PubMed

Anal Sci. 2024 Apr 12. doi: 10.1007/s44211-024-00568-w. Online ahead of print.ABSTRACTThe silk biodegradation process remains unclear and requires elucidation with advanced analytical tools. To address this challenge, the role of microbial primary metabolites in the deterioration of ancient silk was investigated using metabolomics and proteomics techniques in this work. The oxalic and palmitic acids were separately identified as the most abundant organic and fatty acid metabolites for silk-fabric deterioration via metabolomics. Proteomics showed that oxalic acid accelerated the degradation of silk proteins, revealing changes at the molecular level in silk. A high concentration of oxalic acid promoted the dissolution of peptides by activating the cleavage activity of various amino acids on the molecular chain of silk protein. Palmitic acid formed sedimentary particulate matter with peptides solubilised from silk proteins, indicating the possibility that traces of ancient-silk proteins remained in the fatty acids. The work presented new techniques and concepts for studying the degradation of historical fabrics and contributed to the proposal of effective measures to prevent microbial attack on silk.PMID:38607599 | DOI:10.1007/s44211-024-00568-w

Eur Heart J. 2024 Apr 12:ehae188. doi: 10.1093/eurheartj/ehae188. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The crosstalk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. This study aimed to identify its underlying mechanism and explore potential therapeutic targets.METHODS: Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors.RESULTS: In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, but these phenotypes were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α neutralizing antibody could improve cardiac functions in AML mice after DNR treatment.CONCLUSIONS: This study revealed that crosstalk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energy metabolism and impair heart function. IL-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.PMID:38607560 | DOI:10.1093/eurheartj/ehae188

Plant Foods Hum Nutr. 2024 Apr 12. doi: 10.1007/s11130-024-01161-2. Online ahead of print.ABSTRACTBroccoli is commonly consumed as food and as medicine. However, comprehensive metabolic profiling of two broccoli varieties, Romanesco broccoli (RB) and purple broccoli (PB), in relation to their anticholinergic activity has not been fully disclosed. A total of 110 compounds were tentatively identified using UPLC-Q-TOF-MS metabolomics. Distinctively different metabolomic profiles of the two varieties were revealed by principal component analysis (PCA). Furthermore, by volcano diagram analysis, it was found that PB had a significantly higher content of phenolic acids, flavonoids, and glucosinolates, indicating the different beneficial health potentials of PB that demonstrated higher antioxidant and anticholinergic activities. Moreover, Pearson's correlation analysis revealed 18 metabolites, mainly phenolic and sulfur compounds, as the main bioactive. The binding affinity of these biomarkers to the active sites of acetyl- and butyryl-cholinesterase enzymes was further validated using molecular docking studies. Results emphasize the broccoli significance as a functional food and nutraceutical source and highlight its beneficial effects against Alzheimer's disease.PMID:38607508 | DOI:10.1007/s11130-024-01161-2

mSystems. 2024 Apr 12:e0009324. doi: 10.1128/msystems.00093-24. Online ahead of print.ABSTRACTThe increasing resistance of clinically relevant microbes against current commercially available antimicrobials underpins the urgent need for alternative and novel treatment strategies. Cationic lipidated oligomers (CLOs) are innovative alternatives to antimicrobial peptides and have reported antimicrobial potential. An understanding of their antimicrobial mechanism of action is required to rationally design future treatment strategies for CLOs, either in monotherapy or synergistic combinations. In the present study, metabolomics was used to investigate the potential metabolic pathways involved in the mechanisms of antibacterial activity of one CLO, C12-o-(BG-D)-10, which we have previously shown to be effective against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. The metabolomes of MRSA ATCC 43300 at 1, 3, and 6 h following treatment with C12-o-(BG-D)-10 (48 µg/mL, i.e., 3× MIC) were compared to those of the untreated controls. Our findings reveal that the studied CLO, C12-o-(BG-D)-10, disorganized the bacterial membrane as the first step toward its antimicrobial effect, as evidenced by marked perturbations in the bacterial membrane lipids and peptidoglycan biosynthesis observed at early time points, i.e., 1 and 3 h. Central carbon metabolism and the biosynthesis of DNA, RNA, and arginine were also vigorously perturbed, mainly at early time points. Moreover, bacterial cells were under osmotic and oxidative stress across all time points, as evident by perturbations of trehalose biosynthesis and pentose phosphate shunt. Overall, this metabolomics study has, for the first time, revealed that the antimicrobial action of C12-o-(BG-D)-10 may potentially stem from the dysregulation of multiple metabolic pathways.IMPORTANCEAntimicrobial resistance poses a significant challenge to healthcare systems worldwide. Novel anti-infective therapeutics are urgently needed to combat drug-resistant microorganisms. Cationic lipidated oligomers (CLOs) show promise as new antibacterial agents against Gram-positive pathogens like methicillin-resistant Staphylococcus aureus (MRSA). Understanding their molecular mechanism(s) of antimicrobial action may help design synergistic CLO treatments along with monotherapy. Here, we describe the first metabolomics study to investigate the killing mechanism(s) of CLOs against MRSA. The results of our study indicate that the CLO, C12-o-(BG-D)-10, had a notable impact on the biosynthesis and organization of the bacterial cell envelope. C12-o-(BG-D)-10 also inhibits arginine, histidine, central carbon metabolism, and trehalose production, adding to its antibacterial characteristics. This work illuminates the unique mechanism of action of C12-o-(BG-D)-10 and opens an avenue to design innovative antibacterial oligomers/polymers for future clinical applications.PMID:38606960 | DOI:10.1128/msystems.00093-24

Plant Physiol. 2024 Apr 12:kiae202. doi: 10.1093/plphys/kiae202. Online ahead of print.ABSTRACTGinsenosides, the primary bioactive constituents in ginseng (Panax ginseng), possess substantial pharmacological potential and are in high demand in the market. The plant hormone methyl jasmonate (MeJA) effectively elicits ginsenoside biosynthesis in P. ginseng, though the regulatory mechanism remains largely unexplored. NAC transcription factors are critical in intricate plant regulatory networks and participate in numerous plant physiological activities. In this study, we identified a MeJA-responsive NAC transcription factor gene, PgNAC72, from a transcriptome library produced from MeJA-treated P. ginseng callus. Predominantly expressed in P. ginseng flowers, PgNAC72 localizes to the nucleus. Overexpressing PgNAC72 (OE-PgNAC72) in P. ginseng callus notably elevated total saponin levels, particularly dammarane-type ginsenosides, by upregulating dammarenediol synthase (PgDDS), encoding a key enzyme in the ginsenoside biosynthesis pathway. Electrophoretic mobility shift assays and dual-luciferase assays confirmed that PgNAC72 binds to the NAC-binding elements in the PgDDS promoter, thereby activating its transcription. Further RNA-seq and terpenoid metabolomic data in the OE-PgNAC72 line confirmed that PgNAC72 enhances ginsenoside biosynthesis. These findings uncover a regulatory role of PgNAC72 in MeJA-mediated ginsenoside biosynthesis, providing insights into the ginsenoside regulatory network and presenting a valuable target gene for metabolic engineering.PMID:38606940 | DOI:10.1093/plphys/kiae202

World J Mens Health. 2024 Mar 27. doi: 10.5534/wjmh.230268. Online ahead of print.ABSTRACTPURPOSE: This study aimed to investigate the effect of the N6-methyladenosine (m6A) dependent ferroptosis on cisplatininduced Sertoli cell injury.MATERIALS AND METHODS: A cisplatin exposure mouse model was established by intraperitoneal injection of cisplatin in our study. TM4 cell lines was used for in vitro study. Ferroptosis was detected according to metabolomic analysis and a series of assays, including malondialdehyde, glutathione, and glutathione disulfide concentration detection, 2',7'-dichlorodihydrofluorescein diacetate and BODIPY 581/591 C11 probe detection, and transmission electron microscope imaging. Key ferroptosis-related genes were identified via transcriptomic analysis, western blot and immunohistochemistry. The m6A modification was demonstrated via m6A RNA immunoprecipitation and luciferase reporter assays. Immune cell infiltration was detected by mass cytometry, and verified by flow cytometry and immunofluorescence.RESULTS: Ferroptosis, but not other types of programmed cell death, is a significant phenomenon in cisplatin-induced testis damage and Sertoli cell loss. Ferroptosis induced by cisplatin in Sertoli cell/TM4 cell is GPX4 independent but is regulated by SLC7A11 and ALOX12. Both SLC7A11 and ALOX12 are regulated via m6A dependent manner by METTL3. Furthermore, overexpressed ALOX12-12HETE pathway may result in macrophage polarization and inflammatory response in cisplatin exposure testis.CONCLUSIONS: Cisplatin-induced Sertoli cell injury via ferroptosis and promoted ferroptosis in an m6A dependent manner. m6A modification of both SLC7A11 and ALOX12 mRNA could result in ferroptosis in our in vitro model. Further, overexpressed ALOX12 can cause more production of 12-HETE, which may be responsible for testis inflammation caused by cisplatin.PMID:38606861 | DOI:10.5534/wjmh.230268

ACS Appl Mater Interfaces. 2024 Apr 12. doi: 10.1021/acsami.4c00556. Online ahead of print.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma that contributes to aggressive tumor biology and therapeutic resistance. Current in vitro PDAC models lack sufficient optical and physical access for fibrous network visualization, in situ mechanical stiffness measurement, and metabolomic profiling. Here, we describe an openable multilayer microfluidic PDAC-on-a-chip platform that consists of pancreatic tumor cells (PTCs) and pancreatic stellate cells (PSCs) embedded in a 3D collagen matrix that mimics the stroma. Our system allows fibrous network visualization via reflected light confocal (RLC) microscopy, in situ mechanical stiffness testing using atomic force microscopy (AFM), and compartmentalized hydrogel extraction for PSC metabolomic profiling via mass spectrometry (MS) analysis. In comparing cocultures of gel-embedded PSCs and PTCs with PSC-only monocultures, RLC microscopy identified a significant decrease in pore size and corresponding increase in fiber density. In situ AFM indicated significant increases in stiffness, and hallmark characteristics of PSC activation were observed using fluorescence microscopy. PSCs in coculture also demonstrated localized fiber alignment and densification as well as increased collagen production. Finally, an untargeted MS study putatively identified metabolic contributions consistent with in vivo PDAC studies. Taken together, this platform can potentially advance our understanding of tumor-stromal interactions toward the discovery of novel therapies.PMID:38606850 | DOI:10.1021/acsami.4c00556

Front Pharmacol. 2024 Mar 28;15:1347120. doi: 10.3389/fphar.2024.1347120. eCollection 2024.ABSTRACTBackground: The occurrence and development of Hepatic fibrosis (HF) are closely related to the gut microbial composition and alterations in host metabolism. Qijia Rougan decoction (QJ) is a traditional Chinese medicine compound utilized clinically for the treatment of HF with remarkable clinical efficacy. However, its effect on the gut microbiota and metabolite alterations is unknown. Therefore, our objective was to examine the impact of QJ on the gut microbiota and metabolism in Carbon tetrachloride (CCl4)-induced HF. Methods: 40% CCl4 was used to induce HF, followed by QJ administration for 6 weeks. Serum biochemical analyses, histopathology, immunohistochemistry, RT-PCR, 16S rRNA gene sequencing, and non-targeted metabolomics techniques were employed in this study to investigate the interventional effects of QJ on a CCl4-induced HF model in rats. Results: This study demonstrated that QJ could effectively ameliorate CCl4-induced hepatic inflammation and fibrosis. Moreover, QJ upregulated the expression of intestinal tight junction proteins (TJPs) and notably altered the abundance of some gut microbes, for example, 10 genera closely associated with HF-related indicators and TJPs. In addition, metabolomics found 37 key metabolites responded to QJ treatment and strongly associated with HF-related indices and TJPs. Furthermore, a tight relation between 10 genera and 37 metabolites was found post correlation analysis. Among them, Turicibacter, Faecalibaculum, Prevotellaceae UCG 001, and unclassified Peptococcaceae may serve as the core gut microbes of QJ that inhibit HF. Conclusion: These results suggest that QJ ameliorates hepatic inflammation and fibrosis, which may be achieved by improving intestinal tight junctions and modulating gut microbiota composition as well as modulating host metabolism.PMID:38606180 | PMC:PMC11007057 | DOI:10.3389/fphar.2024.1347120

Front Nutr. 2024 Mar 28;11:1370975. doi: 10.3389/fnut.2024.1370975. eCollection 2024.ABSTRACTWith the development of animal husbandry, the shortage of animal feedstuffs has become serious. Dietary fiber plays a crucial role in regulating animal health and production performance. The aim of this study was to investigate the effects of three kinds of corn straw-saccharification fibers (CSSF) such as high-fiber and low-saccharification (HFLS), medium-fiber and medium-saccharification (MFMS), low-fiber and high-saccharification (LFHS) CSSF on the reproductive performance of sows. Thirty-two primiparous Yorkshire sows were randomly assigned to 4 groups, 8 sows for each group. Group A was the basal diet as the control group; groups B - D were added with 6% HFLSCSSF, 6% MFMSCSSF and 6% LFHSCSSF to replace some parts of corn meal and wheat bran in the basal diet, respectively. The experimental period was from day 85 of gestation to the end of lactation (day 25 post-farrowing). The results showed that 6% LFHSCSSF addition significantly increased number of total born (alive) piglets, litter weight at birth (p < 0.05), whereas three kinds of CSSF significantly decreased backfat thickness of sows during gestation (p < 0.001), compared with the control group. Furthermore, CSSF improved the digestibility of crude protein, ether extract and fiber for sows. In addition, the levels of total cholesterol, total triglycerides, and high-density lipoprotein cholesterol in serum of sows were decreased by different kinds of CSSF. Further analysis revealed that CSSF regulated lipid metabolism through adjusting the serum metabolites such as 4-pyridoxic acid, phosphatidyl cholines and L-tyrosine. In summary, CSSF addition to the diets of sows during late gestation and lactation regulated lipid metabolism and improved reproductive performance of sows. This study provided a theoretical basis for the application of corn straw in sow diets.PMID:38606017 | PMC:PMC11007230 | DOI:10.3389/fnut.2024.1370975

Cardiogenetics. 2023 Mar;13(1):33-46. doi: 10.3390/cardiogenetics13010005. Epub 2023 Mar 3.ABSTRACTSalt sensitivity is a trait in which high dietary sodium (Na+) intake causes an increase in blood pressure (BP). We previously demonstrated that in the gut, elevated dietary Na+ causes dysbiosis. The mechanistic interplay between excess dietary Na+-induced alteration in the gut microbiome and sex differences is less understood. The goal of this study was to identify novel metabolites in sex differences and blood pressure in response to a high dietary Na+ intake. We performed stool and plasma metabolomics analysis and measured the BP of human volunteers with salt intake above or below the American Heart Association recommendations. We also performed RNA sequencing on human monocytes treated with high salt in vitro. The relationship between BP and dietary Na+ intake was different in women and men. Network analysis revealed that fatty acids as top subnetworks differentially changed with salt intake. We found that women with high dietary Na+ intake have high levels of arachidonic acid related metabolism, suggesting a role in sex differences of the blood pressure response to Na+. The exposure of monocytes to high salt in vitro upregulates the transcription of fatty acid receptors and arachidonic acid-related genes. These findings provide potentially novel insights into metabolic changes underlying gut dysbiosis and inflammation in salt sensitivity of BP.PMID:38605973 | PMC:PMC11008634 | DOI:10.3390/cardiogenetics13010005

Phenomics. 2023 Sep 21;4(1):51-55. doi: 10.1007/s43657-023-00120-2. eCollection 2024 Feb.ABSTRACTCardiovascular health metrics are now widely recognized as modifiable risk factors for cognitive decline and dementia. Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia. Circulating metabolites profiling by metabolomics may improve understanding of the potential mechanism by which cardiovascular risk factors contribute to cognitive decline. In a prospective community-based cohort in China (n = 725), 312 serum metabolic phenotypes were quantified, and cardiovascular health score was calculated including smoking, exercise, sleep, diet, body mass index, blood pressure, and blood glucose. Cognitive function assessments were conducted in baseline and follow-up visits to identify longitudinal cognitive decline. A better cardiovascular health was significantly associated with lower risk of concentration decline and orientation decline (hazard ratio (HR): 0.84-0.90; p < 0.05). Apolipoprotein-A1, high-density lipoprotein (HDL) cholesterol, cholesterol ester, and phospholipid concentrations were significantly associated with a lower risk of longitudinal memory and orientation decline (p < 0.05 and adjusted-p < 0.20). Mediation analysis suggested that the negative association between health status and the risk of orientation decline was partly mediated by cholesterol ester and total lipids in HDL-2 and -3 (proportion of mediation: 7.68-8.21%, both p < 0.05). Cardiovascular risk factors were associated with greater risks of cognitive decline, which were found to be mediated by circulating lipoproteins, particularly the medium-size HDL components. These findings underscore the potential of utilizing lipoproteins as targets for early stage dementia screening and intervention.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-023-00120-2.PMID:38605906 | PMC:PMC11003945 | DOI:10.1007/s43657-023-00120-2

Front Microbiol. 2024 Mar 28;15:1363776. doi: 10.3389/fmicb.2024.1363776. eCollection 2024.ABSTRACTOBJECTIVE: The objective of this study is to investigate the causal relationship between gut microbiota and juvenile idiopathic arthritis, and to identify and quantify the potential role of plasma metabolites as mediators.METHODS: Using summary-level data from genome-wide association studies, a two-sample Mendelian randomization was conducted involving 131 gut microbiota genus, 1,400 plasma metabolites, and juvenile idiopathic arthritis. Additionally, a two-step approach was employed to quantify the proportion of the effect of gut microbiota on juvenile idiopathic arthritis mediated by plasma metabolites. Effect estimation primarily utilized Inverse Variance Weighting, with further validation using Bayesian weighted Mendelian randomization.RESULTS: In our MR analysis, a positive correlation was observed between Rikenellaceae and the risk of juvenile idiopathic arthritis, while Dorea showed a negative correlation with juvenile idiopathic arthritis risk. Mediation analysis indicated that Furaneol sulfate levels acted as a mediator between Dorea and juvenile idiopathic arthritis, with an indirect effect proportion of 19.94, 95% CI [8.86-31.03%].CONCLUSION: Our study confirms a causal relationship between specific microbial genus and juvenile idiopathic arthritis, and computes the proportion of the effect mediated by plasma metabolites, offering novel insights for clinical interventions in juvenile idiopathic arthritis.PMID:38605717 | PMC:PMC11007183 | DOI:10.3389/fmicb.2024.1363776

Front Microbiol. 2024 Mar 28;15:1373402. doi: 10.3389/fmicb.2024.1373402. eCollection 2024.ABSTRACTINTRODUCTION: The risk of ketosis is assessed by monitoring changes in plasma metabolites and cow behavior during the peripartum period. However, little is known about changes in the fecal bile acid and microbiota of cows before parturition. Therefore, this study clarified the bile acid profile and screened potential warning biomarkers in heifers 7 days before calving.METHODS: Ninety healthy cows were tracked in the transition period, and plasma and feces were collected 7 days before calving, on calving day, and 7 days after calving. The cows were divided into ketosis and healthy groups based on the blood β-hydroxybutyric acid levels from day 7 after calving. The levels of serum biochemical indices were measured at three time points using commercial kits. Ten cows in the ketosis group (KET-7) and 10 healthy cows (HEA-7) were randomly selected 7 days before calving for metabolome and 16S rRNA amplicon sequencing.RESULTS: No significant differences in serum energy-related indices were observed 7 days before calving. The major bile acids in the feces of the KET-7 group were non-conjugated secondary bile acids (UnconSBA). Differential bile acids were primarily derived from UnconSBA. The potential ketosis warning metabolite in feces for 7 days before delivery was isodeoxycholic acid. The abundance of Rikenellaaceae-RC9-gut-group in the KET-7 group increased, whereas the abundance of Oscillospiraceae UCG-010 bacteria significantly decreased. Lactobacillus and Prevotella-9 in feces were potential warning biomarkers for ketosis in dairy cows 7 days before calving. The variation in differential bile acids in the plasma, consistent with the feces, was mainly derived from UnconSBA. Lithocholic acid in the plasma was a potential ketosis warning metabolite 7 days before delivery.CONCLUSION: Ketotic cows experienced bile acid metabolism disorders 7 days before calving, and the gut microbiota was closely related to bile acid metabolism disorders. Future studies should investigate the relationship between secondary bile acids and the development of ketosis.PMID:38605714 | PMC:PMC11006965 | DOI:10.3389/fmicb.2024.1373402

Ann Clin Transl Neurol. 2024 Apr 11. doi: 10.1002/acn3.52047. Online ahead of print.ABSTRACTOBJECTIVE: Alzheimer's disease (AD) is characterized by the progressive degeneration and damage of neurons in the brain. However, developing an accurate diagnostic assay using blood samples remains a challenge in clinic practice. The aim of this study was to explore senescence-associated secretory phenotypes (SASPs) in peripheral blood using mass spectrometry based multi-omics approach and to establish diagnostic assays for AD.METHODS: This retrospective study included 88 participants, consisting of 29 AD patients and 59 cognitively normal (CN) individuals. Plasma and serum samples were examined using high-resolution mass spectrometry to identify proteomic and metabolomic profiles. Receiver operating characteristic (ROC) analysis was employed to screen biomarkers with diagnostic potential. K-nearest neighbors (KNN) algorithm was utilized to construct a multi-dimensional model for distinguishing AD from CN.RESULTS: Proteomics analysis revealed upregulation of five plasma proteins in AD, including RNA helicase aquarius (AQR), zinc finger protein 587B (ZNF587B), C-reactive protein (CRP), fibronectin (FN1), and serum amyloid A-1 protein (SAA1), indicating their potential for AD classification. Interestingly, KNN-based three-dimensional model, comprising AQR, ZNF587B, and CRP, demonstrated its high accuracy in AD recognition, with evaluation possibilities of 0.941, 1.000, and 1.000 for the training, testing, and validation datasets, respectively. Besides, metabolomics analysis suggested elevated levels of serum phenylacetylglutamine (PAGIn) in AD.INTERPRETATION: The multi-omics outcomes highlighted the significance of the SASPs, specifically AQR, ZNF587B, CRP, and PAGIn, in terms of their potential for diagnosing AD and suggested neuronal aging-associated pathophysiology.PMID:38605603 | DOI:10.1002/acn3.52047

Cancer Biol Med. 2024 Apr 9:j.issn.2095-3941.2023.0492. doi: 10.20892/j.issn.2095-3941.2023.0492. Online ahead of print.ABSTRACTOBJECTIVE: Mammographic calcifications are a common feature of breast cancer, but their molecular characteristics and treatment implications in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer remain unclear.METHODS: We retrospectively collected mammography records of an HR+/HER2- breast cancer cohort (n = 316) with matched clinicopathological, genomic, transcriptomic, and metabolomic data. On the basis of mammographic images, we grouped tumors by calcification status into calcification-negative tumors, tumors with probably benign calcifications, tumors with calcification of low-moderate suspicion for maligancy and tumors with calcification of high suspicion for maligancy. We then explored the molecular characteristics associated with each calcification status across multiple dimensions.RESULTS: Among the different statuses, tumors with probably benign calcifications exhibited elevated hormone receptor immunohistochemical staining scores, estrogen receptor (ER) pathway activation, lipid metabolism, and sensitivity to endocrine therapy. Tumors with calcifications of high suspicion for malignancy had relatively larger tumor sizes, elevated lymph node metastasis incidence, Ki-67 staining scores, genomic instability, cell cycle pathway activation, and may benefit from cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors.CONCLUSIONS: Our research established links between tumor calcifications and molecular features, thus proposing potential precision treatment strategies for HR+/HER2- breast cancer.PMID:38605478 | DOI:10.20892/j.issn.2095-3941.2023.0492

J Mass Spectrom. 2024 May;59(5):e5019. doi: 10.1002/jms.5019.ABSTRACTWine is one of the most consumed beverages around the world. Its unique characteristics arise from numerous processes, from the selection of grapevine varieties and grapes, the effect of the terroir and geographical origin, through the biochemical process of fermentation by microorganisms, until its aging. All molecules found in wine define its chemical fingerprint and can be used to tell the story of its origin, production, authenticity and quality. Wine's chemical composition can be characterized using an untargeted metabolomics approach based on extreme resolution mass spectrometry. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is currently the most powerful analytical technique to analyse such complex sample, providing the most comprehensive analysis of the chemical fingerprint of wine.PMID:38605464 | DOI:10.1002/jms.5019

BMJ Open Diabetes Res Care. 2024 Apr 11;12(2):e003973. doi: 10.1136/bmjdrc-2023-003973.ABSTRACTINTRODUCTION: Diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN) share common pathophysiology and pose an additive risk of early mortality.RESEARCH DESIGN AND METHODS: In adults with type 1 diabetes, 49 metabolites previously associated with either DR or DKD were assessed in relation to presence of DSPN. Metabolites overlapping in significance with presence of all three complications were assessed in relation to microvascular burden severity (additive number of complications-ie, presence of DKD±DR±DSPN) using linear regression models. Subsequently, the same metabolites were assessed with progression to endpoints: soft microvascular events (progression in albuminuria grade, ≥30% estimated glomerular filtration rate (eGFR) decline, or any progression in DR grade), hard microvascular events (progression to proliferative DR, chronic kidney failure, or ≥40% eGFR decline), and hard microvascular or macrovascular events (hard microvascular events, cardiovascular events (myocardial infarction, stroke, or arterial interventions), or cardiovascular mortality), using Cox models. All models were adjusted for sex, baseline age, diabetes duration, systolic blood pressure, HbA1c, body mass index, total cholesterol, smoking, and statin treatment.RESULTS: The full cohort investigated consisted of 487 participants. Mean (SD) follow-up was 4.8 (2.9, 5.7) years. Baseline biothesiometry was available in 202 participants, comprising the cross-sectional cohort. Eight metabolites were significantly associated with presence of DR, DKD, and DSPN, and six with additive microvascular burden severity. In the full cohort longitudinal analysis, higher levels of 3,4-dihydroxybutanoic acid (DHBA), 2,4-DHBA, ribonic acid, glycine, and ribitol were associated with development of events in both crude and adjusted models. Adding 3,4-DHBA, ribonic acid, and glycine to a traditional risk factor model improved the discrimination of hard microvascular events.CONCLUSIONS: While prospective studies directly assessing the predictive ability of these markers are needed, our results strengthen the role of clinical metabolomics in relation to risk assessment of diabetic complications in chronic type 1 diabetes.PMID:38604732 | DOI:10.1136/bmjdrc-2023-003973

Mol Metab. 2024 Apr 9:101934. doi: 10.1016/j.molmet.2024.101934. Online ahead of print.ABSTRACTOBJECTIVES: During fasting, liver pivotally regulates blood glucose levels through glycogenolysis and gluconeogenesis. Kidney also produces glucose through gluconeogenesis. Gluconeogenic genes are transactivated by fasting, but their expression patterns are chronologically different between the two organs. We find that renal gluconeogenic gene expressions are positively correlated with the blood β-hydroxybutyrate concentration. Thus, we herein aim to investigate the regulatory mechanism and its physiological implications.METHODS: Gluconeogenic gene expressions in liver and kidney were examined in hyperketogenic mice such as high fat diet (HFD)-fed and ketogenic diet-fed mice, and in hypoketogenic PPARα knockout (PPARα-/-) mice. Renal gluconeogenesis was evaluated by rise in glycemia after glutamine loading in vivo. Functional roles of β-hydroxybutyrate in the regulation of renal gluconeogenesis were investigated by metabolome analysis and RNA-seq analysis of proximal tubule cells.RESULTS: Renal gluconeogenic genes were transactivated concurrently with blood β-hydroxybutyrate uprise under ketogenic states, but the increase was blunted in hypoketogenic PPARα-/- mice. Administration of 1,3-butandiol, a ketone diester, transactivated renal gluconeogenic gene expression in fasted PPARα-/- mice. In addition, HFD-fed mice showed fasting hyperglycemia along with upregulated renal gluconeogenic gene expression, which was blunted in HFD-fed PPARα-/- mice. In vitro experiments and metabolome analysis in renal tubular cells showed that β-hydroxybutyrate directly promotes glucose and NH3 production through transactivating gluconeogenic genes. In addition, RNA-seq analysis revealed that β-hydroxybutyrate-induced transactivation of Pck1 was mediated by C/EBPβ.CONCLUSIONS: Our findings demonstrate that β-hydroxybutyrate mediates hepato-renal interaction to maintain homeostatic regulation of blood glucose and systemic acid-base balance through renal gluconeogenesis regulation.PMID:38604598 | DOI:10.1016/j.molmet.2024.101934

Immunol Lett. 2024 Apr 9:106857. doi: 10.1016/j.imlet.2024.106857. Online ahead of print.ABSTRACTTo control immune responses, regulatory CD4+CD25+Foxp3+ T cells (Treg) maintain their wide and diverse repertoire through continuous arrival of recent thymic emigrants (RTE). However, during puberty, the activity of RTE starts to decline as a natural process of thymic involution, introducing consequences, not completely described, to the repertoire. Type 1 diabetes (T1D) patients show quantitative and qualitative impairments on the Treg cells. Our aim was to evaluate peripheral Treg and RTE cell frequencies, in T1D patients from two distinct age groups (young and adults) and verify if HLA phenotypes are concomitant associated. To this, blood samples from Brazilian twenty established T1D patients (12 young and 8 adults) and twenty-one healthy controls (11 young and 10 adults) were analyzed, by flow cytometry, to verify the percentages of CD4, Treg (CD4+CD25+Foxp3+) and the subsets of CD45RA+ (naive) and CD31+(RTE) within then. Furthermore, the HLA typing was also set. We observed that the young established T1D patients feature decreased frequencies in total Treg cells and naive RTE within Treg cells. Significant prevalence of HLA alleles, associated with risk, in T1D patients, was also identified. Performing a multivariate analysis, we confirmed that the cellular changes described offers significant variables that distinct T1D patients from the controls. Our data collectively highlight relevant aspects about homeostasis imbalances in the Treg cells of T1D patients, especially in young, and disease prognosis; that might contribute for future therapeutic strategies involving Treg cells manipulation.PMID:38604551 | DOI:10.1016/j.imlet.2024.106857

Environ Res. 2024 Apr 9:118910. doi: 10.1016/j.envres.2024.118910. Online ahead of print.ABSTRACTEarthworms can resist high levels of soil copper (Cu) contamination and play an essential role in absorbing them effectively. However, the molecular mechanisms underlying Cu tolerance in earthworms are poorly understood. To address this research gap, we studied alterations of Eisenia fetida in antioxidant enzymes, gut microbiota, metabolites, and genes under varying levels of Cu exposure soils (0, 67.58, 168.96, 337.92 mg/kg). Our results revealed a reduction in antioxidant enzyme activities across all treatment groups, indicating an adaptive response to alleviate Cu-induced oxidative stress. Analysis of gut microbiota revealed a significant increase in the abundance of bacteria associated with nutrient uptake and Cu2+ excretion under Cu stress. Furthermore, metabolomic analysis discovered an increase in certain metabolites associated with energy metabolism, such as pyruvic acid, L-malic acid, and fumaric acid, as Cu concentration escalated. These results suggested that enhanced energy supply contributes to the elevated tolerance of E. fetida towards Cu. Additionally, transcriptome analysis not only identified crucial detoxification genes (Hsp70, CTSL, GST, CHAC, and GCLC), but also confirmed the critical role of glutathione metabolism as a key pathway in E. fetida Cu detoxification processes. These findings provide a new perspective on the molecular mechanisms of Cu tolerance in earthworms.PMID:38604487 | DOI:10.1016/j.envres.2024.118910