PubMed

BMC Pregnancy Childbirth. 2024 Aug 10;24(1):525. doi: 10.1186/s12884-024-06730-6.ABSTRACTBACKGROUND: The pregnant women with intrahepatic cholestasis were at high risk of fetal distress, preterm birth and unexpected stillbirth. Intrahepatic cholestasis of pregnancy (ICP) was mainly caused by disorder of bile acid metabolism, whereas the specific mechanism was obscure.METHODS: We performed proteomics analysis of 10 ICP specimens and 10 placenta specimens from patients without ICP through data-independent acquisition (DIA) technique to disclose differentially expressed proteins. We executed metabolomic analysis of 30 ICP specimens and 30 placenta specimens from patients without ICP through UPLC-MS/MS to identify differentially expressed metabolites. Enrichment and correlation analysis was used to obtain the direct molecular insights of ICP development. The ICP rat models were constructed to validate pathological features.RESULTS: The heatmap of proteomics analysis showed the top 30 up-regulated and 30 down-regulated proteins. The metabolomic analysis revealed 20 richer and 4 less abundant metabolites in ICP samples compared with placenta specimens from patients without ICP, and enrichment pathways by these metabolites included primary bile acid biosynthesis, cholesterol metabolism, bile secretion, nicotinate and nicotinamide metabolism, purine metabolism and metabolic pathways. Combined analysis of multiple omics results demonstrated that bile acids such as Glycohyocholic acid, Glycine deoxycholic acid, beta-Muricholic acid, Noncholic acid, cholic acid, Gamma-Mercholic Acid, alpha-Muricholic acid and Glycochenodeoxycholic Aicd were significantly associated with the expression of GLRX3, MYL1, MYH7, PGGT1B, ACTG1, SP3, LACTB2, C2CD5, APBB2, IPO9, MYH2, PPP3CC, PIN1, BLOC1S1, DNAJC7, RASAL2 and ATCN3 etc. The core protein ACAT2 was involved in lipid metabolic process and animal model showed that ACAT2 was up-regulated in placenta and liver of pregnant rats and fetal rats. The neonates had low birth weight and Safranin O-Fast green FCF staining of animal models showed that poor osteogenic and chondrogenic differentiation of fetal rats.CONCLUSION: Multiple metabolites-alpha-Muricholic acid, beta-Muricholic acid, Glycine deoxycholic acid and Glycochenodeoxycholic Acid etc. were perfect biomarkers to predict occurrence of ICP. Bile acids were significantly associated with varieties of protein expression and these proteins were differentially expressed in ICP samples. Our study provided several biomarkers for ICP detection and potential therapeutic targets for ICP development.PMID:39127651 | DOI:10.1186/s12884-024-06730-6

Ann Pharm Fr. 2024 Aug 8:S0003-4509(24)00109-3. doi: 10.1016/j.pharma.2024.08.002. Online ahead of print.ABSTRACTBACKGROUND: Precision medicine, which looks for high efficacy and low toxicity in therapies, has increased in popularity with omics technology. This study endeavors to unearth innovative low-toxicity therapeutic This work aims to discover novel and low-toxicity therapy options by understanding examining the complex relationship between silodosin-induced side effects and the metabolomic profiles associated with its administration.MATERIALS AND METHODS: LC-Q-TOF/MS/MS was used for analyzing plasma samples from control and silodosin-treated rats. The plasma samples of the control group and silodosin-treated rats were analyzed by LC-Q-TOF-MS/MS. Employing XCMS and MetaboAnalyst software, MS/MS data processed to detect compounds and investigate metabolic pathways. MATLAB 2019b was used for data categorization and multivariate analysis. A thorough comparison of METLIN and HMDB databases revealed 41 m/z values with significant differences between the drug-treated and control groups (p<0.01 and fold analysis≥1.5).RESULTS: According to multivariate data analysis, 17-betaβ-estradiol, taurocholic acid, L-kynurenine, N-formylkynurenine, D-glutamine, L-arginine, prostaglandin H2, prostaglandine G2, 15-keto-prostaglandin E2, calcidiol, thromboxane A2, 5'-methylthioadenosine, L-methionine and S-adenosylmethionine levels changed significantly compared to the control group. Differences in the metabolisms of glycerophospholipid, tyrosine, phenylalanine, arachidonic acid, cysteine and methionine, and biosynthesis of phenylalanine, tyrosine, and tryptophan, and aminoacyl-tRNA have been successfully demonstrated by metabolic pathway analysis. According to this study, vitamin D, L-glutamine, and L-arginine supplements can be recommended to prevent side effects such as fatigue, intraoperative floppy iris syndrome IFIS, blurred vision, and dizziness in the treatment of silodosin. Silodosin treatment negatively affected the immune system by affecting the kynurenine and tryptophan metabolism pathways.CONCLUSIONS: The study is a guide for silodosin treatments that offer low side effects and high therapeutic effect within the scope of precision medicine.PMID:39127320 | DOI:10.1016/j.pharma.2024.08.002

Life Sci. 2024 Aug 8:122952. doi: 10.1016/j.lfs.2024.122952. Online ahead of print.ABSTRACTThe bidirectional regulation between the gut microbiota and brain, known as gut-brain axis, has received significant attention. The myelin sheath, produced by oligodendrocytes or Schwann cells, is essential for efficient nervous signal transmission and the maintenance of brain function. Growing evidence shows that both oligodendrogenesis and myelination are modulated by gut microbiota and its metabolites, and when dysbiosis occurs, changes in the microbiota composition and/or associated metabolites may impact developmental myelination and the occurrence of neurodevelopmental disabilities. Although the link between the microbiota and demyelinating disease such as multiple sclerosis has been extensively studied, our knowledge about the role of the microbiota in other myelin-related disorders, such as neurodegenerative diseases, is limited. Mechanistically, the microbiota-oligodendrocyte axis is primarily mediated by factors such as inflammation, the vagus nerve, endocrine hormones, and microbiota metabolites as evidenced by metagenomics, metabolomics, vagotomy, and morphological and molecular approaches. Treatments targeting this axis include probiotics, prebiotics, microbial metabolites, herbal bioactive compounds, and specific dietary management. In addition to the commonly used approaches, viral vector-mediated tracing and gene manipulation, integrated multiomics and multicenter clinical trials will greatly promote the mechanistic and interventional studies and ultimately, the development of new preventive and therapeutic strategies against gut-oligodendrocyte axis-mediated brain impairments. Interestingly, recent findings showed that microbiota dysbiosis can be induced by hippocampal myelin damage and is reversible by myelin-targeted drugs, which provides new insights into understanding how hippocampus-based functional impairment (such as in neurodegenerative Alzheimer's disease) regulates the peripheral homeostasis of microbiota and associated systemic disorders.PMID:39127317 | DOI:10.1016/j.lfs.2024.122952

Int J Biol Macromol. 2024 Aug 8:134607. doi: 10.1016/j.ijbiomac.2024.134607. Online ahead of print.ABSTRACTCordyceps guangdongensis, a novel edible mushroom in China, has shown many positive health effects. In this study, we extracted the C. guangdongensis polysaccharides (CGP) from the fruiting bodies, and investigated the mechanism for CGP improved high-fat diet-induced (HFDI) metabolic diseases. We found that CGP notably reduced fat mass, improved blood lipid levels and hepatic damage, and restored the gut microbiota dysbiosis induced by high-fat diet (HFD). Metabolome analyses showed that CGP changed the composition of bile acids, and regulated HFDI metabolic disorder in hepatic tissue. Transcriptome comparison showed that the improvement of hepatic steatosis for CGP was mainly related to lipid and carbohydrate metabolism. Association analysis result revealed that Odoribacter, Bifidobacterium and Bi. pseudolongum were negatively correlated to fat and blood lipid indicators, and were significantly associated with genes and metabolites related to carbohydrate and lipid metabolism. Collectively, these results indicate that CGP may be a promising supplement for the treatment of obesity and related metabolic diseases.PMID:39127294 | DOI:10.1016/j.ijbiomac.2024.134607

J Biol Chem. 2024 Aug 7:107645. doi: 10.1016/j.jbc.2024.107645. Online ahead of print.ABSTRACTEpstein-Barr virus (EBV), the causative agent of infectious mononucleosis, persistently infects over 90% of the human adult population and is associated with several human cancers. To establish life-long infection, EBV tampers with the induction of type I interferon (IFN I)-dependent antiviral immunity in the host. How various EBV genes help orchestrate this crucial strategy is incompletely defined. Here, we reveal a mechanism by which the EBV nuclear antigen 3A (EBNA3A) may inhibit IFNβ induction. Using proximity biotinylation we identify the histone acetyltransferase P300, a member of the IFNβ transcriptional complex, as a binding partner of EBNA3A. We further show that EBNA3A also interacts with the activated IFN-inducing transcription factor IRF3 that collaborates with P300 in the nucleus. Both events are mediated by the N-terminal domain of EBNA3A. We propose that EBNA3A limits binding of IRF3 to the IFNβ promoter, thereby hampering downstream IFN I signaling. Collectively, our findings suggest a new mechanism of immune evasion by EBV, affected by its latency gene EBNA3A.PMID:39127175 | DOI:10.1016/j.jbc.2024.107645

J Lipid Res. 2024 Aug 8:100618. doi: 10.1016/j.jlr.2024.100618. Online ahead of print.ABSTRACTUnsaturated fatty acids (UFA) play a crucial role in central cellular processes in animals, including membrane function, development, and disease. Disruptions in UFA homeostasis can contribute to the onset of metabolic, cardiovascular, and neurodegenerative disorders. Consequently, there is a high demand for analytical techniques to study lipid compositions in live cells and multicellular organisms. Conventional analysis of UFA compositions in cells, tissues and organisms involves solvent extraction procedures coupled with analytical techniques such as gas chromatography,mass spectrometry (MS) and/or nuclear magnetic resonance (NMR) spectroscopy. As a non-destructive and non-targeted technique, NMR spectroscopy is uniquely capable of characterizing the chemical profiling of living cells and multicellular organisms. Here we use NMR spectroscopy to analyze C. elegans, enabling the determination of their lipid compositions and fatty acid unsaturation levels both in cell-free lipid extracts and in vivo. The NMR spectra of lipid extracts from wild-type and fat-3 mutant C. elegans strains revealed notable differences due to the absence of Δ-6 fatty acid desaturase activity, including the lack of arachidonic and eicosapentaenoic acyl chains. Uniform 13C-isotope labeling and high-resolution 2D solution-state NMR of live worms confirmed these findings, indicating that the signals originated from fast-tumbling lipid molecules within lipid droplets. Overall, this strategy permits the analysis of lipid storage in intact worms and has enough resolution and sensitivity to identify differences between wild type and mutant animals with impaired fatty acid desaturation. Our results establish methodological benchmarks for future investigations of fatty acid regulation in live C. elegans using NMR.PMID:39127170 | DOI:10.1016/j.jlr.2024.100618

Acta Trop. 2024 Aug 8:107327. doi: 10.1016/j.actatropica.2024.107327. Online ahead of print.ABSTRACTBACKGROUND: Early diagnosis of urogenital schistosomiasis is key to its control and elimination. The current gold standard microscopic examination techniques lack sensitivity in detecting light Schistosomiasis infections in pre-school aged children thus it is urgent to develop diagnostic tools that may be integrated into control programs. In this study, we evaluated the diagnostic performance of urine metabolite biomarkers using a chemical reagent strip in the detection of S. haematobium infection in pre-school aged children.METHODS: A case-control study was conducted involving 82 pre-school aged children that were age and sex matched. Urine samples were collected for 3 consecutive days and were evaluated using urine filtration gold techniques as the gold standard method. The samples were simultaneously measured for metabolite biomarkers specifically haematuria, proteins, ketones, nitrites, glucose, bilirubin and urobilinogen using chemical reagent strips. Pearson correlation test was used to measure the relationship between S. haematobium infection and the urine metabolite biomarkers.RESULTS: The diagnostic performance of urine biomarkers were correlated with the microscopic examination urine filtration technique. Haematuria (r = 0.592, p = 0.0001) and proteinuria (r = 0.448, p = 0.0001) were correlated to S. haematobium infection. Negative correlations with p > 0.05 were recorded for ketones and urobilinogen. Highest sensitivity was 65.9% (CI, 49.4 - 79.9) for haematuria whilst protein (albumin) biomarker had a lower specificity value of 43.9% (28.5 - 60.3). Inversely, highest sensitivity was 87.8% (73.8 - 95.9) for proteinuria whilst haematuria had a lower sensitivity value of 82.9% (67.9 - 92.8). The positive predictive values ranged from 57.7% (41.6 - 72.2) to 79.4% (65.5 - 88.7) whereas negative predictive values ranged from 70.8% (60.8 - 79.2) to 52.0% (48.7 - 55.3). With respect to diagnostic efficiency, haematuria had a fair diagnostic performance with an area under the curve of 0.76 followed by proteinuria with proteinuria whilst the remaining metabolites fail discriminating ability with an area under the curve of less than 0.5.CONCLUSION: Although haematuria and protein biomarkers in urine are moderately sensitive and specific, they are important morbidity indicators of urogenital schistosomiasis in pre-school aged that may be utilised during screening in schistosomiasis control programs. We recommend comprehensive analysis of biomarkers using metabolomics techniques to identify novel urine biomarkers.PMID:39127139 | DOI:10.1016/j.actatropica.2024.107327

Int J Radiat Oncol Biol Phys. 2024 Aug 8:S0360-3016(24)03176-6. doi: 10.1016/j.ijrobp.2024.07.2327. Online ahead of print.ABSTRACTPURPOSE: radiotherapy stands as an important complementary treatment for head and neck squamous cell carcinoma (HNSCC), yet it does not invariably result in complete tumor regression. The infiltration of immunosuppressive macrophages is believed to mediate the radiotherapy resistance, which mechanism remains largely unexplored. This study aimed to elucidate the role of immunosuppressive macrophages during radiotherapy and the associated underlying mechanisms.MATERIALS AND METHODS: Male C3H mice bearing syngeneic SCC-VII tumor were received irradiation (2 × 8Gy). The impact of irradiation on tumor-infiltrating macrophages were assessed. Bone marrow derived macrophages were evaluated in differentiation, proliferation, migration, and inflammatory cytokines after treatment of irradiated tumor culture medium (irCM) and irradiated tumor derived extracellular vesicles (irTEVs). A comprehensive metabolomics profiling of the irTEVs was conducted using liquid chromatography-mass spectrometry, while key metabolites were investigated the mechanism in macrophage in vitro and in vivo.RESULTS: Radiotherapy on SCC-VII syngeneic graft tumors increased polarization of both M1 and M2 macrophages in tumor microenvironment and drove infiltrated macrophages towards an immunosuppressive phenotype. Irradiation-induced polarization and immunosuppression of macrophages were dependent on irTEVs which delivered an increased amount of nicotinamide (NAM) to macrophages. NAM directly bound to the NF-κB transcriptional activity regulator USP7, through which NAM reduced translocation of NF-κB into the nucleus, thereby decreasing the release of cytokines IL6 and IL8. Increased enzyme activity of nicotinamide phosphoribosyl transferase (NAMPT) which is the rate-limiting enzyme of NAD+ metabolism, contributed to the irradiation-induced accumulation levels of NAM in irradiated HNSCC and irTEVs. Inhibition of NAMPT decreased NAM levels in irTEVs and increased radiotherapy sensitivity through alleviating immunosuppressive function of macrophages.CONCLUSIONS: Radiotherapy could induce NAD+ metabolic reprogramming of HNSCC cells, which regulate macrophage towards an immunosuppressive phenotype. Pharmacological targeting NAD+ metabolism might be a promising strategy for radiotherapy sensitization of HNSCC.PMID:39127084 | DOI:10.1016/j.ijrobp.2024.07.2327

Transl Oncol. 2024 Aug 8;49:102082. doi: 10.1016/j.tranon.2024.102082. Online ahead of print.ABSTRACTBACKGROUND: The mechanisms by which SLC2A1 enhances chemo-resistance of taxanes to non-small cell lung cancer (NSCLC) remains enigmatic.METHODS: An investigation into the SLC2A1 expression pattern and prognosis across diverse datasets, as well as our internally collected samples, was undertaken. Additionally, the biological function of SLC2A1 was further delved into through in vitro experiments. The study also examined the chemo-resistance of NSCLC to taxanes using CCK-8, Annexin-V, and caspase-3 assays. Furthermore, the impact of taxanes on SLC2A1 expression was determined via western blot analysis. The effects of SLC2A1 on the formation of CSCs was examined via flow cytometry and metabolomics techniques. Finally, the impact of SLC2A1 on the tumor microenvironment was analyzed using single-cell sequencing and cellchat.RESULTS: In the present investigation, it was observed that there was an elevated expression of SLC2A1 in NSCLC tumor tissues, which exhibited a significant association with a poorer prognosis. SLC2A1 overexpression in vitro promoted NSCLC cell proliferation, invasion, migration, chemo-resistance, and the formation of CD90+ and EpCAM+ CSCs. NSCLC cells were categorized based on SLC2A1 and EpCAM expression. SLC2A1highEpCAM+ CSCs were more chemo-resistance to taxanes. NSCLC patients with high SLC2A1 and EpCAM expression had poorer prognosis. Mechanically, SLC2A1 promoted the formation of CD90+ and EpCAM+ CSCs via activating glycolysis. Finally, SLC2A1low tumor cells promoted CD8+T cell function via HLA-A, B, C, and suppressed NK cell function via HLA-E.CONCLUSION: Together, SLC2A1 plays an important role in enhancing chemo-resistance of taxanes to NSCLC.PMID:39126936 | DOI:10.1016/j.tranon.2024.102082

Phytomedicine. 2024 Aug 3;133:155922. doi: 10.1016/j.phymed.2024.155922. Online ahead of print.ABSTRACTBACKGROUND: Cartilage metabolism dysregulation is a crucial driver in knee osteoarthritis (KOA). Modulating the homeostasis can mitigate the cartilage degeneration in KOA. Curcumenol, derived from traditional Chinese medicine Curcuma Longa L., has demonstrated potential in enhancing chondrocyte proliferation and reducing apoptosis. However, the specific mechanism of Curcumenol in treating KOA remains unclear. This study aimed to demonstrate the molecular mechanism of Curcumenol in treating KOA based on the transcriptomics and metabolomics, and both in vivo and in vitro experimental validations.MATERIALS AND METHODS: In this study, a destabilization medial meniscus (DMM)-induced KOA mouse model was established. And the mice were intraperitoneally injected with Curcumenol at 4 and 8 mg/kg concentrations. The effects of Curcumenol on KOA cartilage and subchondral was evaluated using micro-CT, histopathology, and immunohistochemistry (IHC). In vitro, OA chondrocytes were induced with 10 μg/mL lipopolysaccharide (LPS) and treated with Curcumenol to evaluate the proliferation, apoptosis, and extracellular matrix (ECM) metabolism through CCK8 assay, flow cytometry, and chondrocyte staining. Furthermore, transcriptomics and metabolomics were utilized to identify differentially expressed genes (DEGs) and metabolites. Finally, integrating multi-omics analysis, virtual molecular docking (VMD), and molecular dynamics simulation (MDS), IHC, immunofluorescence (IF), PCR, and Western blot (WB) validation were conducted to elucidate the mechanism by which Curcumenol ameliorates KOA cartilage degeneration.RESULTS: Curcumenol ameliorated cartilage destruction and subchondral bone loss in KOA mice, promoted cartilage repair, upregulated the expression of COL2 while downregulated MMP3, and improved ECM synthesis metabolism. Additionally, Curcumenol also alleviated the damage of LPS on the proliferation activity and suppressed apoptosis, promoted ECM synthesis. Transcriptomic analysis combined with weighted gene co-expression network analysis (WGCNA) identified a significant downregulation of 19 key genes in KOA. Metabolomic profiling showed that Curcumenol downregulates the expression of d-Alanyl-d-alanine, 17a-Estradiol, Glutathione, and Succinic acid, while upregulating Sterculic acid and Azelaic acid. The integrated multi-omics analysis suggested that Curcumenol targeted KDM6B to regulate downstream protein H3K27me3 expression, which inhibited methylation at the histone H3K27, consequently reducing Succinic acid levels and improving KOA cartilage metabolism homeostasis. Finally, both in vivo and in vitro findings indicated that Curcumenol upregulated KDM6B, suppressed H3K27me3 expression, and stimulated collagen II expression and ECM synthesis, thus maintaining cartilage metabolism homeostasis and alleviating KOA cartilage degeneration.CONCLUSION: Curcumenol promotes cartilage repair and ameliorates cartilage degeneration in KOA by upregulating KDM6B expression, thereby reducing H3K27 methylation and downregulating Succinic Acid, restoring metabolic stability and ECM synthesis.PMID:39126921 | DOI:10.1016/j.phymed.2024.155922

J Hazard Mater. 2024 Aug 3;478:135354. doi: 10.1016/j.jhazmat.2024.135354. Online ahead of print.ABSTRACTCo-culturing fungi and microalgae may effectively remediate wastewater containing Cd and harvest microalgae. Nevertheless, a detailed study of the mechanisms underlying the synergistic interactions between fungi and microalgae under Cd(II) exposure is lacking. In this study, Cd(II) exposure resulted in a significant enhancement of antioxidants, such as glutathione (GSH), malondialdehyde (MDA), hydrogen peroxide (H2O2) and superoxide dismutase (SOD) compared to the control group, suggesting that the cellular antioxidant defense response was activated. Extracellular proteins and extracellular polysaccharides of the symbiotic system were increased by 60.61 % and ,24.29 %, respectively, after Cd(II) exposure for 72 h. The adsorption behavior of Cd(II) was investigated using three-dimensional fluorescence excitation-emission matrix (3D-EEM), fourier transform infrared spectroscopy (FTIR), and scanning electron microscope (SEM). Metabolomics results showed that the TCA cycle provided effective material and energy supply for the symbiotic system to resist the toxicity of Cd(II); Proline, histidine, and glutamine strengthened the synergistic adsorption capacity of the fungus and microalgae. Overall, the theoretical foundation for a deep comprehension of the beneficial interactions between fungi and microalgae under Cd(II) exposure and the role of the fungal-algal symbiotic system in the management of heavy metal pollution is provided by this combined physiological and metabolomic investigation.PMID:39126852 | DOI:10.1016/j.jhazmat.2024.135354

J Food Sci. 2024 Aug 10. doi: 10.1111/1750-3841.17229. Online ahead of print.ABSTRACTGerminated brown rice has recently garnered widespread attention due to its high nutritional value. Previous research demonstrated that the bioactive components and functional properties of germinated brown rice varieties exhibit significant differences. Three germinated rice cultivars weedy rice WR04-6 (WR) and two cultivated rice cultivars with superior eating quality, Koshihikari (YG) and Daohuaxiang (DHX), were analyzed using metabolites and transcriptome profiling. Widely targeted metabolomics results showed that 85.9% and 71.2% of differential metabolites for WR vs. YG and WR vs. DHX were enriched in WR, respectively. The substances mainly included amino acids and derivatives, carbohydrates and its derivatives, organic acids and its derivatives, and flavonoids. Higher antioxidant activity was detected in WR compared to cultivated rice in metabolome analysis. Transcriptome analyses indicated that 18 responsive genes played pivotal roles in the conversion of key metabolites. These findings will provide theoretical underpinnings for the development of rice germplasm resources and the formulation of functional germinated grain foods.PMID:39126703 | DOI:10.1111/1750-3841.17229

Clin Rheumatol. 2024 Aug 10. doi: 10.1007/s10067-024-07094-0. Online ahead of print.ABSTRACTSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a significant health burden. There is an essential need for novel biomarkers and therapeutic targets to improve diagnosis and management. Mendelian randomization (MR) was applied to explore causal links between SLE and various biomarkers like immune cells, metabolites, and inflammatory cytokines using multiple databases. Initially, biomarkers significantly associated with SLE were identified. Bidirectional MR helped clarify these relationships, and a two-step mediation MR examined their effects on SLE risk. Intersection analysis was used to identify biomarkers with consistent effects across datasets. Four biomarkers were identified as having significant associations with SLE risk: 1-palmitoyl-2-arachidonoyl-GPI levels [odds ratio (OR), 1.379; 95% confidence interval (CI), 1.180 to 1.613; FDR, 0.046], IL-17A levels (OR, 2.197; 95% CI, 1.412 to 3.418; FDR, 0.044), N-acetyl-aspartyl-glutamate (NAAG) levels (OR, 0.882; 95% CI, 0.831 to 0.936; FDR, 0.030), and ribitol levels (OR, 0.743; 95% CI, 0.644 to 0.857; FDR, 0.012). Bidirectional MR showed an inverse effect of NAAG on IL-17A levels (OR, 0.978; 95% CI, 0.962 to 0.994; p = 0.006). Mediation analysis indicated that NAAG influenced SLE risk both directly (beta = - 0.108) and indirectly through IL-17A (beta = - 0.018), highlighting the potential mediating role of IL-17A. After expanding the significance criteria to p < 0.05, intersection analysis across multiple datasets revealed 29 biomarkers with consistent beta directions, including 19 potential risk factors (beta > 0) and 10 protective factors (beta < 0) for SLE. This research has revealed significant genetic associations with SLE and demonstrated that IL-17A mediates the relationship between NAAG levels and SLE risk, highlighting potential new targets for personalized therapeutic interventions. Key Points • This study employs MR to identify significant genetic associations between various biomarkers and SLE, providing novel insights into potential biomarkers and therapeutic targets. • Four key biomarkers were identified as significantly associated with SLE risk: 1-palmitoyl-2-arachidonoyl-GPI, IL-17A, N-acetyl-aspartyl-glutamate (NAAG), and ribitol. • The findings suggest that NAAG levels have a protective effect against SLE, partly mediated through IL-17A, indicating a complex interplay between these biomarkers in the pathogenesis of SLE. • Intersectional analysis across multiple datasets revealed 29 biomarkers with consistent effects on SLE risk, highlighting new directions for future research and potential personalized therapeutic strategies.PMID:39126578 | DOI:10.1007/s10067-024-07094-0

World J Microbiol Biotechnol. 2024 Aug 10;40(10):297. doi: 10.1007/s11274-024-04105-9.ABSTRACTVancomycin is a clinically important glycopeptide antibiotic against Gram-positive pathogenic bacteria, especially methicillin-resistant Staphylococcus aureus. In the mutant strain of Amycolatopsis keratiniphila HCCB10007 Δeco-cds4-27, the production of ECO-0501 was disrupted, but enhanced vancomycin yield by 55% was observed compared with the original strain of A. keratiniphila HCCB10007. To gain insights into the mechanism of the enhanced production of vancomycin in the mutant strain, comparative metabolomics analyses were performed between the mutant strain and the original strain, A. keratiniphila HCCB10007 via GC-TOF-MS and UPLC-HRMS. The results of PCA and OPLS-DA revealed a significant distinction of the intracellular metabolites between the two strains during the fermentation process. 64 intracellular metabolites, which involved in amino acids, fatty acids and central carbon metabolism, were identified as differential metabolites. The high-yield mutant strain maintained high levels of glucose-1-phosphate and glucose-6-phosphate and they declined with the increases of vancomycin production. Particularly, a strong association of fatty acids accumulation as well as 3,5-dihydroxyphenylacetic acid and non-proteinogenic amino acid 3,5-dihydroxyphenylglycine (Dpg) with enhancement of vancomycin production was observed in the high-yield mutant strain, indicating that the consumption of fatty acid pools might be beneficial for giving rise to 3,5-dihydroxyphenylacetic acid and Dpg which further lead to improve vancomycin production. In addition, the lower levels of glyoxylic acid and lactic acid and the higher levels of sulfur amino acids might be beneficial for improving vancomycin production. These findings proposed more advanced elucidation of metabolomic characteristics in the high-yield strain for vancomycin production and could provide potential strategies to enhance the vancomycin production.PMID:39126539 | DOI:10.1007/s11274-024-04105-9

J Bone Miner Res. 2024 Aug 10:zjae121. doi: 10.1093/jbmr/zjae121. Online ahead of print.ABSTRACTThe skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine (DMOG) rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.PMID:39126376 | DOI:10.1093/jbmr/zjae121

Biomed Chromatogr. 2024 Aug 10:e5969. doi: 10.1002/bmc.5969. Online ahead of print.ABSTRACTThis study aimed to explore the pharmacodynamics and mechanisms of different processing methods of Ligustrum lucidum Ait. (LLA) in addressing kidney-yin deficiency (KYD). Forty-eight Sprague-Dawley rats were divided into eight groups based on their weight. The KYD model was established by intragastric administration of levothyroxine sodium. Each group was administered the corresponding treatment for 15 consecutive days. The general condition of the rats during the treatment period was observed. In addition, the levels of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and the ratio of cAMP to cGMP in the serum of rats from different groups were measured. Serum samples were analyzed using the ultra-performance liquid chromatography (UPLC)-Orbitrap Fusion MS technique for metabolomics analysis. Compared with the model group, the general condition of the rats in the wine-steamed L. lucidum group (WL) and salt-steamed L. lucidum group (SSL) groups showed significant improvement. The serum levels of cAMP, cGMP, and the cAMP-to-cGMP ratio tended to return to normal. Metabolic analysis identified 38 relevant biomarkers and revealed 3 major metabolic pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; phenylalanine metabolism; and sphingolipid metabolism. The different processing methods of LLA demonstrated therapeutic effects on KYD in rats, likely related to the restoration of disturbed metabolism by adjusting the levels of endogenous metabolites in the kidney. The SSL demonstrated significantly superior effects compared with the other four types of LLA processed products.PMID:39126348 | DOI:10.1002/bmc.5969

Physiol Plant. 2024 Jul-Aug;176(4):e14465. doi: 10.1111/ppl.14465.ABSTRACTSugar is vital for plant growth and determines fruit quality via its content and composition. This study explores the differential sugar accumulation in two plum varieties, 'Fengtangli (FTL)' and 'Siyueli (SYL)'. The result showed that 'FTL' fruit displayed higher soluble solids and sugar content at various development stages. Metabolomic analysis indicated increased sorbitol in 'FTL', linked to elevated sorbitol-6-phosphate-dehydrogenase (S6PDH) activity. Transcriptome analysis identified a key gene for sorbitol synthesis, PsS6PDH4, which was significantly higher expressed in 'FTL' than in 'SYL'. The function of the PsS6PDH4 gene was verified in strawberry, apple, and plum fruits using transient overexpression and virus-induced gene silencing techniques. The results showed that overexpression of the PsS6PDH4 gene in strawberry, apple, and plum fruits promoted the accumulation of soluble solids content and sorbitol, while inhibition of the gene reduced soluble solids content and sorbitol content. Meanwhile, analysis of the relationship between PsS6PDH4 gene expression, sorbitol, and soluble solids content in four different plum varieties revealed a significant correlation between PsS6PDH4 gene expression and soluble solids content as well as sorbitol content. This research discovered PsS6PDH4 as a crucial regulator of sugar metabolism in plum, with potential applications in improving fruit sweetness and nutritional value in various fruit species. Understanding these molecular pathways can lead to innovative approaches for enhancing fruit quality, benefiting sustainable agriculture and consumer preferences in the global fruit industry.PMID:39126176 | DOI:10.1111/ppl.14465

Proteomics. 2024 Aug 9:e2300591. doi: 10.1002/pmic.202300591. Online ahead of print.ABSTRACTINSC94Y transgenic pigs represent a model for mutant insulin gene-induced diabetes of youth, with impaired insulin secretion and beta cell loss, leading to elevated fasting blood glucose levels. A key complication of diabetes mellitus is diabetic retinopathy (DR), characterized by hyperglycemia-induced abnormalities in the retina. Adjacent to the retina lies the vitreous, a gelatinous matrix vital for ocular function. It harbors proteins and signaling molecules, offering insights into vitreous biology and ocular health. Moreover, as a reservoir for secreted molecules, the vitreous illuminates molecular processes within intraocular structures, especially under pathological conditions. To uncover the proteomic profile of porcine vitreous and explore its relevance to DR, we employed discovery proteomics to compare vitreous samples from INSC94Y transgenic pigs and wild-type controls. Our analysis identified 1404 proteins, with 266 showing differential abundance in INSC94Y vitreous. Notably, the abundances of ITGB1, COX2, and GRIFIN were significantly elevated in INSC94Y vitreous. Gene Set Enrichment Analysis unveiled heightened MYC and mTORC1 signaling in INSC94Y vitreous, shedding light on its biological significance in diabetes-associated ocular pathophysiology. These findings deepen our understanding of vitreous involvement in DR and provide valuable insights into potential therapeutic targets. Raw data are accessible via ProteomeXchange (PXD038198).PMID:39126128 | DOI:10.1002/pmic.202300591

Int J Mol Sci. 2024 Aug 5;25(15):8538. doi: 10.3390/ijms25158538.ABSTRACTThe senescence of bone marrow mesenchymal stromal cells (MSCs) leads to the impairment of stemness and osteogenic differentiation capacity. In a previous study, we screened out stearoyl-CoA desaturase 2 (SCD2), the most evidently changed differential gene in lipid metabolism, using combined transcriptomic and metabolomic analyses, and verified that SCD2 could mitigate MSC senescence. However, the underlying molecular mechanism by which the rate-limiting enzyme of lipogenesis SCD2 manipulates MSC senescence has not been completely understood. In this study, we demonstrate that SCD2 over-expression alleviates MSC replicative senescence and ameliorates their osteogenic differentiation through the regulation of lipogenesis. Furthermore, SCD2 expression is reduced, whereas miR-200c-3p expression is elevated in replicative senescent MSCs. SCD2 is the direct target gene of miR-200c-3p, which can bind to the 3'-UTR of SCD2. MiR-200c-3p replenishment in young MSCs is able to diminish SCD2 expression levels due to epigenetic modulation. In addition, SCD2-rescued MSC senescence and enhanced osteogenic differentiation can be attenuated by miR-200c-3p repletion via suppressing lipogenesis. Taken together, we reveal the potential mechanism of SCD2 influencing MSC senescence from the perspective of lipid metabolism and epigenetics, which provides both an experimental basis for elucidating the mechanism of stem cell senescence and a novel target for delaying stem cell senescence.PMID:39126105 | DOI:10.3390/ijms25158538

Int J Mol Sci. 2024 Aug 2;25(15):8448. doi: 10.3390/ijms25158448.ABSTRACTTherapy-induced senescence (TIS) represents a major cellular response to anticancer treatments. Both malignant and non-malignant cells in the tumor microenvironment undergo TIS and may be harmful for cancer patients since TIS cells develop a senescence-associated secretory phenotype (SASP) that can sustain tumor growth. The SASP also modulates anti-tumor immunity, although the immune populations involved and the final results appear to be context-dependent. In addition, senescent cancer cells are able to evade senescence growth arrest and to resume proliferation, likely contributing to relapse. So, research data suggest that TIS induction negatively affects therapy outcomes in cancer patients. In line with this, new interventions aimed at the removal of senescent cells or the reprogramming of their SASP, called senotherapy, have become attractive therapeutic options. To date, the lack of reliable, cost-effective, and easy-to-use TIS biomarkers hinders the application of recent anti-senescence therapeutic approaches in the clinic. Hence, the identification of biomarkers for the detection of TIS tumor cells and TIS non-neoplastic cells is a high priority in cancer research. In this review article, we describe the current knowledge about TIS, outline critical gaps in our knowledge, and address recent advances and novel approaches for the discovery of TIS biomarkers.PMID:39126015 | DOI:10.3390/ijms25158448