. Through this work, we intend to discuss the current understanding of cardiac circadian rhythms, in terms of quantifiable parameters like BP and HR. We also elaborate on the molecular regulators and the molecular cascades along with their specific genetic aspects involved in modulating circadian rhythms, with specific reference to cardiovascular health and cardiovascular diseases. Along with this, we also presented the latest pharmacogenomic and metabolomics markers involved in chronobiological control of the cardiovascular system along with their possible utility in cardiovascular disease diagnosis and therapeutics. Finally, we reviewed the current expert opinions on chronotherapeutic approaches for utilizing the conventional as well as the new pharmacological molecules for antihypertensive chronotherapy.PMID:36624649 | DOI:10.2174/1573402119666230109142156

J Food Sci. 2023 Jan 9. doi: 10.1111/1750-3841.16443. Online ahead of print.ABSTRACTSaffron floral bio-residues (SFB) are a valuable natural source of antioxidants and dyes that can contribute to the development of new food products and cosmetic products. Color change was usually observed during SFB storage, which may result in quality degradation of SFB or even cause potential hazard to human health. In order to clarify the mechanism of color change of SFB sample, the chemical differences among SFB samples stored under different conditions were analyzed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and chemometrics methods, from which differential flavonols and anthocyanins were screened and their kinetic variations during sample storage summarized. In addition, the color change of the SFB sample was digitalized using an electronic eye (E-eye), which was found to be related to the content of delphinidin-3,5-di-O-glucoside (DDG). Moreover, the degradation kinetic parameters of DDG under different storage conditions were studied. In conclusion, the variation of kaempferol-, isorhamnetin-, and quercetin-type flavonol, and delphinidin- and petunidin-type anthocyanin resulted in the color change of SFB sample, and anthocyanin was found more unstable than flavonol. PRACTICAL APPLICATION: Saffron floral bio-residues (SFB) are popular natural sources of antioxidants and colorants that can be used in food and cosmetic products. Color change usually occurs during SFB storage period. Clarifying the mechanism of the color change of SFB will help us to ensure the quality of SFB.PMID:36624623 | DOI:10.1111/1750-3841.16443

Microbiome. 2023 Jan 10;11(1):5. doi: 10.1186/s40168-022-01450-5.ABSTRACTBACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is thought to involve alterations in the gut microbiome, but robust microbial signatures have been challenging to identify. As prior studies have primarily focused on composition, we hypothesized that multi-omics assessment of microbial function incorporating both metatranscriptomics and metabolomics would further delineate microbial profiles of IBS and its subtypes.METHODS: Fecal samples were collected from a racially/ethnically diverse cohort of 495 subjects, including 318 IBS patients and 177 healthy controls, for analysis by 16S rRNA gene sequencing (n = 486), metatranscriptomics (n = 327), and untargeted metabolomics (n = 368). Differentially abundant microbes, predicted genes, transcripts, and metabolites in IBS were identified by multivariate models incorporating age, sex, race/ethnicity, BMI, diet, and HAD-Anxiety. Inter-omic functional relationships were assessed by transcript/gene ratios and microbial metabolic modeling. Differential features were used to construct random forests classifiers.RESULTS: IBS was associated with global alterations in microbiome composition by 16S rRNA sequencing and metatranscriptomics, and in microbiome function by predicted metagenomics, metatranscriptomics, and metabolomics. After adjusting for age, sex, race/ethnicity, BMI, diet, and anxiety, IBS was associated with differential abundance of bacterial taxa such as Bacteroides dorei; metabolites including increased tyramine and decreased gentisate and hydrocinnamate; and transcripts related to fructooligosaccharide and polyol utilization. IBS further showed transcriptional upregulation of enzymes involved in fructose and glucan metabolism as well as the succinate pathway of carbohydrate fermentation. A multi-omics classifier for IBS had significantly higher accuracy (AUC 0.82) than classifiers using individual datasets. Diarrhea-predominant IBS (IBS-D) demonstrated shifts in the metatranscriptome and metabolome including increased bile acids, polyamines, succinate pathway intermediates (malate, fumarate), and transcripts involved in fructose, mannose, and polyol metabolism compared to constipation-predominant IBS (IBS-C). A classifier incorporating metabolites and gene-normalized transcripts differentiated IBS-D from IBS-C with high accuracy (AUC 0.86).CONCLUSIONS: IBS is characterized by a multi-omics microbial signature indicating increased capacity to utilize fermentable carbohydrates-consistent with the clinical benefit of diets restricting this energy source-that also includes multiple previously unrecognized metabolites and metabolic pathways. These findings support the need for integrative assessment of microbial function to investigate the microbiome in IBS and identify novel microbiome-related therapeutic targets. Video Abstract.PMID:36624530 | DOI:10.1186/s40168-022-01450-5

Alzheimers Res Ther. 2023 Jan 9;15(1):8. doi: 10.1186/s13195-023-01162-4.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by altered cellular metabolism in the brain. Several of these alterations have been found to be exacerbated in females, known to be disproportionately affected by AD. We aimed to unravel metabolic alterations in AD at the metabolic pathway level and evaluate whether they are sex-specific through integrative metabolomic, lipidomic, and proteomic analysis of mouse brain tissue.METHODS: We analyzed male and female triple-transgenic mouse whole brain tissue by untargeted mass spectrometry-based methods to obtain a molecular signature consisting of polar metabolite, complex lipid, and protein data. These data were analyzed using multi-omics factor analysis. Pathway-level alterations were identified through joint pathway enrichment analysis or by separately evaluating lipid ontology and known proteins related to lipid metabolism.RESULTS: Our analysis revealed significant AD-associated and in part sex-specific alterations across the molecular signature. Sex-dependent alterations were identified in GABA synthesis, arginine biosynthesis, and in alanine, aspartate, and glutamate metabolism. AD-associated alterations involving lipids were also found in the fatty acid elongation pathway and lysophospholipid metabolism, with a significant sex-specific effect for the latter.CONCLUSIONS: Through multi-omics analysis, we report AD-associated and sex-specific metabolic alterations in the AD brain involving lysophospholipid and amino acid metabolism. These findings contribute to the characterization of the AD phenotype at the molecular level while considering the effect of sex, an overlooked yet determinant metabolic variable.PMID:36624525 | DOI:10.1186/s13195-023-01162-4

J Transl Med. 2023 Jan 9;21(1):12. doi: 10.1186/s12967-022-03760-6.ABSTRACTBACKGROUND/AIMS: Nonobese metabolic dysfunction-associated fatty liver disease (MAFLD) is paradoxically associated with improved metabolic and pathological features at diagnosis but similar cardiovascular diseases (CVD) prognosis to obese MAFLD. We aimed to utilize the metabolomics to identify the potential metabolite profiles accounting for this phenomenon.METHODS: This prospective multicenter cross-sectional study was conducted in China enrolling derivation and validation cohorts. Liquid chromatography coupled with mass spectrometry and gas chromatography-mass spectrometry were applied to perform a metabolomics measurement.RESULTS: The study involved 120 MAFLD patients and 60 non-MAFLD controls in the derivation cohort. Controls were divided into two groups according to the presence of carotid atherosclerosis (CAS). The MAFLD group was further divided into nonobese MAFLD with/without CAS groups and obese MAFLD with/without CAS groups. Fifty-six metabolites were statistically significant for discriminating the six groups. Among the top 10 metabolites related to CAS in nonobese MAFLD, only phosphatidylethanolamine (PE 20:2/16:0), phosphatidylglycerol (PG 18:0/20:4) and de novo lipogenesis (16:0/18:2n-6) achieved significant areas under the ROC curve (AUCs, 0.67, p = 0.03; 0.79, p = 0.02; 0.63, p = 0.03, respectively). The combination of these three metabolites and liver stiffness achieved a significantly higher AUC (0.92, p < 0.01). In obese MAFLD patients, cystine was found to be significant with an AUC of 0.69 (p = 0.015), followed by sphingomyelin (SM 16:1/18:1) (0.71, p = 0.004) and de novo lipogenesis (16:0/18:2n-6) (0.73, p = 0.004). The combination of these three metabolites, liver fat content and age attained a significantly higher AUC of 0.91 (p < 0.001). The AUCs of these metabolites remained highly significant in the independent validation cohorts involving 200 MAFLD patients and 90 controls.CONCLUSIONS: Diagnostic models combining different metabolites according to BMI categories could raise the accuracy of identifying subclinical CAS. Trial registration The study protocol was approved by the local ethics committee and all the participants have provided written informed consent (Approval number: [2014] No. 112, registered at the Chinese Clinical Trial Registry, ChiCTR-ChiCTR2000034197).PMID:36624524 | DOI:10.1186/s12967-022-03760-6

Mol Cancer. 2023 Jan 9;22(1):4. doi: 10.1186/s12943-022-01703-9.ABSTRACTBACKGROUND: Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood.METHODS: PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations.RESULTS: Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers.CONCLUSIONS: This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.PMID:36624516 | DOI:10.1186/s12943-022-01703-9

Microbiome. 2023 Jan 9;11(1):3. doi: 10.1186/s40168-022-01443-4.ABSTRACTBACKGROUND: Chronic kidney disease (CKD) is a severe public health problem associated with a disordered gut microbiome. However, the functional alterations of microbiota and their cross talk with metabolism pathways based on disease severity remain unclear.RESULTS: We performed metagenomics and untargeted metabolomics in a cohort of 68 patients with CKD of differing severities and 20 healthy controls to characterize the complex interplay between the gut microbiome and fecal and serum metabolites during CKD progression. We identified 26 microbial species that significantly changed in patients with CKD; 18 species changed as the disease progressed, and eight species changed only in a specific CKD group. These distinct changes in gut microbiota were accompanied by functional alterations in arginine and proline, arachidonic acid, and glutathione metabolism and ubiquinone and other terpenoid-quinone biosynthesis pathways during CKD progression. Further metabolomic analyses revealed that the distributions of toxic and pro-oxidant metabolites from these four essential metabolic pathways varied in the feces and serum as CKD progressed. Furthermore, we observed a complex co-occurrence between CKD severity-related bacteria and the characterized metabolites from the four essential metabolic pathways. Notably, Ruminococcus bromii, fecal hydroquinone, and serum creatinine were identified as the main contributors to the integrated network, indicating their key roles in CKD progression. Moreover, a noninvasive model including R. bromii and fecal hydroquinone, L-cystine, and 12-keto-tetrahydro-LTB4 levels classified the CKD severity (area under the curve [AUC]: > 0.9) and had better performance than the serum creatinine level for mild CKD (AUC: 0.972 vs. 0.896).CONCLUSIONS: Perturbed CKD severity-related gut microbiota may contribute to unbalanced toxic and pro-oxidant metabolism in the gut and host, accelerating CKD progression, which may be an early diagnostic and therapeutic target for CKD. Video Abstract.PMID:36624472 | DOI:10.1186/s40168-022-01443-4

BMC Pregnancy Childbirth. 2023 Jan 9;23(1):14. doi: 10.1186/s12884-023-05346-6.ABSTRACTAIMS: The aim of this study was to characterize the metabolites associated with small- and large-gestational-age newborns in maternal and cord blood, and to investigate potential mechanisms underlying the association between birthweight and metabolic disturbances.RESEARCH DESIGN AND METHODS: We recorded detailed anthropometric data of mother-offspring dyads. Untargeted metabolomic assays were performed on 67 pairs of cord blood and maternal fasting plasma samples including 16 pairs of small-for-gestational (SGA, < 10th percentile) dyads, 28 pairs of appropriate-for-gestational (AGA, approximate 50 percentile) dyads, and 23 pairs of large-for-gestational (LGA, > 90th percentile) dyads. The association of metabolites with newborn birthweight was conducted to screen for metabolites with U-shaped and line-shaped distributions. The association of metabolites with maternal and fetal phenotypes was also performed.RESULTS: We found 2 types of metabolites that changed in different patterns according to newborn birthweight. One type of metabolite exhibited a "U-shaped" trend of abundance fluctuation in the SGA-AGA-LGA groups. The results demonstrated that cuminaldehyde level was lower in the SGA and LGA groups, and its abundance in cord blood was negatively correlated with maternal BMI (r = -0.352 p = 0.009) and weight gain (r = -0.267 p = 0.043). 2-Methoxy-estradiol-17b 3-glucuronide, which showed enrichment in the SGA and LGA groups, was positively correlated with homocysteine (r = 0.44, p < 0.001) and free fatty acid (r = 0.42, p < 0.001) in maternal blood. Serotonin and 13(S)-HODE were the second type of metabolites, denoted as "line-shaped", which both showed increasing trends in the SGA-AGA-LGA groups in both maternal and cord blood and were both significantly positively correlated with maternal BMI before pregnancy. Moreover, cuminaldehyde, serotonin, 13(S)-HODE and some lipid metabolites showed a strong correlation between maternal and cord blood.CONCLUSIONS: These investigations demonstrate broad-scale metabolomic differences associated with newborn birthweight in both pregnant women and their newborns. The U-shaped metabolites associated with both the SGA and LGA groups might explain the U-shaped association between birthweight and metabolic dysregulation. The line-shaped metabolites might participate in intrauterine growth regulation. These observations might help to provide new insights into the insulin resistance and the risk of metabolic disturbance of SGA and LGA babies in adulthood and might identify potential new markers for adverse newborn outcomes in pregnant women.PMID:36624413 | DOI:10.1186/s12884-023-05346-6

Nat Med. 2023 Jan 9. doi: 10.1038/s41591-022-02097-3. Online ahead of print.ABSTRACTInnovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.PMID:36624312 | DOI:10.1038/s41591-022-02097-3

Commun Med (Lond). 2023 Jan 9;3(1):5. doi: 10.1038/s43856-022-00231-3.ABSTRACTBACKGROUND: Type 2 diabetes is a common disease around the world and its major complications are diabetic retinopathy (DR) and diabetic kidney disease (DKD). Persons with type 2 diabetes with complications, especially who have both DR and DKD, have poorer prognoses than those without complications. Therefore, prevention and early identification of the complications of type 2 diabetes are necessary to improve the prognosis of persons with type 2 diabetes. The aim of this study is to identify factors associated with the development of multiple complications of type 2 diabetes.METHODS: We profiled serum metabolites of persons with type 2 diabetes with both DR and DKD (N = 141) and without complications (N = 159) using a comprehensive non-targeted metabolomics approach with mass spectrometry. Based on the serum metabolite profiles, case-control comparisons and metabolite set enrichment analysis (MSEA) were performed.RESULTS: Here we show that five metabolites (cyclohexylamine, P = 4.5 × 10-6; 1,2-distearoyl-glycero-3-phosphocholine, P = 7.3 × 10-6; piperidine, P = 4.8 × 10-4; N-acetylneuraminic acid, P = 5.1 × 10-4; stearoyl ethanolamide, P = 6.8 × 10-4) are significantly increased in those with the complications. MSEA identifies fatty acid biosynthesis as the type 2 diabetes complications-associated biological pathway (P = 0.0020).CONCLUSIONS: Our metabolome analysis identifies the serum metabolite features of the persons with type 2 diabetes with multiple complications, which could potentially be used as biomarkers.PMID:36624208 | DOI:10.1038/s43856-022-00231-3

Annu Rev Food Sci Technol. 2022 Jan 9. doi: 10.1146/annurev-food-060822-113022. Online ahead of print.ABSTRACTDespite the almost universal acceptance of the phrase "you are what you eat," investment in understanding diet-based nutrition to address human health has been dwarfed compared to that for medicine-based interventions. Moreover, traditional breeding has focused on yield to the detriment of nutritional quality, meaning that although caloric content has remained high, the incidence of nutritional deficiencies and accompanying diseases (so-called hidden hunger) has risen dramatically. We review how genome sequencing coupled with metabolomics can facilitate the screening of genebank collections in the search for superior alleles related to the nutritional quality of crops. We argue that the first examples are very promising, suggesting that this approach could benefit broader ranges of crops and compounds with known relevance for human health. We argue that this represents an approach complementary to metabolic engineering by transgenesis or gene editing that could be used to reverse some of the losses incurred through a recent focus on breeding for yield, although we caution that ensuring such approaches are not (re)introducing antinutrients is also necessary. Furthermore, deploying effective postharvest processing technologies to increase the density of nutrients in the food matrix and improve palatability remains an attractive alternative. Expected final online publication date for the Annual Review of Food Science and Technology, Volume 14 is March 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.PMID:36623924 | DOI:10.1146/annurev-food-060822-113022