PubMed

Rev Cardiovasc Med. 2024 Nov 7;25(11):395. doi: 10.31083/j.rcm2511395. eCollection 2024 Nov.ABSTRACTBACKGROUND: Coronary thrombosis events continue to be the leading cause of morbidity and mortality worldwide. Recently, emerging evidence has highlighted the role of gut microbiota in cardiovascular disease, but few studies have systematically investigated the gut microbiota variation associated with atherothrombosis.METHODS: We conducted multi-omics analysis (metagenomics sequencing and serum metabolomics) on 146 subjects from Peking Union Medical College Hospital-Coronary Artery Disease (PUMCH-CAD) cohort. We analyzed the key strains and metabolic pathways related to coronary artery disease (CAD) development, explored the bacterial functional pathway which contributes to atherothrombosis at strain level in depth. Single strain colonization procedures on germ free mice demonstrated the promotion of platelet activation and thrombotic phenotypes of the disordered gut microbiota.RESULTS: Gut microbiome and serum metabolome shifts were apparent in cases of CAD progression, Bacteroides spp. disturbed the development of CAD by participating in lipopolysaccharide (LPS), menaquinone and methanogenesis pathways. Particularly, coronary thrombosis is characterized by increased circulatory levels of L-tryptophan, which correlate with Bacteroides thetaiotaomicron that has enriched biosynthetic potential. In germ free mice we demonstrate that Bacteroides thetaiotaomicron colonization could induce thrombosis, aggravate platelet hyperreactivity and augment fecal levels of L-tryptophan.CONCLUSIONS: The disordered gut microbiota of CAD contributed to the occurrence and development of atherothrombosis. The key members of the bacterial and metabolic features may become biomarkers for predicting the cardiovascular thrombosis event. Targeting the microbial pathway may have the potential to reduce the incidence of cardiovascular disorders.CLINICAL TRIAL REGISTRATION: ChiCTR2000033897, https://www.chictr.org.cn/showproj.html?proj=55023.PMID:39618850 | PMC:PMC11607515 | DOI:10.31083/j.rcm2511395

Drug Des Devel Ther. 2024 Nov 27;18:5423-5444. doi: 10.2147/DDDT.S479014. eCollection 2024.ABSTRACTPURPOSE: Xiangqin Jiere Granules (XQJRG), a Chinese patent medicine used to treat acute fever in children caused by colds, seasonal flu, and coronavirus disease 2019 has been proven to have antipyretic and anti-inflammatory effects in young febrile rats. Fever is known to affect the host-gut microbiota crosstalk. However, the pharmacological mechanism of XQJRG in this regard remains unclear.METHODS: This study utilized a young febrile rat model previously reported by our team and extended the rat body temperature monitoring period following drug administration to explore the differences in efficacy between XQJRG and the commonly used pediatric antipyretic ibuprofen. Subsequently, the colonic contents of rats were analyzed using 16S rRNA gene sequencing and untargeted metabolomics. The short-chain fatty acid content was quantified using high-throughput targeted metabolomics. The expression of short-chain fatty acid receptors and pro-inflammatory genes in the colonic tissue was evaluated using quantitative real-time PCR, Western blot, and enzyme-linked immunosorbent assay.RESULTS: XQJRG showed a longer antipyretic duration than ibuprofen. XQJRG improved dysbiosis of the intestinal microbiota in young febrile rats, bringing its flora composition closer to that of normal rats. It significantly increased the relative abundance of s_Phascolarctobacterium_faecium and s_Roseburia_sp. related to the production of short-chain fatty acids (SCFAs), the contents of butyric acid and nonanoic acid and protein levels of SCFAs receptor GPR41. Moreover, XQJRG significantly increased the levels of metabolites with anti-inflammatory effects, reduced the contents of metabolites directly associated with fever, and decreased the levels of pro-inflammatory cytokines interleukin-1β and monocyte chemotactic protein-1 in the colon of young febrile rats to normal levels.CONCLUSION: XQJRG exhibited a more stable and persistent antipyretic effect in young febrile rats compared to ibuprofen. Its mechanism was at least partially attributed to regulating intestinal flora disorders, increasing anti-inflammatory metabolites, and inhibiting the production of inflammatory factors in young febrile rats.PMID:39618427 | PMC:PMC11608549 | DOI:10.2147/DDDT.S479014

Mol Nutr Food Res. 2024 Dec 1:e2400424. doi: 10.1002/mnfr.202400424. Online ahead of print.ABSTRACTSCOPE: Human milk (HM) is rich in bioactive compounds and essential nutrients. While research has focused on lipids, minerals, immune markers, microbiota, and oligosaccharides, specific metabolites are less studied. This study uses targeted metabolomics to identify and quantify metabolites in HM and explores the impact of perinatal and dietary factors on the metabolomic profile.METHODS AND RESULTS: In a cross-sectional study of 123 healthy lactating women, HM samples were collected up to 1 month postpartum and analyzed using the Biocrates MxP Quant 500 kit. Maternal and neonatal clinical, anthropometric, and nutritional data were collected. A total of 432 metabolites were quantified and categorized into 20 groups. The metabolomic profiles formed three distinct clusters, primarily driven by triglyceride concentration differences. Docosahexaenoic acid (DHA) levels were higher in HM from mothers with vaginal delivery compared to C-section births and differences in hexoses were found between exclusive and mixed-feeding practices. Maternal diets rich in lipids and animal proteins were associated with elevated amino acids, sphingolipids, and glycosyl-ceramides.CONCLUSION: The HM metabolome was grouped into three clusters influenced by delivery mode, lactation practices, and maternal diet. This comprehensive analysis opens new avenues to explore HM composition and offers valuable insights for future dietary interventions aimed at modulating HM.PMID:39617972 | DOI:10.1002/mnfr.202400424

Cell Commun Signal. 2024 Dec 2;22(1):574. doi: 10.1186/s12964-024-01928-9.ABSTRACTBACKGROUND: A key factor in the propagation of α-synuclein pathology is the compromised protein quality control system. Variations in membrane association and astrocytic uptake between different α-synuclein forms suggest differences in exocytosis or membrane cleavage, potentially impacting the secretome's influence on dopaminergic neurons. We aimed to understand differences in protein degradation mechanisms of astrocytes for both wild-type (WT) and mutant forms of α-synuclein, specifically during periods of reduced degradation efficiency. We also investigated α-synuclein release into the secretome and its effects on healthy dopaminergic neurons.METHODS: Cellular models used were rat primary astrocytes alongside hiPSC-derived astrocytes, whose impact on rat primary dopaminergic neurons and the human SH-SY5Y cell line was investigated. We examined the release and accumulation of α-synuclein resulting from impaired degradatory pathways, including matrix metalloprotease-MMP9, the ubiquitin proteasomal pathway-UPS, and the autophagy-lysosomal pathway-ALP, using immunocytochemical analysis and flow cytometry. Additionally, we explored the effect of astrocytic secretome on dopaminergic-neuronal survival, neurite collapse and function.RESULTS: At early stages, astrocytes were able to deal efficiently with monomeric α-synuclein (via UPS), and larger aggregates (through MMP9 and autophagy), clearing extracellular α-synuclein and maintaining neuronal health. However, extended exposure to extracellular monomeric and aggregated α-synuclein compromised their proteasomal activity, inhibiting MMP9 and destabilizing autophagy, transforming astrocytes from protectors to promoters of neurodegeneration. This study is the first to elucidate the astrocytes' preferred degradation pathways for both monomeric and aggregated forms of α-synuclein, along with the subsequent effects of these payloads on the cellular degradation machinery. The astrocytic transformation is characterized by α-synuclein expulsion, increased release of inflammatory cytokines, and diminished secretion of growth factors leading to dopaminergic neuronal apoptosis and dysfunction, particularly neurite collapse, intracellular Ca2+ response and vesicular dopamine release. The presence of phosphorylated and nitrated α-synuclein species in astrocytes also suggests their potential involvement in modifying both forms of the protein.CONCLUSION: The initial protective action of astrocytes in clearing and degrading extracellular α-synuclein is severely compromised at latter stages, leading to astrocytic dysfunction and impairing neuron-glia cross-talk. This study underscores the criticality of integrating astrocytes into treatment paradigms in synucleinopathies.PMID:39617881 | DOI:10.1186/s12964-024-01928-9

J Sep Sci. 2024 Dec;47(23):e70030. doi: 10.1002/jssc.70030.ABSTRACTShenhua Tablet (SHT), a Chinese herbal medicine comprising seven crude drugs, is utilized in the treatment of immunoglobulin A nephropathy (IgAN). However, due to its complex composition, the chemical constituents of SHT in vitro are still incompletely known, which has restricted the comprehensive development and utilization of SHT in clinical practice. In the present study based on ultra-high performance liquid chromatography-quadrupole-orbitrap-linear ion trap mass spectrometry (UHPLC-Q-Orbitrap-LTQ-MS) in data dependent acquisition mode, combining the accurate mass and structural information, the profiling and characterization of chemical constituents in SHT were carried out. The automated spectral matching (of experimental MS2 spectra against library spectra of mzCloud) method with a high mass accuracy (within 5 ppm) was used for the rapid identification of compounds. A total of 183 compounds, consisting of 64 flavonoids, 52 terpenoids, 37 organic acids, 6 phenylpropanoids, 5 phenols, and 19 other phytochemicals, were successfully characterized. In addition, the fragmentation pathways and characteristic fragments of some representative compounds were elucidated. The results offered clear insights into its chemical profile, thereby facilitating quality control and advancing pharmacological research.PMID:39617872 | DOI:10.1002/jssc.70030

Sci Rep. 2024 Dec 1;14(1):29839. doi: 10.1038/s41598-024-80169-9.ABSTRACTThe effectiveness of indirect Intravascular laser irradiation of blood (ILIB) is not fully understood. In this study, we provided a novel experiment that employs metabolomics to investigate the effects of ILIB in women. Twenty-eight volunteers underwent indirect ILIB and had their plasma collected before and after this procedure. The ILIB was applied at the radial artery for 30 min, using low-power photobiomodulation (660 nm), and a power output of 0.1 W. Plasma samples were extracted and analyzed using liquid chromatography-high-resolution mass spectrometry in an untargeted approach. Partial Least Squares Discriminant Analysis revealed 151 molecules with the Variable In Projection score of ≥ 1. From these, 26 were identified. After checking for molecules related to dietary intake, fasting, medication, or part of the human exposome, 15 were affected by ILIB. The abundances of Estradiol 17b-glucuronide 3-sulfate, CAR 14:3, PI 22:6/PGJ2, and CAR 12:1 significantly increased by ILIB, while AcylGlcADG 62:9, Tyrosyl-Glutamine, and CDP-DG 22:3/PGF1 had the contrary effect. ILIB was shown to modulate molecules from different chemical classes, although its impact on plasma metaboloma was minimal. Further research is warranted to fully elucidate the implications of these findings across various metabolic pathways, thus advancing the science surrounding ILIB.PMID:39617830 | DOI:10.1038/s41598-024-80169-9

Cell Death Dis. 2024 Dec 1;15(12):872. doi: 10.1038/s41419-024-07257-6.ABSTRACTThe metabolic reprogramming in high-grade serous ovarian carcinoma (HGSOC) affects the tumor stemness, which mediates tumor recurrence and progression. Knowledge of the stemness and metabolic characteristics of HGSOC is insufficient. Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, was significantly upregulated in HGSOC samples with a fold change of about 4 in the RNA sequencing analysis. SQLE was positively related to peritoneal metastasis and poor prognosis of HGSOC patients. Functionally, SQLE drove cancer cell proliferation and inhibited apoptosis to accelerate HGSOC growth. SQLE was highly expressed in ALDH+CD133+ FACS-sorted cells derived from HGSOC cells and ovarian cancer stem cells (OCSCs)-enriched tumorspheres. SQLE overexpression resulted in enhanced CSC-like properties, including increased tumorsphere formation and stemness markers expression. In vivo, SQLE not only promoted cell line-derived xenografts growth but extended the OCSCs subpopulation of single-cell suspension. Moreover, non-targeted metabolomics profiling from UPLC-MS/MS system identified 90 differential metabolites responding to SQLE overexpression in HGSOC cells. Among them, the dysfunctional metabolisms of cholesterol and glutathione were involved in the maintenance of HGSOC stemness. Previous studies showed the alteration of N6-Methyladenosine (m6A) modification in HGSOC development. Herein, the m6A modification in the 3'UTR and CDS regions of SQLE mRNA was increased due to upregulated methyltransferases WTAP and downregulated demethylases FTO, which was recognized by m6A-binding proteins IGF2BP3, rather than IGF2BP1 or IGF2BP2, thereby stabilizing the SQLE mRNA. These results suggested that SQLE was a novel potential clinical marker for predicting the HGSOC development and prognosis, as well as a potential therapeutic target of HGSOC.PMID:39617776 | DOI:10.1038/s41419-024-07257-6

Chem Biodivers. 2024 Dec 1:e202402282. doi: 10.1002/cbdv.202402282. Online ahead of print.ABSTRACTThe UHPLC-MS/MS metabolomics approach was employed to profile and characterize multi-components in Halamphora sp. extracted with different solvents that contribute to quorum sensing inhibitory (QSI) activity. A total of 37 and 34 metabolites were tentatively identified from negative and positive ion modes, respectively. The metabolites have been assigned to various groups, including fatty acids, glycolipids, sterols, diazines, flavonoids, peptides, carotenoids, and pigments. ibitis study, a metabolomics apMultivariate data analysis showed that the QSI activity in the acetone extract was due to tumonoic acid A, terpeptin derivatives, pheophorbide A, hydroxyhexadeca-1,5-dien-3-ynoxy]propane-1,2-diol, L-methionyl-L-tyrosine, stearidonic, hexadecadienoic, tricosenoic, palmitic and linolenic acids. These metabolites were more concentrated and differed significantly in acetone extract compared to other extracts. Acetone extract displayed a cluster of nodulisporic acid and fucoxanthin through MS/MS-based molecular networking (MN) platform. The present study shows that the LCMS-based metabolomics and MN effectively identify QSI-active metabolites in Halamphora sp. extracts, which can be promoted as a natural antifoulant.PMID:39617725 | DOI:10.1002/cbdv.202402282

Angew Chem Int Ed Engl. 2024 Dec 1:e202420104. doi: 10.1002/anie.202420104. Online ahead of print.ABSTRACTLanostane-type triterpenoids are important bioactive secondary metabolites of mushrooms, though their biosynthetic study has been challenging due to scattered genes. Herein, the strategies of combining metabolomics and transcriptomics analyses, functional motif blast, and KEGG (Kyoto Encyclopedia of Genes and Genomes) annotation were used to discover three key post-modification enzymes involved in the biosynthesis of lanostanoids in the medicinal mushroom Antrodia camphorata. The cytochrome P450 enzyme AcCYP4 could generate a Δ7,9(11) diene structure and introduce a 15α-hydroxy group to the triterpene skeleton. The short-chain dehydrogenase AcSDR6 could regio- and stereo- selectively catalyze the dehydrogenation of 3β-OH to produce 3-keto triterpenoids, and the catalytic mechanisms were interpreted by crystal structure analysis. AcSMT1 could introduce the methyl group at C-24 to produce a unique 31-carbon triterpene skeleton. This work elucidated the major biosynthetic pathway of Antrodia lanostanoids in vitro, and the discovered enzymes could be used to synthesize a series of bioactive triterpenoids.PMID:39617723 | DOI:10.1002/anie.202420104

J Tradit Chin Med. 2024 Dec;44(6):1187-1193. doi: 10.19852/j.cnki.jtcm.2024.06.007.ABSTRACTOBJECTIVE: To investigate the effect of baijinpingchuan (, BJPC) on the asthma rat model and identify differential metabolites and disturbed metabolic pathways.METHODS: The rats were categorized into six groups: control, dexamethasone (DEX), ovalbumin (OVA), and low-, median-, and high-dose BJPC. The rats, except for the control group, were initially treated with OVA to develop the asthma model, which was then activated using DEX, OVA, and low-, median-, and high-dose BJPC. Enzyme-linked immunosorbent assay kit was used to detect the expression of interleukin (IL)-33, IL-25, thymic stromal lymphopoietin (TSLP), and transforming growth factor-beta 1 (TGF-β1). Hematoxylin and eosin staining were performed to observe the pathological condition of the lung. Untargeted serum metabonomic analysis was conducted to identify differential metabolites and disturbed metabolic pathways.RESULTS: High-dose BJPC significantly inhibited the expression of IL-33, IL-25, TSLP, and TGF-β1 (P < 0.0001). Further, high-dose BJPC improved inflammatory cell infiltration, which plays a similar role in asthma as DEX. OVA-induced and BJPC-treated rats were identified through 17 differential metabolites, especially cholic acid. Furthermore, primary bile acid biosynthesis was a significantly differential pathway in the mechanism of BJPC for treating asthma.CONCLUSIONS: BJPC plays an anti-inflammation role in asthma, which might be a promising therapy through mediating primary bile acid biosynthesis.PMID:39617704 | DOI:10.19852/j.cnki.jtcm.2024.06.007

J Tradit Chin Med. 2024 Dec;44(6):1127-1136. doi: 10.19852/j.cnki.jtcm.20240927.005.ABSTRACTOBJECTIVE: To investigate the mechanism of Qixuan Yijianing (,QYN) in minimizing cardiac injury in Graves' disease (GD) mice using microRNA (miRNA) sequencing analysis.METHODS: Female BALB/c mice were randomly divided into the modeling and control groups (CG). The modeling group was established with Ad-TSHR289. Following 10 weeks of successful modeling, the mice were randomly assigned to four groups: model (MG), methimazole (MMI), QYN low-dose (LD), and high-dose (HD). After four weeks of treatment, the heart rate, heart volume, and heart index were measured, and the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), α-hydroxybutyrate dehydrogenase (α-HBD), creatine kinase (CK), and creatine kinase MB isoenzyme (CK-MB) in the serum were detected using a biochemical analyzer. Hematoxylin-eosin and Masson staining were used to determine histological changes in cardiac tissue. The heart tissues in the CG, MG, and HD groups were selected, and miRNA sequencing was used to identify differentially expressed miRNAs. A bioinformatics database was used to predict the target genes of differential miRNAs, and Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted on the predicted target genes.RESULTS: As compared to the CG group, the MG group's heart rate, heart volume, heart index, AST, CK, CK-MB, LDH, α-HBD, myocardial fiber thickness, and collagen fiber significantly increased, all P < 0.01, while following QYN, these indicators improved in the HD group, all P < 0.01 or P < 0.05. Compared to the CG group, the MG group identified 151 differentially expressed miRNAs, with 42 miRNAs downregulated and 109 miRNAs upregulated; compared to the MG group, the HD group identified 70 differentially expressed miRNAs, 40 were downregulated, and 30 were upregulated. The GO functions of differential miRNA target genes are mostly enriched in cardiac development regulation, cardiac contraction control, heart rate regulation, and so on. The most enriched KEGG pathways include the mitogen-activated protein kinase, ErbB, Hippo, forkhead box protein O, and Wnt signaling pathways.CONCLUSION: QYN may protect the cardiac structure and function and minimize cardiac damage caused by GD by regulating relevant target genes and signaling pathways through miRNAs which include miR-206-3p, miR-122-5p, and miR-200a-3p.PMID:39617698 | DOI:10.19852/j.cnki.jtcm.20240927.005

J Environ Sci (China). 2025 Jun;152:313-327. doi: 10.1016/j.jes.2024.05.028. Epub 2024 May 22.ABSTRACTEnvironmental residues of the fungicide difenoconazole (DFZ) have been shown to pose a threat to mammals. However, the risk assessment of DFZ for cultured carp remains unclear. The aim of this study was to investigate the adverse effects of DFZ on carp liver and their molecular mechanisms by simulating the environmental contamination concentrations of DFZ. Our results showed that DFZ induced structural damage in the liver, including edema, vacuolation, and congestion. In addition, DFZ residues were detected in liver tissues. Mechanistically, DFZ causes mitochondrial dysfunction by promoting Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria via IP3R, leading to the onset of ROS burst and apoptosis, and the inhibition of Nrf2 antioxidant function by DFZ also results in uncontrolled ROS. Mitophagy was also activated intracellularly to counteract mitochondrial damage. Interestingly, treatment with 2-APB alleviated mitochondrial dysfunction, restored the mitochondrial membrane potential, and inhibited apoptosis by blocking the translocation of Ca2+ from the ER to the mitochondria. Metabolomic analysis revealed that DFZ disrupted energy metabolism in carp liver, whereas 2-APB reversed DFZ-induced metabolic alterations. In conclusion, the present study elucidates the threat of DFZ to carp liver and highlights the mechanism of damage, thereby helping to explain the impact of agriculture on the aquatic environment.PMID:39617555 | DOI:10.1016/j.jes.2024.05.028

Neurobiol Dis. 2024 Nov 29:106747. doi: 10.1016/j.nbd.2024.106747. Online ahead of print.ABSTRACTAlzheimer's disease (AD) affects more women than men. Although women live longer than men, it is not longevity alone, but other factors, including metabolic changes, that contribute to the higher risk of AD in women. Metabolic pathways have been implicated in AD progression, but studies to date examined targeted pathways, leaving many metabolites unmeasured. Sex is often a neglected biological variable, and most metabolomic studies were not designed to investigate sex differences in metabolomic profiles. Here, we performed untargeted metabolomic profiling of sera from male and female patients with mild cognitive impairment (MCI), a common precursor to AD, and matched controls. We discovered significant metabolic changes in individuals with MCI, and found several pathways that were strongly associated with sex. Peptide energy metabolism demonstrated sexual dimorphism. Lipid pathways exhibited the strongest differences between female and male MCI patients, including specific phosphatidylcholine lipids, lysophospholipids, long-chain fatty acids, and monoacylglycerols. 1-palmitoleoyl glycerol and 1-arachidonoyl glycerol were higher in female MCI subjects than in male MCI subjects with no differences between control males and females. Conversely, specific dicarboxylic fatty acids were lower in female MCI subjects than male MCI subjects. In cultured astrocytes, 1-arachidonoyl glycerol promoted phosphorylation of the transcriptional regulator sphingosine kinase 2, which was inhibited by the transient receptor potential vanilloid 1 receptor antagonists, as well as chromatin remodelling. Overall, we identified novel sex-specific metabolites in MCI patients that could serve as biomarkers of MCI in both sexes, help further define AD etiology, and reveal new potential prevention strategies for AD.PMID:39617329 | DOI:10.1016/j.nbd.2024.106747

J Hepatol. 2024 Nov 29:S0168-8278(24)02740-5. doi: 10.1016/j.jhep.2024.11.038. Online ahead of print.NO ABSTRACTPMID:39617134 | DOI:10.1016/j.jhep.2024.11.038

J Ethnopharmacol. 2024 Nov 29:119176. doi: 10.1016/j.jep.2024.119176. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Quanduzhong capsule (QDZ), derived from Eucommia ulmoides Oliv. has been traditionally used in Chinese medicine for its beneficial effects on musculoskeletal health. Its clinical application has extended to conditions such as spontaneous hypertension combined with knee osteoarthritis (SKOA). However, the specific mechanisms by which QDZ alleviates symptoms and improves outcomes in this complex condition remain to be fully elucidated.AIM OF THE STUDY: This study aims to evaluate the therapeutic potential of QDZ in treating SKOA. By performing serum proteomics and metabolomics, we seek to explore the related biological pathways and elucidate the mechanisms underlying QDZ's effects on SKOA.MATERIALS AND METHODS: Serum samples from control, spontaneous hypertension (SHR), SKOA, and SKOA treated with QDZ groups were analyzed using data-independent acquisition-based proteomics to identify differentially expressed proteins. Serum levels of angiotensin II, norepinephrine, endothelin-1, classical pro-inflammatory factors such as macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-1 beta were measured. Additionally, serum metabolomics was performed to examine the changes in metabolite profiles. Correlation analysis was conducted to link changed proteins and metabolites with key pathways affected by QDZ.RESULTS: Proteomics analysis revealed significant alterations in serum protein expression between control, SHR, and SKOA groups, with changes in pathways related to immune regulation, and vascular function. KEGG enrichment analysis highlighted pathways such as endocytosis, synaptic vesicle cycling, and immune responses were enriched in SKOA group compared with control group. QDZ treatment significantly modulated above pathways and reduced inflammatory and cardiovascular markers which were upregulated in SKOA group. Metabolomics analysis showed that QDZ reversed SKOA-induced changes in amino acid and organic acid metabolism, affecting pathways including valine, leucine, and isoleucine metabolism, as well as the TCA cycle. Correlation analysis revealed significant relationships between key proteins and metabolites, underscoring the integrated role of immune and metabolic pathways in QDZ's effects.CONCLUSIONS: Our results indicate QDZ has a significant therapeutic potential for SKOA by modulating both protein and metabolite profiles associated with inflammation, vascular dysfunction, and metabolic imbalance. Our findings provide insights into the mechanisms through which QDZ exerts its effects and support its use as a promising treatment for SKOA. This study highlights the impact of QDZ on proteomic and metabolomic alterations, offering a basis for its broader application in treating SKOA.PMID:39617089 | DOI:10.1016/j.jep.2024.119176

J Ethnopharmacol. 2024 Nov 29:119128. doi: 10.1016/j.jep.2024.119128. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Pioglitazone (PIO) was an anti type 2 diabetes (T2D) agent but caused bone loss and bone marrow fat accumulation. Puerarin (PUE) was a natural component of herbal medicine extracted from Pueraria lobata (Willd.) Ohwi and reduced glycemia and improved bone mass as a supplementary drug. A combination of PIO and PUE might be good for maintaining bone mass and blood glucose.AIM OF THE STUDY: We aimed to elucidate the potential correlation and underlying mechanisms of dietary supplement PUE in reducing side effects caused by PIO.MATERIALS AND METHODS: In vitro, alkaline phosphatase (ALP) staining, alizarin S (ARS) staining and qRT-PCR were performed to detect the osteogenesis activity in MC3T3-E1 cells. In vivo, we established the T2D model by treating C57BL6/J mice with high-fat diets and streptozotocin (STZ). Micro-CT, hematoxylin and eosin (H&E) staining and tartrate-resistant acid phosphatase (TRAcP) staining were performed to observe the difference in skeletal phenotype. Serum metabolomics and 16S rRNA amplicon sequencing were applied to analyze the potential effect of the combination of PIO and PUE.RESULTS: We showed that the PUE could increase ALP activity and mineralization nodes of MC3T3-E1 with PIO. PIO could aggravate bone loss but PUE alleviated the effect caused by PIO in T2D mice. PUE promoted alpha-linolenic acid metabolism and glycerophospholipid metabolism, and affected the alpha diversity of the gut microbiome by regulating the genera of Alloprevotella, Fusobacterium, Rodentibacter, etc. Correlation analysis indicated that sphingosine-1-phosphate, nonadecylic acid, and margaric acid were associated with the effect of PUE.CONCLUSIONS: Taken together, we demonstrated that PIO combined with PUE was able to lower blood sugar levels without causing bone loss. The effect of PUE mainly correlated with the genua of Alloprevotella, Fusobacterium, Rodentibacter, and Alistipes. Also, alpha-linolenic acid metabolism and glycerophospholipid metabolism were major targets of PUE.PMID:39617084 | DOI:10.1016/j.jep.2024.119128

J Ethnopharmacol. 2024 Nov 29:119166. doi: 10.1016/j.jep.2024.119166. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Chinese materia medica (CMM) has a long history and extensive experience in treating ischemic stroke. Wen Ezhu, the rhizome of Curcuma wenyujin Y.H. Chen et C. Ling, is renowned for promoting blood circulation, dispersing blood stasis, alleviating pain, and eliminating masses. Promoting blood circulation and removing blood stasis are essential principles in Traditional Chinese Medicine for treating stroke. Consequently, Wen Ezhu is frequently used in clinical practice as a key CMM for treating stroke. The Elemene active fraction (ELE), a sesquiterpene compound extracted from Wen Ezhu, primarily consists of β-Elemene. It also contains β-Caryophyllene, γ-Elemene, and δ-Elemene isomers. ELE has shown potential pharmacological effects in various diseases, including ischemic stroke. However, its precise mechanism of action in treating stroke remains to be confirmed.AIM OF THE STUDY: To explore the therapeutic potential of ELE in acute ischemic stroke and elucidate its underlying mechanisms.MATERIALS AND METHODS: A rat model of middle cerebral artery occlusion reperfusion (MCAO/R) was used to evaluate ELE's effects. Therapeutic efficacy was assessed through mNSS scoring, magnetic resonance imaging (MRI), tetrazolium chloride (TTC) staining, Hematoxylin and eosin (H&E), and Nissl staining. Non-targeted metabolomics identified key pathways, confirmed using biochemical analysis, immunohistochemistry, and Western blotting. ROS levels and apoptosis-related proteins were also evaluated.RESULTS: Our findings show that ELE administration significantly reduced the cerebral infarct area and lowered modified neurological severity scores (mNSS) in animals, indicating a strong neuroprotective effect. Metabolomics results highlight the glutathione (GSH) metabolic pathway as a key mechanism through which ELE exerts its therapeutic effects. Specifically, ELE upregulates glutathione reductase (GR) protein expression and downregulates glutathione peroxidase (GPX) expression. The regulatory process of ELE decreases oxidized glutathione (GSSG) levels and increases GSH levels, effectively reducing oxidative stress damage (lower reactive oxygen species levels) during CI/RI. This results in the downregulation of the pro-apoptotic protein Bax and the upregulation of the pro-survival protein Bcl-2, thus reducing neuronal apoptosis.CONCLUSIONS: ELE protects neurons in MCAO/R rats through the GSH metabolism pathway, balancing GSH and GSSG levels to mitigate oxidative stress and enhance neuroprotection in cerebral ischemia/reperfusion injury.PMID:39617083 | DOI:10.1016/j.jep.2024.119166

Microb Physiol. 2024 Nov 29:1-18. doi: 10.1159/000542892. Online ahead of print.ABSTRACTINTRODUCTION: The low yield of bioflocculants has been a bottleneck problem that limits their industrial applications. Understanding the metabolic mechanism of bacteria that produce bioflocculants, could provide valuable insights and strategies to directly regulate their yield in future.METHODS: To investigate the change of metabolites in the process of bioflocculant production by a biomass-degrading bacterium, Pseudomonas boreopolis GO2, an untargeted metabolome analysis was performed.RESULTS: The results showed that metabolites significantly differed during the fermentation process when corn stover was used as the sole carbon source. The differential metabolites were divided into four co-expression modules based on the weighted gene co-expression network analysis. Among them, a module (yellow module) was closely related to the flocculating efficiency, and the metabolites in this module were mainly involved in carbohydrate, lipid and amino acid metabolism. The top 30 metabolites with the highest degree in the yellow module were identified as hub metabolites for bioflocculants' production. Finally, 10 hub metabolites were selected to perform the additional experiments, and the addition of L-rhamnose, tyramine, tryptophan, and glutaric acid alone all could significantly improve the flocculating efficiency of GO2 strain.CONCLUSION: These results indicated that the hub metabolites were key for bioflocculant production in GO2 strain, and could help guide the improvement of high-efficiency and low-cost bioflocculant production.PMID:39616990 | DOI:10.1159/000542892

J Hazard Mater. 2024 Nov 29;483:136693. doi: 10.1016/j.jhazmat.2024.136693. Online ahead of print.ABSTRACTThe harmful influence caused by cadmium (Cd) to agriculture is severe and enduring. Efforts to reduce the damage by Cd to crop is an important topic. In this study, we investigated the effect of MgO NPs on tobacco seedlings' growth under Cd stress and explored its mechanism. Results showed Cd inhibited seedling growth, but MgO NPs alleviated this toxicity. With MgO NPs, shoot and root fresh weight increased by 35.12 % and 45.73 %. This was mainly due to MgO NPs reducing Cd accumulation by 40 % in root and 20.48 % in shoot compared to Cd treatment. MgO NPs not only reduced Cd accumulation but redistributed it to inactive cell walls: up to 55 % in shoot and 22 % in root (compared to 47 % and 22 % in Cd treatment). The primary mechanism was the change in cell wall's main ingredient: lignin. MgO NPs increased lignin content by 50.62 % compared to Cd treatment. To further investigate the underlying molecular mechanism, multi-omics analysis was conducted. Comparing Cd + MgO NPs with Cd, 1358 DEGs (694 up, 664 down) and 160 DEMs (44 up, 116 down) were identified. Furthermore, we identified ABA-regulated phenylpropanoid pathway as the key mechanism for lignin synthesis. MgO NPs boosted ABA levels by 6.72 % compared to Cd treatment. The multi-omics analysis revealed upregulation of ABA synthesis and signal transduction, leading to increased phenylpropanoid pathway metabolites and gene expressions. Notably, POD, a key enzyme, increased by 92.05 %. It was concluded that MgO NPs represent a highly efficient alternative for enhancing plant resistance to Cd.PMID:39616846 | DOI:10.1016/j.jhazmat.2024.136693

Plant Physiol Biochem. 2024 Nov 26;219:109334. doi: 10.1016/j.plaphy.2024.109334. Online ahead of print.ABSTRACTAbiotic stresses, such as extreme temperatures, drought, and salinity, significantly affect plant growth and productivity. Among these, cold stress is particularly detrimental, impairing cellular processes and leading to reduced crop yields. In recent years, stress-associated proteins (SAPs) containing A20 and AN1 zinc-finger domains have emerged as crucial regulators in plant stress responses. However, the functions of SAPs in tobacco plants remain unclear. Here, we isolated Nicotiana tabacum SAP9 (NtSAP9), whose expression was induced by cold treatment, based on RNA-sequences data. Knock down of NtSAP9 expression reduced freezing tolerance, while overexpression conferred freezing tolerance in transgenic tobacco plants, as indicated by relative electrolytic leakage and photosystem II photochemical efficiency. Untargeted metabolomics via liquid chromatography-tandem mass spectrometry revealed distinct metabolic profiles between WT and NtSAP9-overexpressing tobacco plants under normal and low temperature conditions. Upregulation of amino acids like D-Glutamine, DL-Glutamine, and O-Acetyl-L-serine suggests NtSAP9 enhances cold tolerance. Further expression analysis by quantitative real-time PCR indicated that NtSAP9 participates in cold stress response possibly through amino acid synthesis-related genes expression, such as glutamine synthetase and glutamate dehydrogenase. These findings improve our understanding of SAP proteins in tobacco's response to cold stress.PMID:39616799 | DOI:10.1016/j.plaphy.2024.109334