PubMed

Mol Biol Rep. 2023 Apr 19. doi: 10.1007/s11033-023-08421-5. Online ahead of print.ABSTRACTThe self-renew ability of cancer stem cells (CSCs) continues to challenge our determination for accomplishing cancer therapy breakthrough. Ineffectiveness of current cancer therapies to eradicate CSCs has contributed to chemoresistance and tumor recurrence. Yet, the discoveries of highly effective therapies have not been thoroughly developed. Further insights into cancer metabolomics and gene-regulated mechanisms of mitochondria in CSCs can expedite the development of novel anticancer drugs. In cancer cells, the metabolism is reprogrammed from oxidative phosphorylation (OXPHOS) to glycolysis. This alteration allows the cancer cell to receive continuous energy supplies and avoid apoptosis. The pyruvate obtained from glycolysis produces acetyl-coenzyme A (Acetyl-CoA) via oxidative decarboxylation and enters the tricarboxylic acid cycle for adenosine triphosphate generation. Mitochondrial calcium ion (Ca2+) uptake is responsible for mitochondrial physiology regulation, and reduced uptake of Ca2+ inhibits apoptosis and enhances cell survival in cancer. There have been many discoveries of mitochondria-associated microRNAs (miRNAs) stimulating the metabolic alterations in mitochondria via gene regulation which promote cancer cell survival. These miRNAs are also found in CSCs where they regulate genes and activate different mechanisms to destroy the mitochondria and enhance CSCs survival. By targeting the miRNAs that induced mitochondrial destruction, the mitochondrial functions can be restored; thus, it triggers CSCs apoptosis and completely eliminates the CSCs. In general, this review article aims to address the associations between miRNAs with mitochondrial activities in cancer cells and cancer stem cells that support cancer cell survival and self-renewal.PMID:37074612 | DOI:10.1007/s11033-023-08421-5

Food Chem Toxicol. 2023 Apr 18:113777. doi: 10.1016/j.fct.2023.113777. Online ahead of print.ABSTRACTP: radix is a perennial herb, and its extracts have various biological properties that make it a potential candidate for the treatment of tumors, edema, and lymphatic stasis. However, the main factor contributing to its toxicity are not clear. Here, we used a zebrafish toxicological model to study the main toxicity factor of P. radix and explore the potential mechanisms involved. The results revealed that Esculentoside B was the major toxic factor of P. radix. Exposure of zebrafish larvae to Esculentoside B caused developmental abnormalities, neurotoxicity and altered locomotor behavior. The combination of AChE activity and the expression levels of genes relevant to CNS development demonstrated that Esculentoside B is neurotoxic to zebrafish larvae, impairs their CNS development, and that AChE may be a toxic target of Esculentoside B. Metabolomic analysis has revealed that Esculentoside B exposure can disrupt D-Amino acid metabolism, protein export, autophagy, and mTOR signaling pathways in zebrafish larvae. These findings provide insights into the molecular mechanisms underlying EsB-induced neurotoxicity in zebrafish, which can facilitate further research and development of P. radix for safe consumption.PMID:37080526 | DOI:10.1016/j.fct.2023.113777

J Affect Disord. 2023 Apr 18:S0165-0327(23)00492-5. doi: 10.1016/j.jad.2023.04.031. Online ahead of print.ABSTRACTBACKGROUND: The gut-brain axis has been shown to play an important role in depression. However, few studies have examined proteomic changes in the intestine of the nonhuman primate model of depression.METHODS: We investigated the intestinal proteome of macaques (Macaca fascicularis) with depression-like (DL) behaviors by data-independent acquisition techniques. We also performed integration analyses of proteomic changes, previous metabolomic and microbiotic data. Moreover, we confirmed the gene expressions of key proteins.RESULTS: Sixty-five differentially expressed proteins (DEPs) were identified, of which fifty-four DEPs were down-regulated and the others were altered conversely in DL macaques compared with the control group. Pathway analysis indicated that mitochondrial function and energy metabolism were representative functions of DEPs. The key DEPs were significantly associated with glycerophospholipid metabolism and imbalances of gut microbe. We confirmed that key molecules (NDUFB4, UQCR10, PISD) were significantly inhibited, which may disturb the energy transformation of the electron respiratory chain and the homeostasis of the mitochondrial membrane.LIMITATIONS: Further research is warranted to determine the effects of depression on other peripheral organs.CONCLUSIONS: These findings suggest the functional disorder of intestinal mitochondria in DL macaques. The disturbances of glycerophospholipid metabolism and gut microbiota may exacerbate disruptions of energy metabolism. Taking together, our study provides new clues to the relationship between depression and intestinal proteome.PMID:37080496 | DOI:10.1016/j.jad.2023.04.031

Int J Biol Macromol. 2023 Apr 18:124419. doi: 10.1016/j.ijbiomac.2023.124419. Online ahead of print.ABSTRACTThe intestinal mucosal barrier is one of the important barriers to prevent harmful substances and pathogens from entering the body environment and to maintain intestinal homeostasis. This study investigated the reparative effect and possible mechanism of Tetrastigma hemsleyanum polysaccharides (THP) on ceftriaxone-induced intestinal mucosal damage. Our results suggested that THP repaired the mechanical barrier damage of intestinal mucosa by enhancing the expression of intestinal tight junction proteins, reducing intestinal mucosal permeability and improving the pathological state of intestinal epithelial cells. Intestinal immune and chemical barrier was further restored by THP via the increment of the body's cytokine levels, intestinal SIgA levels, intestinal goblet cell number, intestinal mucin-2 levels, and short-chain fatty acid levels. In addition, THP increased the abundance of probiotic bacteria (such as Lactobacillus), reduced the abundance of harmful bacteria (such as Enterococcus) to repair the intestinal biological barrier, restored intestinal mucosal barrier function, and maintains intestinal homeostasis. The possible mechanisms were related to sphingolipid metabolism, linoleic acid metabolism, and d-glutamine and D-glutamate metabolism. Our results demonstrated the potential therapeutic effect of THP against intestinal flora disorders and intestinal barrier function impairment caused by antibiotics.PMID:37080409 | DOI:10.1016/j.ijbiomac.2023.124419

J Ethnopharmacol. 2023 Apr 18:116505. doi: 10.1016/j.jep.2023.116505. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Dachaihu decoction (DCH), a classic formula for Yangming and Shaoyang Syndrome Complex recorded in "Treatise on Cold Damage", has been widely used in treating intestinal disorders and inflammatory diseases with few side effects in China. However, the mechanism of DCH on septic intestinal injury (SII) remain to be explored.AIM OF THE STUDY: This study aimed to clarify the mechanism of DCH on SII.MATERIALS AND METHODS: SII model of rat, established by cecal ligation and puncture (CLP), was used to study the effect of DCH on SII. 24 h mortality was recorded. Histological changes were observed by H&E staining. The expression of tight junction protein ZO-1 (ZO-1) and mucin2 (MUC2) was determined by immunohistochemical analysis. Secretory IgA (sIgA), diamine oxidase (DAO) and intestinal fatty acid binding protein (iFABP) were determined by enzyme-linked immunosorbent assay (ELISA). IL-1β, IL-6 and TNF-α were measured by ELISA and quantitative Real-time PCR (RT-qPCR). The gut microbiota was analyzed by 16 S rRNA sequencing. The potential targets and pathways of DCH in treating SII were analyzed by integrative analysis of transcriptomic and metabolomic methods. Total glutathione (T-GSH), GSH, GSSG (reduced form of GSH), GSH peroxidase (GPX), superoxide dismutase (SOD), malonaldehyde (MDA) and indicators of hepatic and renal function were measured by biochemical kits.RESULTS: Medium dose of DCH improved 24 h mortality of SII rats, reduced the pathological changes of ileum, and increased the expression levels of ZO-1, MUC2 and sIgA. DCH decreased DAO, iFABP of serum and IL-1β, IL-6, TNF-α of ileum. DCH improved α- and β-diversity and modulated the structure of gut microbiota, with Escherichia_Shigella decreased and Bacteroides and Ruminococcus increased. GSH metabolism was identified as the key pathway of DCH on SII by integrative analysis of transcriptome and metabolome. GSH/GSSG and the most common indicators of oxidative stress, were validated. Antioxidative T-GSH, GSH, GPX and SOD were increased, while MDA, the mark of lipid peroxidation was downregulated by DCH. Eventually, DCH was proved to be safe and hepato- and nephro-protective.CONCLUSION: DCH ameliorated septic intestinal injury possibly by modulating the gut microbiota and enhancing glutathione metabolism of SII rats, without hepatotoxicity and nephrotoxicity.PMID:37080366 | DOI:10.1016/j.jep.2023.116505

Crit Care. 2023 Apr 18;27(1):147. doi: 10.1186/s13054-023-04435-4.NO ABSTRACTPMID:37072785 | PMC:PMC10114463 | DOI:10.1186/s13054-023-04435-4

Gut. 2023 Apr 18:gutjnl-2022-329213. doi: 10.1136/gutjnl-2022-329213. Online ahead of print.ABSTRACTOBJECTIVE: Bile acid diarrhoea (BAD) is debilitating yet treatable, but it remains underdiagnosed due to challenging diagnostics. We developed a blood test-based method to guide BAD diagnosis.DESIGN: We included serum from 50 treatment-naive patients with BAD diagnosed by gold standard 75selenium homotaurocholic acid test, 56 feature-matched controls and 37 patients with non-alcoholic fatty liver disease (NAFLD). Metabolomes were generated using mass spectrometry covering 1295 metabolites and compared between groups. Machine learning was used to develop a BAD Diagnostic Score (BDS).RESULTS: Metabolomes of patients with BAD significantly differed from controls and NAFLD. We detected 70 metabolites with a discriminatory performance in the discovery set with an area under receiver-operating curve metric above 0.80. Logistic regression modelling using concentrations of decanoylcarnitine, cholesterol ester (22:5), eicosatrienoic acid, L-alpha-lysophosphatidylinositol (18:0) and phosphatidylethanolamine (O-16:0/18:1) distinguished BAD from controls with a sensitivity of 0.78 (95% CI 0.64 to 0.89) and a specificity of 0.93 (95% CI 0.83 to 0.98). The model was independent of covariates (age, sex, body mass index) and distinguished BAD from NAFLD irrespective of fibrosis stage. BDS outperformed other blood test-based tests (7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19) currently under development.CONCLUSIONS: BDS derived from serum metabolites in a single-blood sample showed robust identification of patients with BAD with superior specificity and sensitivity compared with current blood test-based diagnostics.PMID:37072179 | DOI:10.1136/gutjnl-2022-329213

J Ethnopharmacol. 2023 Apr 16:116481. doi: 10.1016/j.jep.2023.116481. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The combined prescription of two classical decoctions (Ma-Xing-Shi-Gan decoction with Xiao-Chai-Hu decoction), named as San-Yang-He-Zhi (SYHZ) decoction, has been widely used for the treatment of influenza virus (IFV) infections for decades.AIM OF THE STUDY: This study aimed to evaluate the anti-influenza effect of SYHZ decoction and explore the underlying mechanism.MATERIALS AND METHODS: The ingredients of SYHZ decoction were analyzed by mass spectrometry. An animal model of IFV infection was established by challenging C57BL/6J mice with PR8 virus. Three groups of mice were infected with lethal or non-lethal doses of IFV, then followed by oral administration of phosphate-buffered saline (PBS), or SYHZ, or oseltamir; blank control mice (without IFV infection) were treated with PBS. Survival rate, Lung index, colon length, body weight loss and IFV viral load were measured 7 days post infection; histology and electron-microscopy examinations of lung tissue were performed; cytokine and chemokine levels in lung and serum were measured; and the intestinal metagenome, the cecum metabolome, and the lung transcriptome were analyzed.RESULTS: SYHZ treatment significantly improved survival rate compared with PBS (40% vs 0%); improved lung index, colon length, and body weight loss; and alleviated lung histological damage and viral load. SYHZ-treated mice had significantly lower levels of IL-1β, TNF-α, IL-6, CCL2, CXCL10 in lung and serum, and increased levels of multiple bioactive components in cecum. Pro-inflammatory cytokines, Toll- and NOD-like receptors, pro-apoptosis molecules, and lung-injury-related proteins were downregulated in SYHZ mice, whereas surfactant protein and mucin were upregulated. The NOD-like receptor pathway, Toll-like receptor pathway, and NF-κB pathway were downregulated by SYHZ treatment.CONCLUSIONS: SYHZ decoction alleviated IFV infection in a mouse model. Multiple bioactive ingredients of SYHZ may inhibit replication of IFV and suppress excessive immune response.PMID:37072090 | DOI:10.1016/j.jep.2023.116481

Int J Biol Macromol. 2023 Apr 16:124479. doi: 10.1016/j.ijbiomac.2023.124479. Online ahead of print.ABSTRACTAmmopiptanthus mongolicus, an evergreen broad-leaved plant, can tolerate severe freezing stress (temperatures as low as -20 °C in winter). The apoplast is the space outside the plasma membrane that plays an important role in plant responses to environmental stress. Here, we investigated, using a multi-omics approach, the dynamic alterations in the levels of proteins and metabolites in the apoplast and related gene expression changes involved in the adaptation of A. mongolicus to winter freezing stress. Of the 962 proteins identified in the apoplast, the abundance of several PR proteins, including PR3 and PR5, increased significantly in winter, which may contribute to winter freezing-stress tolerance by functioning as antifreeze proteins. The increased abundance of the cell-wall polysaccharides and cell wall-modifying proteins, including PMEI, XTH32, and EXLA1, may enhance the mechanical properties of the cell wall in A. mongolicus. Accumulation of flavonoids and free amino acids in the apoplast may be beneficial for ROS scavenging and the maintenance of osmotic homeostasis. Integrated analyses revealed gene expression changes associated with alterations in the levels of apoplast proteins and metabolites. Our study improved the current understanding of the roles of apoplast proteins and metabolites in plant adaptation to winter freezing stress.PMID:37072058 | DOI:10.1016/j.ijbiomac.2023.124479

Physiol Plant. 2023 Apr 18:e13914. doi: 10.1111/ppl.13914. Online ahead of print.ABSTRACTHydrangea (Hydrangea arborescens var. 'Annabelle') flowers are composed of sweet aroma sepals rather than true petals and can change color. Floral volatiles play important roles in plants, such as attracting pollinators, defending against herbivores, and signaling. However, the biosynthesis and regulatory mechanisms underlying fragrance formation in H. arborescens during flower development remain unknown. In this study, a combination of metabolite profiling and RNA sequencing (RNA-seq) was employed to identify genes associated with floral scent biosynthesis mechanisms in 'Annabelle' flowers at three developmental stages (F1, F2, and F3). The floral volatile data revealed that the 'Annabelle' volatile profile includes a total of 33 volatile organic compounds (VOCs), and VOCs were abundant during the F2 stage of flower development, followed by the F1 and F3 stages, respectively. Terpenoids and benzenoids/phenylpropanoids were abundant during the F2 and F1 stages, with the latter being the most abundant, whereas fatty acid derivatives and other compounds were found in large amount during the F3 stage. According to ultra performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS) analysis, benzene and substituted derivatives, carboxylic acids and derivatives, and fatty acyls play a significant role in the floral metabolite profile. The transcriptome data revealed a total of 17,461 differentially expressed genes (DEGs), with 7,585, 12,795, and 9,044 DEGs discovered between the F2 and F1, F3 and F1, and F2 and F3 stages, respectively. Several terpenoids and benzenoids/phenylpropanoids biosynthesis-related DEGs were identified, and GRAS/bHLH/MYB/AP2/WRKY were more abundant among transcription factors (TFs). Finally, DEGs interlinked with VOCs compounds were determined using cytoscape and k-means analysis. Our results paves the way for the discovery of new genes, critical data for future genetic studies, and a platform for the metabolic engineering of genes involved in the production of Hydrangea's signature floral fragrance.PMID:37072650 | DOI:10.1111/ppl.13914

Nat Commun. 2023 Apr 18;14(1):2210. doi: 10.1038/s41467-023-37843-9.ABSTRACTThe number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-Seq, RNA-seq, ribo-profiling and proteomics we observed distinct molecular consequences of single tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.PMID:37072429 | DOI:10.1038/s41467-023-37843-9

Chem Biodivers. 2023 Apr 18:e202201047. doi: 10.1002/cbdv.202201047. Online ahead of print.ABSTRACTPhenylpropionamides in the seed of Cannabis sativa L. (PHS) have a protective effect on neuroinflammation and antioxidant activity. In this study, the UHPLC-Orbitrap-fusion-TMS-based metabolomics approach was used to analyze the serum samples and identify potential biomarkers in Streptozotocin (STZ) induced Alzheimer's disease (AD) rats. The results revealed that ptimary bile acid biosynthesis and taurine and hypotaurine metabolism were significantly correlated with STZ-induced AD rats. In addition, the key enzymes in these two pathways were verified at the protein level. The levels of cysteine dioxygenase type I (CDO1), cysteine sulfinic acid decarboxylase (CSAD), cysteamine (2-aminoethanethiol) dioxygenase (ADO), 7α-hydroxylase (CYP7A1), and sterol 12α-hydroxylase (CYP8B1) were the key enzymes affecting the two pathways in AD rats compared with the control group (CON). Furthermore, after a high-dose group of phenylpropionamides in the seed of Cannabis sativa L. (PHS-H) was administrated, the levels of CDO1, CSAD, CYP7A1, and CYP8B1 were all callback. These findings demonstrate for the first time that the anti-AD effect of PHS is associated with the regulation of primary bile acid biosynthesis and taurine and hypotaurine metabolism in STZ-induced AD rats.PMID:37072341 | DOI:10.1002/cbdv.202201047

Bioinformatics. 2023 Apr 18:btad195. doi: 10.1093/bioinformatics/btad195. Online ahead of print.ABSTRACTMOTIVATION: Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) is widely used in composition profiling in untargeted metabolomics research. While retaining complete sample information, mass spectrometry (MS) data naturally have the characteristics of high dimensionality, high complexity, and huge data volume. In mainstream quantification methods, none of the existing methods can perform direct three-dimensional analysis on lossless profile MS signals. All software simplifies calculations by dimensionality reduction or lossy grid transformation, ignoring the full three-dimensional signal distribution of mass spectrometry data and resulting in inaccurate feature detection and quantification.RESULTS: On the basis that the neural network is effective for high-dimensional data analysis and can discover implicit features from large amounts of complex data, in this work, we propose 3D-MSNet, a novel deep-learning-based model for untargeted feature extraction. 3D-MSNet performs direct feature detection on three-dimensional MS point clouds as an instance segmentation task. After training on a self-annotated 3D feature dataset, we compared our model with 9 popular software (MS-DIAL, MZmine 2, XCMS Online, MarkerView, Compound Discoverer, MaxQuant, Dinosaur, DeepIso, PointIso) on two metabolomics and one proteomics public benchmark datasets. Our 3D-MSNet model outperformed other software with significant improvement in feature detection and quantification accuracy on all evaluation datasets. Furthermore, 3D-MSNet has high feature extraction robustness and can be widely applied to profile MS data acquired with various high-resolution mass spectrometers with various resolutions.AVAILABILITY: 3D-MSNet is open-source and freely available at https://github.com/CSi-Studio/3D-MSNet under a permissive license. Benchmark datasets, training dataset, evaluation methods and results are available at https://doi.org/10.5281/zenodo.6582912.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.PMID:37071700 | DOI:10.1093/bioinformatics/btad195

J Hypertens. 2023 Apr 6. doi: 10.1097/HJH.0000000000003423. Online ahead of print.ABSTRACTBACKGROUND: Hypertension is the largest risk factor affecting global mortality. Despite available medications, uncontrolled hypertension is on the rise, whereby there is an urgent need to develop novel and sustainable therapeutics. Because gut microbiota is now recognized as an important entity in blood pressure regulation, one such new avenue is to target the gut-liver axis wherein metabolites are transacted via host-microbiota interactions. Knowledge on which metabolites within the gut-liver axis regulate blood pressure is largely unknown.METHOD: To address this, we analyzed bile acid profiles of both human and hypertensive rat models and report that conjugated bile acids are inversely correlated with blood pressure in humans and rats.RESULTS: Notably intervening with taurine rescued bile acid conjugation and reduced blood pressure in hypertensive rats. Subsequently, untargeted metabolomics uncovered lower energy metabolism following conjugation of bile acids as a mechanism alleviating high blood pressure.CONCLUSION: Together this work reveals conjugated bile acids as nutritionally re-programmable anti-hypertensive metabolites.GRAPHICAL ABSTRACT: http://links.lww.com/HJH/C165.PMID:37071431 | DOI:10.1097/HJH.0000000000003423

Dig Dis Sci. 2023 Apr 18. doi: 10.1007/s10620-023-07931-3. Online ahead of print.ABSTRACTBACKGROUND: Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to its therapeutic resistance. Inactivation of vitamin D/vitamin D receptor (VDR) signaling may contribute to the malignant phenotype of PDA and altered expression of oncoprotein mucin 1 (MUC1) may be involved in drug resistance of cancer cells.AIM: To determine whether vitamin D/VDR signaling regulates the expression and function of MUC1 and its effect on acquired gemcitabine resistance of pancreatic cancer cells.METHODS: Molecular analyses and animal models were used to determine the impact of vitamin D/VDR signaling on MUC1 expression and response to gemcitabine treatment.RESULTS: RPPA analysis indicated that MUC1 protein expression was significantly reduced in human PDA cells after treatment with vitamin D3 or its analog calcipotriol. VDR regulated MUC1 expression in both gain- and loss-of-function assays. Vitamin D3 or calcipotriol significantly induced VDR and inhibited MUC1 expression in acquired gemcitabine-resistant PDA cells and sensitized the resistant cells to gemcitabine treatment, while siRNA inhibition of MUC1 was associated with paricalcitol-associated sensitization of PDA cells to gemcitabine treatment in vitro. Administration of paricalcitol significantly enhanced the therapeutic efficacy of gemcitabine in xenograft and orthotopic mouse models and increased the intratumoral concentration of dFdCTP, the active metabolite of gemcitabine.CONCLUSION: These findings demonstrate a previously unidentified vitamin D/VDR-MUC1 signaling axis involved in the regulation of gemcitabine resistance in PDA and suggests that combinational therapies that include targeted activation of vitamin D/VDR signaling may improve the outcomes of patients with PDA.PMID:37071246 | DOI:10.1007/s10620-023-07931-3

Eur Radiol. 2023 Apr 18. doi: 10.1007/s00330-023-09638-5. Online ahead of print.NO ABSTRACTPMID:37071172 | DOI:10.1007/s00330-023-09638-5

Appl Microbiol Biotechnol. 2023 Apr 18. doi: 10.1007/s00253-023-12524-1. Online ahead of print.ABSTRACTPrevious studies regarding the gastrointestinal biogeography of microbiomes generally focused on longitudinal comparisons, whereas few studies have compared luminal and mucosal microbiomes. Investigations of the snake gut microbiome have attracted interest because of the unique digestive physiology and hibernation behavior, but adequate sampling methods must be developed. Here, we used an omics approach combining 16S rRNA gene sequencing with untargeted metabolomics to profile the luminal and mucosal gut microbiomes and metabolomes in oriental rat snakes, with the goal of revealing the heterogeneity and co-occurrence at these sites. The α-diversity of the gut microbiome was significantly higher at mucosal sites than at luminal sites. Microbial composition also differed according to sampling site, with significant differences in the abundances of dominant phyla and genera, as well as β-diversity clustering and distribution. Metabolome profiling revealed differences that were mainly related to cholinergic substances and nucleic acids. Analysis of variations in Kyoto Encyclopedia of Genes and Genomes functions of microbes and metabolites showed that the mucosal microbiome was more frequently involved in genetic information processing and cellular processes, whereas the luminal microbiome generally participated in metabolic regulation. Notably, we found a greater abundance of the opportunistic pathogen genus Escherichia-Shigella at luminal sites and higher levels of the lipid-regulator metabolite fenfluramine at mucosal sites. Despite the extensive differences between the two sampling sites, the results revealed similarities in terms of amplicon sequence variant composition and dominant core microbes. This pilot exploration of luminal and mucosal microbiomes and metabolites provides key insights to guide future research. KEY POINTS: • Snake luminal and mucosal microbiota was distinct in composition and function. • Metabolome profiling revealed differences related to different metabolites. • The pathogenic microbes are more likely to colonize the gut lumina.PMID:37071138 | DOI:10.1007/s00253-023-12524-1

Radiology. 2023 Apr 18:222010. doi: 10.1148/radiol.222010. Online ahead of print.ABSTRACTBackground Prostate-specific membrane antigen (PSMA) PET has high specificity in localizing primary tumors and metastases in patients with prostate cancer, but the individual overall survival probability is still difficult to estimate. Purpose To develop a prognostic risk score using PSMA PET-derived organ-specific total tumor volumes for predicting overall survival in patients with prostate cancer. Materials and Methods Men with prostate cancer who underwent PSMA PET/CT from January 2014 to December 2018 were evaluated retrospectively. All patients from center A were split into training (80%) and internal validation (20%) cohorts. Randomly selected patients from center B were used for external validation. Organ-specific tumor volumes were automatically quantified from PSMA PET scans by a neural network. A prognostic score was selected using multivariable Cox regression guided by the Akaike information criterion (AIC). The final prognostic risk score fitted on the training set was applied to both validation cohorts. Results A total of 1348 men (mean age, 70 years ± 8 [SD]) were included, with 918 patients in the training cohort, 230 in the internal validation cohort, and 200 in the external validation cohort. The median follow-up time was 55.7 months (IQR, 46.7-65.1 months; >4 years; 429 deaths occurred). A body weight-adjusted prognostic risk score integrating total, bone, and visceral tumor volumes obtained high C index values in the internal (0.82) and external (0.74) validation cohorts, as well as in patients with castration-resistant (0.75) and hormone-sensitive (0.68) disease. The fit of the statistical model for the prognostic score was improved compared with a model containing total tumor volume only (AIC, 3324 vs 3351; likelihood ratio test, P < .001). Calibration plots ascertained good model fit. Conclusion The newly developed risk score that included prostate-specific membrane antigen PET-derived organ-specific tumor volumes had good model fit for predicting overall survival in both internal and external validation cohorts. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Civelek in this issue.PMID:37070991 | DOI:10.1148/radiol.222010

Scand J Gastroenterol. 2023 Apr 18:1-10. doi: 10.1080/00365521.2023.2200518. Online ahead of print.ABSTRACTBACKGROUND: The indolent course of treatment-naive patients with inflammatory bowel disease (IBD) is confirmed predictable based on clinical characteristics. Current evidences supported that bile acids (BAs) alteration might be promising biomarkers in the field of IBD. We aimed to analyze the alterations of BAs as the disease progresses and explore their predictive value for indolent course of IBD.METHODS: The indolent course of IBD was defined as a disease course without need for strict interventions throughout the entire follow-up. A targeted metabolomics method was used to detect the concentration of 27 BAs from serum sample in treatment-naive patients with IBD (Crohn's disease [CD], n = 27; ulcerative colitis [UC], n = 50). Patients with CD and UC were individually divided into two groups for further study according to the median time of indolent course. The overall BAs profile and the clinical value of BAs in predicting indolent course of IBD were identified between different groups.RESULTS: For CD, the levels of deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycolithocholic acid-3-sulfate disodium salt and iso-lithocholic acid were significantly increased in patients with indolent course > 18 M (p < 0.05). These five BAs owned 83.5% accuracy for predicting indolent course over 18 months in CD. For UC, the concentration of deoxycholic acid and glycodeoxycholic acid were significantly higher, while dehydrocholic acid were lower in patients with indolent course > 48 M (p < 0.05). These three BAs predicted indolent course over 48 months of 69.8% accuracy in UC.CONCLUSION: The specific BAs alterations might be potential biomarkers in predicting disease course of IBD patients.PMID:37070769 | DOI:10.1080/00365521.2023.2200518

Am J Physiol Lung Cell Mol Physiol. 2023 Apr 18. doi: 10.1152/ajplung.00003.2023. Online ahead of print.ABSTRACTBACKGROUND: Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH.METHODS: Consecutive subjects with PAH (n=23) underwent rest and exercise right heart catheterization with multi-beat pressure volume loop analysis. Pulmonary arterial blood was collected at rest and during exercise. Mass spectrometry-based targeted metabolomics were performed, and metabolic associations with hemodynamics and comprehensive measures of RV function were determined using sparse partial least squares regression. Metabolite profiles were compared to pro-BNP measurements for accuracy in modeling ventriculo-arterial parameters.RESULTS: Thirteen metabolites changed in abundance with exercise, including metabolites reflecting increased arginine bioavailability, precursors of catecholamine and nucleotide synthesis, and branched chain amino acids. Higher resting arginine bioavailability predicted more favorable exercise hemodynamics and pressure-flow relationships. Subjects with more severe PAH augmented arginine bioavailability with exercise to a greater extent than subjects with less severe PAH. We identified relationships between kynurenine pathway metabolism and impaired ventriculo-arterial coupling, worse RV diastolic function, lower RV contractility, diminished RV contractility with exercise, and RV dilation with exercise. Metabolite profiles outperformed pro-BNP in modeling RV contractility, diastolic function, and exercise performance.CONCLUSIONS: Specific metabolite profiles correspond to RV functional measurements only obtainable via invasive pressure-volume loop analysis and predict RV responses to exercise. Metabolic profiling may inform discovery of RV functional biomarkers.PMID:37070742 | DOI:10.1152/ajplung.00003.2023