PubMed

J Ethnopharmacol. 2024 Dec 28:119300. doi: 10.1016/j.jep.2024.119300. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Daqinjiao decoction (DQJT), a classical prescription, has been utilized for millennia in stroke management, yet its underlying mechanisms remained obscure.AIM OF THE STUDY: The aim of this study was to elucidate the mechanisms through which DQJT mitigates cerebral ischemia/reperfusion injury (CI/RI).MATERIALS AND METHODS: The quantification of DQJT's primary components were performed by HPLC. Pharmacological assessments were then conducted to ascertain DQJT's efficacy in a Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R) model. Following this, untargeted metabolomics, lipidomics and network pharmacology analyses were undertaken to unveil potential mechanisms, which were subsequently validated. UPLC-Q-TOF/MS was utilized to detect DQJT-derived chemicals in brain tissue, and molecular docking techniques were employed to investigate the bioactive compounds.RESULTS: DQJT treatment reduced brain damage induced by MCAO/R, as evidenced by decreased infarct sizes, enhanced behavioral function scores, and diminished neuronal damages. Untargeted metabolomics and lipidomics revealed that DQJT improved metabolism of unsaturated fatty acids. According to network pharmacology, lipid metabolism, cAMP signaling pathway and toll-like receptor signaling pathway pathways were notably affected, with HSP90AA1, TLR4, and PKA identified as potential targets of DQJT. Immunofluorescence and Western blot analyses further demonstrated that DQJT counteracted necroptosis and ferroptosis by inhibiting the HSP90AA1 and TLR4 pathways and enhancing the PKA pathway. Molecular docking results supported that the possible pharmacodynamic substances of DQJT in protecting against CI/RI.CONCLUSION: This research established that DQJT attenuates brain injury induced by MCAO/R through the modulation of necroptosis and ferroptosis via pathways including HSP90AA1, TLR4, and PKA. It shed light on the potential mechanisms and effective constituents of DQJT in stroke treatment, paving the way for further exploration of this ancient formula.PMID:39736347 | DOI:10.1016/j.jep.2024.119300

J Ethnopharmacol. 2024 Dec 28:119293. doi: 10.1016/j.jep.2024.119293. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cisplatin (CP), a widely used antineoplastic agent, is a leading cause of drug-induced liver injury (DILI) due to its hepatotoxic effects. Licorice (GC), an established remedy in traditional Chinese medicine (TCM), has shown promise in addressing liver diseases and DILI. Nonetheless, the specific active components and underlying mechanisms of GC in mitigating CP-induced liver injury remain inadequately investigated.AIM OF THE STUDY: This study examined the active components and efficacy of GC in addressing CP-induced hepatotoxicity, focusing on its mechanisms related to bile acid metabolism and gut microbiota regulation.MATERIALS AND METHODS: Utilizing a CP-induced rat liver injury model, this study evaluated changes in liver coefficient, liver function indices, and pathological morphology while assessing the efficacy of GC for both prevention and treatment of CP-induced liver injury. Subsequently, UPLC-Q-TOF-MS qualitatively analyzed GC's blood-entering components, elucidating its pharmacodynamic material basis. Network pharmacology analysis identified potential pathways and targets of GC's blood components in relation to CP-induced liver injury. Furthermore, metabolomics and 16S rRNA sequencing were employed to clarify the pharmacodynamic mechanisms of GC in modulating bile acid metabolism and gut microbiota, offering insights into its preventive and therapeutic roles.RESULTS: The pharmacodynamic results revealed that GC significantly reduced liver function biomarkers and improved pathological changes in liver tissue. UPLC-Q-TOF-MS analysis identified 16 blood-entering components as potential pharmacodynamic agents of GC for preventing and treating CP-induced liver injury. Network pharmacology analysis suggested a link between GC's efficacy and the bile acid metabolic pathway. Furthermore, metabolomics analysis, immunoblotting, and 16S rRNA sequencing demonstrated that GC regulated bile acid metabolites in both liver and feces, enhanced FXR and BSEP expressions in the liver, and decreased CYP27A1 expression. Additionally, GC mitigated CP-induced intestinal dysbiosis by altering the abundance of gut microbiota.CONCLUSIONS: UPLC-Q-TOF-MS performed a qualitative analysis of 16 blood-entering components linked to GC, providing a basis for further exploration of the pharmacodynamic material underpinning GC. The protective role of GC in CP-induced liver injury appears connected to enhanced bile acid metabolism and restoration of gut microbiota balance.PMID:39736346 | DOI:10.1016/j.jep.2024.119293

Clin Nutr. 2024 Dec 19;45:31-35. doi: 10.1016/j.clnu.2024.12.016. Online ahead of print.ABSTRACTBACKGROUND&AIMS: Celiac disease (CD) and potential CD (pCD) are immune-mediated disorders triggered by the ingestion of gluten. In non-celiac gluten sensitivity (NCGS) neither allergic nor autoimmune mechanisms are involved. Relationships between NCGS and CD need to be further investigated.METHODS: Serum metabolomics and lipoproteomics, performed via nuclear magnetic resonance spectroscopy, were used to characterize these three gluten-related disorders. Lasso regression models were calculated to discriminate the groups of interest.RESULTS: Several metabolites and lipoprotein-related parameters (particularly those associated with HDL cholesterol) allowed the selective discrimination between CD (and pCD) and NCGS. This evidence pointed to possible alterations of the gut microbiota in NCGS patients. Cross-validated regression models were able to discriminate between CD and NCGS, and pCD and NCGS with AUCs of 0.90 and 0.83, respectively.CONCLUSION: This pilot study suggests changes in the gut microbiota and paves the way to the elucidation of the underlying mechanisms of NCGS.PMID:39736173 | DOI:10.1016/j.clnu.2024.12.016

Mov Disord. 2024 Dec 30. doi: 10.1002/mds.30095. Online ahead of print.ABSTRACTBACKGROUND: Lewy body diseases, including dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation, leading to dementia. Previous studies suggest distinct epigenetic and metabolomic profiles in DLB.OBJECTIVE: This study aims to identify diagnostic biomarkers by analyzing the methylome and metabolome in the Brodmann area 7 of postmortem brain tissues from DLB patients and control subjects using multiomics approaches.METHODS: Methylation analysis was performed using the Illumina EPIC array, and metabolomics profiling was conducted via 1H nuclear magnetic resonance (NMR) and direct injection/liquid chromatography coupled with mass spectrometry. Differential methylation and metabolite analysis were conducted, followed by pathway enrichment to explore biological relevance.RESULTS: We identified 3478 significantly differentially methylated cytosines, mostly hypermethylated, enriched in CpG islands near transcription start sites. Pathway enrichment analysis showed significant pathways, primarily linked to olfactory and synaptic functions. Metabolomics profiling identified 15 significantly altered metabolites, with Phosphatidylethanolamine (PE) Biosynthesis being the most affected pathway. Key correlations between differentially methylated cytosines and metabolites, particularly in the PE Biosynthesis pathway involving PTDSS1 and PCYT2 genes, were observed.CONCLUSIONS: Notably, sex-specific differences were found, with females exhibiting more epigenetic and metabolomic changes than males. Increased hypermethylation, linked to transcriptional silencing, and disruptions in PE biosynthesis suggest a role in synaptic dysfunction and olfactory deficits. In addition, α-aminoadipic acid was strongly associated with vascular functions, hinting at a possible overlap between vascular health and DLB. This study provides new insights into DLB mechanisms and potential therapeutic targets. © 2024 International Parkinson and Movement Disorder Society.PMID:39736077 | DOI:10.1002/mds.30095

Bioinform Adv. 2024 Nov 27;5(1):vbae192. doi: 10.1093/bioadv/vbae192. eCollection 2025.ABSTRACTMOTIVATION: NMR-based metabolomics is a field driven by technological advancements, necessitating the use of advanced preprocessing tools. Despite this need, there is a remarkable scarcity of comprehensive and user-friendly preprocessing tools in Python. To bridge this gap, we have developed Protomix-a Python package designed for metabolomics research. Protomix offers a set of automated, efficient, and user-friendly signal-preprocessing steps, tailored to streamline and enhance the preprocessing phase in metabolomics studies.RESULTS: This package presents a comprehensive preprocessing pipeline compatible with various data analysis tools. It encompasses a suite of functionalities for data extraction, preprocessing, and interactive visualization. Additionally, it includes a tutorial in the form of a Python Jupyter notebook, specifically designed for the analysis of 1D 1H-NMR metabolomics data related to prostate cancer and benign prostatic hyperplasia.AVAILABILITY AND IMPLEMENTATION: Protomix can be accessed at https://github.com/mzniber/protomix and https://protomix.readthedocs.io/en/latest/index.html.PMID:39735575 | PMC:PMC11671038 | DOI:10.1093/bioadv/vbae192

Front Immunol. 2024 Dec 13;15:1449103. doi: 10.3389/fimmu.2024.1449103. eCollection 2024.ABSTRACTBACKGROUND: Cancer remains a leading cause of mortality worldwide. A non-invasive screening solution was required for early diagnosis of cancer. Multi-cancer early detection (MCED) tests have been considered to address the challenge by simultaneously identifying multiple types of cancer within a single test using minimally invasive blood samples. However, a multi-cancer screening strategy utilizing urine-based metabolomics has not yet been developed.METHODS: We enrolled 911 cancer patients with 548 lung cancer (LC), 177 with gastric cancer (GC), and 186 with colorectal cancer (CRC), alongside 563 individuals with non-cancerous benign diseases and 229 healthy controls (HC) and investigated the metabolic profiles of urine samples. Participants were randomly allocated to discovery and validation cohorts. The discovery cohort was used for identifying multi-cancer and tissue-specific signatures to build the cancer screening and tumor origin prediction models, while the validation cohort was employed for assessing the performance of these models.RESULTS: We identified and annotated a total of 360 metabolites from the urine samples. Using the LASSO regression algorithm, 18 metabolites were characterized as urinary metabolic biomarkers and exhibited excellent discriminative performance between cancer patients and HC with AUC of 0.96 in the validation cohort. In comparison with the performance of traditional tumor markers CEA, the screening model performed higher sensitivity across the cancer stages, with a particularly increase in sensitivity among early-stage cancer patients. Moreover, the screening model also exhibited in high classification of cancers from non-cancerous group, comprising with HC and benign disease participants. Furthermore, two non-overlapping metabolic panels were selected to differentiate LC from Non-LC and GC from CRC with the AUC values of 0.87 and 0.83 in validation cohorts, respectively. Additionally, the model accurately predicted the origin of three lethal cancers: lung, gastric, and colorectal, with an overall accuracy of 0.75. The AUC values for LC, GC, and CRC were 0.88, 0.88, and 0.80, respectively.DISCUSSION: Our study demonstrates the potential of urine-based metabolomics for multi-cancer early detection. The approach offers non-invasive cancer screening, promising widespread implementation in population-based programs for early detection and improved outcomes. Further validation and expansion are needed for broader clinical applicability.PMID:39735533 | PMC:PMC11671364 | DOI:10.3389/fimmu.2024.1449103

J Diabetes Res. 2024 Dec 19;2024:8559677. doi: 10.1155/jdr/8559677. eCollection 2024.ABSTRACTBackground and Aims: Coronary heart disease (CHD), hypertension (HTN), depression (Dep), and Type 2 diabetes mellitus (T2DM) are often comorbid, resulting in an exacerbated patient condition and worsened prognosis. A lack of systematic metabolomic studies on comorbidities of CHD remains. Therefore, comprehensive metabolomic-based evaluation of comorbidities of CHD is necessary. Methods and Results: In the current study, 169 healthy subjects, 149 CHD subjects, 107 CHD + HTN subjects, 126 CHD + Dep subjects, and 58 CHD + T2DM subjects were recruited. Gas chromatography-mass spectrometry was used for metabolite determination, and multivariate statistical analysis was conducted to identify metabolites that are differentially expressed with the comorbidities of CHD. There were 9, 16, 14, and 10 metabolites identified in the healthy and CHD group, the CHD and CHD + HTN group, the CHD and CHD + Dep group, and the CHD and CHD + T2DM group, respectively. Six metabolic pathways were affected, involving starch and sucrose metabolism; fructose and mannose metabolism; citrate cycle; alanine, aspartate, and glutamate metabolism; fatty acid biosynthesis; and glycolysis. Conclusion: Our study has systematically elucidated the metabolic changes underlying the comorbidities of CHD, thereby providing insight into the mechanisms associated with these alterations.PMID:39735415 | PMC:PMC11671664 | DOI:10.1155/jdr/8559677

Front Cell Infect Microbiol. 2024 Dec 13;14:1432422. doi: 10.3389/fcimb.2024.1432422. eCollection 2024.ABSTRACTLactic acid bacteria are widely regarded as safe alternatives to antibiotics in livestock and poultry farming and have probiotic potential. Ligilactobacillus agilis (L. agilis) is a prominent component of pigeon crop microbiota; however, its function is unknown. In this study, a strain of L. agilis 1003 from pigeon cecum was identified by combining whole genome sequencing and phenotypic analysis, and its safety and probiotic properties were studied. Whole-genome sequencing revealed that the L. agilis 1003 genome length is 2.58 Mb, its average percent guanine-cytosine is 40.43%, and it encodes 1,757 protein-coding genes. Annotation of clusters of orthologous groups classified predicted proteins from the assembled genome as having cellular, metabolic, and information-related functions. A gene cluster associated with the synthesis of a broad-spectrum antimicrobial compound confirmed by antibacterial spectrum testing was identified using genome mining tools. Based on hemolysis test results, the strain was determined to be safe. This strain exhibited a high survival rate in the presence of bile salts and acidic conditions and a significant self-aggregation propensity and hydrophobicity. In vivo animal experiments showed that L. agilis 1003 exhibits probiotic and antibacterial effects and that the substances exerting antibacterial effects are organic acids. Metabolomics analysis revealed that L. agilis 1003 supernatant contained seven organic acids, including butyric acid. L. agilis 1003 showed good safety and probiotic potential in genomics, physiological biochemistry, and animal experiments, and could be considered a suitable candidate for promoting livestock and poultry health.PMID:39735258 | PMC:PMC11673764 | DOI:10.3389/fcimb.2024.1432422

Front Microbiol. 2024 Dec 13;15:1461456. doi: 10.3389/fmicb.2024.1461456. eCollection 2024.ABSTRACTINTRODUCTION: Liver cirrhosis (LC) and hepatocellular carcinoma (HCC) resulting from chronic hepatitis B virus (HBV) infection are major health concerns. Identifying critical biomarkers and molecular targets is needed for early diagnosis, prognosis, and therapy of these diseases.METHODS: In this study, we explored the gene expression and metabolism in the liver tissues of LC, HCC, and healthy controls, to analyse and identify potential biomarkers of disease progression. Mass spectrometry imaging was used to evaluate the spatial distribution of key metabolites.RESULTS AND DISCUSSION: The results revealed significant changes in gene expression and metabolic pathways along with disease progression. The upregulated genes were associated with extracellular matrix remodeling and cancer pathways, including LAMC1-3, COL9A2, COL1A1, MYL9, MYH11, and KAT2A. The downregulated genes were linked to immune response and fatty acid metabolism. Metabolomic analysis showed major changes in lipid and choline metabolism. Consistent changes in the expression of specific genes and metabolites were correlated with clinical data. Notably, metabolites such as L-acetylcarnitine, histamine, and 4-trimethylammoniobutanoic acid demonstrated high accuracy (AUC > 0.85) in distinguishing between healthy, LC, and HCC groups. This study identifies key gene and metabolite changes in HBV related LC and HCC, highlighting critical pathways involved in disease progression. Biomarkers like L-acetylcarnitine and KAT2A show promise for early diagnosis and prognosis, potentially improving outcomes for hepatitis liver disease patients.PMID:39735192 | PMC:PMC11671487 | DOI:10.3389/fmicb.2024.1461456

Fundam Res. 2022 Nov 9;4(6):1523-1532. doi: 10.1016/j.fmre.2022.09.033. eCollection 2024 Nov.ABSTRACTEndogenous benzoic acid causes detrimental effects on public health, but the underlying mechanisms often remain elusive. Benzoic acid (0.00-40.00 mg L -1) was detected from sixty fermented goat milk samples in six replicates, indicating the existence of endogenous benzoic acid. Herein, we investigated the effects of benzoic acid on the variations of metabolome and proteome signatures in fermented goat milk via integrative metabolomics (LOQ 2.39-98.98 μg L -1) and proteomics approach based on UHPLC-Q-Orbitrap HRMS. Explicitly, benzoic acid reduced the content of taurine (7.06-4.80 mg L -1) and hypotaurine (3.86-1.74 mg L -1) due to a significant decrease in the levels of glutamate decarboxylase 1 by benzoic acid. The reduction in lactose (7.13-5.31 mg L -1) and d-galactose (4.39-3.37 mg L -1) content was related to the decrease in α-lactalbumin and β-galactosidase levels, respectively, in fermented goat milk containing 40.00 mg L -1 benzoic acid. Meanwhile, the levels of maltose (22.84-16.53 mg L -1) and raffinose (4.19-3.10 mg L -1) progressively decreased with increasing benzoic acid concentrations (0.00-40.00 mg L -1), which had detrimental effects on the nutritional quality of fermented goat milk. Additionally, the concentration of benzoic acid and fermentation temperature are the most important factors to control the loss of nutrients in fermented dairy products.PMID:39734529 | PMC:PMC11670729 | DOI:10.1016/j.fmre.2022.09.033

Front Neurosci. 2024 Dec 13;18:1514678. doi: 10.3389/fnins.2024.1514678. eCollection 2024.ABSTRACTBACKGROUND: Autism spectrum disorder is a distinctive developmental condition which is caused by an interaction between genetic vulnerability and environmental factors. Biomarkers play a crucial role in understanding disease characteristics for diagnosis, prognosis, and treatment. This study employs bibliometric analysis to identify and review the 100 top-cited articles' characteristics, current research hotspots and future directions of autism biomarkers.METHODS: A comprehensive search of autism biomarkers studies was retrieved from the Web of Science Core Collection database with a combined keyword search strategy. A comprehensive analysis of the top 100 articles was conducted with CiteSpace, VOSviewer, and Excel, including citations, countries, authors, and keywords.RESULTS: The top 100 cited studies were published between 1988 and 2021, with the United States led in productivity. Core biomarkers such as genetics, children, oxidative stress, and mitochondrial dysfunction are well-established. Potential trends for future research may include brain studies, metabolomics, and associations with other psychiatric disorders.CONCLUSION: This pioneering bibliometric analysis provides a comprehensive compilation of the 100 most-cited studies on autism, which not only offers a valuable resource for doctors, and researchers but shedding insights into current shortcomings and future endeavors. Future research should prioritize the application of emerging technologies for biomarkers, longitudinal study of biomarkers, and specificity of autism biomarkers to advance the precision of ASD diagnosis and treatment.PMID:39734494 | PMC:PMC11671500 | DOI:10.3389/fnins.2024.1514678

Adv Pharmacol Pharm Sci. 2024 Dec 20;2024:5543717. doi: 10.1155/adpp/5543717. eCollection 2024.ABSTRACTBackground: Antithrombotic medications, including antiplatelet agents, are standard treatments for patients with hyperlipidemia who have a high risk of developing cardiovascular disease (CVD). The ongoing exploration of new antiplatelet agents with minimal bleeding effects is crucial, including the investigation of potential compounds derived from natural products. This study intended to evaluate the antiplatelet effects of a combined extract of sappan wood (Caesalpinia sappan L.) and red ginger (Zingiber officinale var. Rubrum) in high-fat diet-(HFD)-induced rats. Methods: Eighteen male Wistar rats were grouped into six groups (n = 3): control, negative, positive, and three groups of various combinations of extracts. All groups, excluding the control group, were fed an HFD for 8 weeks. In the eighth week, the control and negative groups were given carboxyl methyl cellulose (CMC) 0.5%, the positive control group was administered aspirin, and the other three groups were administered the combination extract of sappan wood and red ginger at various doses for 2 weeks. Blood samples were collected to assess the levels of hyperlipidemia and platelet hyperactivity markers by enzyme-linked immunosorbent assay (ELISA). The physiological effects of platelet hyperactivity were evaluated using the tail bleeding assay. Results: HFD-induced hypertriglyceridemia and hypercholesterolemia synergistically enhanced platelet hyperactivity after 8 weeks of induction. Interestingly, administration of all doses of the combined extract for 2 weeks significantly decreased the platelet activation markers P-selectin, RANTES, and PCSK9 in a dose-dependent manner compared with the negative control. In addition, the combination of sappan wood and red ginger extract at dose 3 (sappan wood:red ginger: 200:800 mg/200 bw/day) significantly extended the bleeding time of rats (p < 0.05) compared to the negative control. Conclusion: Collectively, our results highlight the antiplatelet effect of a combination of sappan wood and red ginger extract in HFD-fed rats.PMID:39734397 | PMC:PMC11679274 | DOI:10.1155/adpp/5543717

Life Sci. 2024 Dec 27:123337. doi: 10.1016/j.lfs.2024.123337. Online ahead of print.ABSTRACTAIMS: This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease-susceptible transgenic pigs via multiomics analysis.MATERIALS AND METHODS: The triple-transgenic (PNPLA3I148M-GIPRdn-hIAPP) pig model (TG pig) was successfully constructed in our laboratory via the CRISPR/Cas9 technique previously described. Wild-type (WT) pigs and TG pigs after 2 or 12 months of high-fat and high-sucrose diet (HFHSD) induction (WT2, TG2, WT12, and TG12 groups, respectively) were used as materials. The transcriptome, metabolome, and lipidome were used to investigate the molecular mechanisms of the liver in pigs.KEY FINDINGS: The TG2 pigs presented mild metaflammation and insulin resistance (IR) which is similar to WT12 pigs. Compared with the other three groups, the TG12 pigs presented severe hepatocyte ballooning, fat deposition, and portal area fibrosis. The transcriptome data suggested that the TG2 pigs presented upregulated gene expression in the extracellular matrix (ECM). The TG12 pigs presented more severe metaflammation and exhibited imbalanced glycolipid metabolism. Interestingly, genes such as ETNPPL, GABBR2, and BMP8B might be key regulatory targets for liver injury. The metabolome and lipidome suggested that long-chain polyunsaturated fatty acids (LCPUFAs) and phospholipids with corresponding LCPUFAs were remodelled. Importantly, bis(monoacylglycerol) phosphates (BMPs) and sulfatides (SLs) could be the key regulatory metabolites in liver injury.SIGNIFICANCE: ETNPPL, GABBR2, and BMP8B might be potential therapeutic targets for liver injury. BMPs and SLs might be biomarkers for the diagnosis and treatment of liver diseases.PMID:39734013 | DOI:10.1016/j.lfs.2024.123337

Part Fibre Toxicol. 2024 Dec 30;21(1):55. doi: 10.1186/s12989-024-00605-6.ABSTRACTBACKGROUND: Exposure to air pollution is associated with worldwide morbidity and mortality. Diesel exhaust (DE) emissions are important contributors which induce vascular inflammation and metabolic disturbances by unknown mechanisms. We aimed to determine molecular pathways activated by DE in the liver that could be responsible for its cardiometabolic toxicity.METHODS: Apolipoprotein E knockout (ApoE KO) mice were exposed to DE or filtered air (FA) for two weeks, or DE for two weeks followed by FA for 1 week. Expression microarrays and global metabolomics assessment were performed in the liver. An integrated transcriptomic and metabolomic analytical strategy was employed to dissect critical pathways and identify candidate genes that could dissect DE-induced pathogenesis. HepG2 cells were treated with an organic extract of DE particles (DEP) vs. vehicle control to test candidate genes.RESULTS: DE exposure for 2 weeks dysregulated 658 liver genes overrepresented in whole cell metabolic pathways, especially including lipid and carbohydrate metabolism, and the respiratory electron transport pathway. DE exposure significantly dysregulated 118 metabolites, resulting in increased levels of triglycerides and fatty acids due to mitochondrial dysfunction as well as increased levels of glucose and oligosaccharides. Consistently, DEP treatment of HepG2 cells led to increased gluconeogenesis and glycogenolysis indicating the ability of the in-vitro approach to model effects induced by DE in vivo. As an example, while gene network analysis of DE livers identified phosphoenolpyruvate carboxykinase 1 (Pck1) as a key driver gene of DE response, DEP treatment of HepG2 cells resulted in increased mRNA expression of Pck1 and glucose production, the latter replicated in mouse primary hepatocytes. Importantly, Pck1 inhibitor mercaptopicolinic acid suppressed DE-induced glucose production in HepG2 cells indicating that DE-induced elevation of hepatic glucose was due in part to upregulation of Pck1 and increased gluconeogenesis.CONCLUSIONS: Short-term exposure to DE induced widespread alterations in metabolic pathways in the liver of ApoE KO mice, especially involving carbohydrate and lipid metabolism, together with mitochondrial dysfunction. Pck1 was identified as a key driver gene regulating increased glucose production by activation of the gluconeogenesis pathway.PMID:39734207 | DOI:10.1186/s12989-024-00605-6

Hepatobiliary Pancreat Dis Int. 2024 Dec 21:S1499-3872(24)00168-1. doi: 10.1016/j.hbpd.2024.12.006. Online ahead of print.ABSTRACTBACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic with high mortality, and the treatment options for the severe patients remain limited. Previous studies reported the altered gut microbiota in severe COVID-19. But there are no comprehensive data on the role of microbial metabolites in COVID-19 patients.METHODS: We identified 153 serum microbial metabolites and assessed the changes in 72 COVID-19 patients upon admission and one-month after their discharge, comparing these changes to those in 133 healthy control individuals from the outpatient department during the same period.RESULTS: Our study revealed that microbial metabolites varied across different stages and severity of COVID-19 patients. These altered microbial metabolites included tryptophan, bile acids, fatty acids, amino acids, vitamins and those containing benzene. A total of 13 distinct microbial metabolites were identified in COVID-19 patients compared to healthy controls. Notably, correlations were found among these disrupted metabolites and organ injury and inflammatory responses related to COVID-19. Furthermore, these metabolites did not restore to the normal levels one month after discharge. Importantly, two microbial metabolites were the core microbial metabolites related to the severity of COVID-19 patients.CONCLUSIONS: The microbial metabolites were altered in the acute and recovery stage, correlating with disease severity of COVID-19. These results indicated the important role of gut microbiota in the progression of COVID-19, and facilitated the potential therapeutic microbial target for severe COVID-19 patients.PMID:39734160 | DOI:10.1016/j.hbpd.2024.12.006

Int J Biol Macromol. 2024 Dec 27:139197. doi: 10.1016/j.ijbiomac.2024.139197. Online ahead of print.ABSTRACTThe present study aimed to investigate the impact of Sparassis latifolia polysaccharides (SLPs) on hepatic immune function in cyclophosphamide (CTX)-induced immunocompromised mice. Our findings demonstrated that SLPs effectively suppressed the production of alanine aminotransferase (ALT), aspartate aminotransferase (AST), inflammatory factors, and acute phase proteins, while improving the hepatic oxidative stress state. Additionally, SLPs exerted inhibitory effects on inflammatory cell infiltration within hepatic tissue. Transcriptomic results revealed that 246 differentially-expressed genes (DEGs) were identified. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis showed that the more DEGs in SLPs group were mainly related to immune signal transduction and metabolism pathways. And more DEGs were mainly related to MAPK signaling pathway and JAK/STAT signaling pathway. Metabolome analysis demonstrated that SLPs significantly modulated specific metabolites in the liver, including lipids and lipid-like molecules, organic acids and their derivatives, organic heterocyclic compounds, phenylpropanoids and polyketones, organic oxygenates, and benzene. The comprehensive analysis of transcriptome and metabonomics revealed the activation of immune-related signal pathways in mice liver stimulated by CTX. Notably, the involvement of diverse genes and metabolites was observed in the metabolism of arachidonic acid (AA) and JAK/STAT pathway. Correlation analysis also showed that there was a certain correlation between metabolites and differential genes. The present findings offer novel insights into the regulatory mechanism of liver immune injury by SLPs, which exhibits potential application value in improving immunocompromised populations.PMID:39733888 | DOI:10.1016/j.ijbiomac.2024.139197

Int J Biol Macromol. 2024 Dec 27:139223. doi: 10.1016/j.ijbiomac.2024.139223. Online ahead of print.ABSTRACTOsteoporosis is a systemic, progressive bone disease that causes metabolic disorders. Previous study identified the preventive effects of hydrolyzed egg yolk peptide (YPEP) on osteoporosis. However, the underlying antiosteoporosis mechanism remains unclear. Herein, 30 female rats were randomly divided into 5 groups (n = 6), including the sham, OVX, E2 (25 μg/kg/d 17β-estradiol), LYPEP (10 mg/kg/d YPEP), and HYPEP (40 mg/kg/d YPEP) groups. YPEP treatment significantly changed bone turnover marker levels and prevented the deterioration of bone structure and strength caused by ovariectomy. YPEP supplementation significantly changed endogenous metabolites related to lipid metabolism in the serum of ovariectomized rats, identifying 46 metabolites closely linked to bone biomarkers. Additionally, YPEP reduced the expression of the lipid metabolism-related protein peroxisome proliferator-activated receptor PPARγ and increased the expression of bone formation proteins BMP2 and RUNX2. Collectively, these results elucidated that YPEP improves osteoporosis by inhibiting lipogenesis to promote bone formation. This study provides novel evidence for the use of YPEP in treating osteoporosis.PMID:39733873 | DOI:10.1016/j.ijbiomac.2024.139223

J Adv Res. 2024 Dec 27:S2090-1232(24)00614-3. doi: 10.1016/j.jare.2024.12.035. Online ahead of print.ABSTRACTINTRODUCTION: Mammalian sperm within a single ejaculate exhibit significant heterogeneity, with only a subset possessing the molecular characteristics required for successful fertilization. Identifying the defining traits of these high-fertility sperm remains an open question.OBJECTIVES: To elucidate the molecular markers and mechanisms underlying the fertilization potential of sperm in both mice and humans, with a focus on the role of D-mannose.METHODS: Sperm morphology and functionality were analyzed using flow cytometry, biochemical assays, and immunofluorescence. Multi-omics analyses, including proteomics, metabolomics, and lipidomics, were conducted to identify distinct molecular signatures. Pharmacological interventions were employed to validate the role of key pathways, particularly Akt/mTOR signaling.RESULTS: Sperm with longer flagella demonstrated enhanced motility, mitochondrial activity, and fertilization potential in both mice and humans. Multi-omics analyses revealed distinct molecular profiles in high-fertility sperm, characterized by specific proteins, lipids, and metabolites. Notably, D-mannose supplementation enhanced sperm motility and fertilization capacity, even in asthenozoospermic sperm, by activating the Akt/mTOR pathway. This effect was not replicated by D-glucose or ATP supplementation. Mechanistically, D-mannose bypassed glycolytic rate-limiting steps, increasing ATP production and promoting mitochondrial and acrosomal integrity.CONCLUSION: This study identifies key molecular signatures of fertilization-competent sperm and highlights D-mannose as a novel modulator of sperm quality and function. These findings provide valuable insights into sperm biology and propose innovative therapeutic strategies for treating male infertility and optimizing assisted reproduction technologies.PMID:39733858 | DOI:10.1016/j.jare.2024.12.035

Dev Comp Immunol. 2024 Dec 27:105311. doi: 10.1016/j.dci.2024.105311. Online ahead of print.ABSTRACTSaprolegniasis is a common fungal disease in aquaculture. It will form white flocculent hyphae on the skin of fish, and the hyphae may grow inward and penetrate into muscle tissue, which will reduce the immunity of the body and eventually lead to death. However, there are still some gaps in the mechanism of the fish body surface against the invasion of Saprolegnia. This study explored the defense mechanism of Epithelioma papulosum cyprini cell (EPC) in the process of Saprolegnia parasitica infection from the perspective of pathogenic bacteria and host cells, so as to provide a theoretical basis for further exploring the mechanism of host resistance to S. parasitica invasion. The EPC cell was used as the research object. The EPC cells were treated with 1×106 CFU/mL of S. parasitica for 0, 6, 12, 24, 48 and 72 h. Cell viability and cell membrane damage were detected, and the non-specific immune enzyme activity in the cells was detected. Based on the above research, the apoptosis genes and antioxidant genes in the cells were detected to analyze the effect of S. parasitica on the metabolism of the EPC cells. The results showed that with the prolongation of the co-culture time of S. parasitica and cells, the cell viability gradually decreased and the cell membrane integrity was destroyed, but at the same time, the activity of non-specific immune enzymes increased to resist the infection of S. parasitica. In addition, the detection of EPC apoptosis gene casp3a and CTSD showed that the relative content of casp3a gene increased significantly at 24 h and reached the maximum value of the culture time (P<0.05). The content of CTSD gene increased significantly at 12 h and reached the maximum value (P<0.05). The results of antioxidant immune genes serpinh1a and gpx1a were opposite to the structure of apoptotic genes. The content of serpinh1a and gpx1a genes decreased significantly at 12 h (P<0.05), but with the prolongation of culture time, the content increased significantly at 24 h and 48 h (P<0.05). After stimulation of EPC cells by S. parasitica, the differential metabolites were mainly concentrated in Lipids, Compounds with biological roles and Phytochemical compounds. The KEGG pathway mainly focused on ABC transporters, Glycerophospholipid metabolism, Cysteine and methionine metabolism, Glycine, serine and threonine metabolism, Purine metabolism. In general, S. parasitica can affect cell activity, destroy the cell membrane of EPC cells, and cause apoptosis. However, EPC cells can also resist the invasion of S. parasitica by regulating their own non-specific immunity and their own metabolites, thereby protecting the body from the infection of S. parasitica.PMID:39733846 | DOI:10.1016/j.dci.2024.105311

Virus Res. 2024 Dec 27:199518. doi: 10.1016/j.virusres.2024.199518. Online ahead of print.ABSTRACTAmong flaviviruses, Zika virus (ZIKV) is the only arbovirus officially recognized as a teratogenic agent, as a consequence of its ability to infect and cross the placental barrier causing congenital malformation in the fetus. While many studies have focused on understanding ZIKV pathogenesis during pregnancy, the viral mechanisms affecting fetal development remain largely unclear. In this study, we investigated ZIKV virulence in placental trophoblasts, using viruses with distinct lipid profiles. Firstly, we propagated a ZIKV strain belonging to the Asian lineage in either mammalian or mosquito cells, obtaining two viral stocks, which were purified and analyzed to determine their genetic and lipid composition. Successively, we assessed the infectivity of the two stocks in placental cells using both immortalized cell lines and explants. We found that the two viral stocks displayed identical consensus sequences with homogeneous quasispecies composition. However, the lipid composition of their envelope significantly varied depending on the cell of origin, with the mammalian-derived viral stock characterized by a higher content of phosphatidylcholines compared to the virions originating from mosquito cells. Notably, ZIKV stocks derived from mammalian cells showed a higher infectivity in immortalized villous trophoblasts and full-term placental explants of human origin. This increased infectivity was linked to enhanced fusion efficiency during the viral uncoating phase in trophoblast cells, as demonstrated using a lipophilic probe. Collectively, our data suggest a potential role of viral lipids as determinants of ZIKV infectivity in full-term placenta, underscoring the importance of lipidomic research in virology.PMID:39733819 | DOI:10.1016/j.virusres.2024.199518