PubMed

Life Sci. 2024 Oct 22:123167. doi: 10.1016/j.lfs.2024.123167. Online ahead of print.ABSTRACTProspective prediction from the Australian Institute of Health and Welfare (AIHW) showed a likely incidence of 1 in 23 women diagnosed with gynaecological malignancy, where the incidence of relapse with a drug-resistant clone poses a significant challenge in dealing with it even after initial treatment. Glucose metabolism has been exploited as a therapeutic target under anti-metabolomic study, but the non-specificity narrowed its applicability in cancer. Novel updates over epigenetics as a target in gynaecological cancer offer a rational idea of using this in the metabolic rewiring in mutated glycolytic flux-induced drug resistance. This review focuses on the application of epigenetic intervention at a diagnostic and therapeutic level to shift the current treatment paradigm of gynaecological cancers from reactive medicine to predictive, preventive, and personalised medicine. It presents the likely epigenetic targets that can be exploited potentially to prevent the therapeutic failure associated with glucose metabolism-induced chemotherapeutic drug resistance.PMID:39447732 | DOI:10.1016/j.lfs.2024.123167

Life Sci. 2024 Oct 22:123165. doi: 10.1016/j.lfs.2024.123165. Online ahead of print.ABSTRACTAIMS: Regorafenib, an FDA-approved drug for advanced primary liver cancer (PLC), could provide survival benefits for patients. However, markers for its therapeutic sensitivity are lacking. This study seeks to identify sensitive targets of regorafenib in PLC from the perspective of small molecular metabolites.MATERIALS AND METHODS: Initiated with network pharmacology (NP) to map regorafenib's target landscape and metabolic regulatory network in liver cancer. Subsequently, regorafenib's impact on hepatoma cells was evaluated by flow cytometry, western blotting (WB) and cell viability assay. Advanced metabolomics and lipidomics were employed to elucidate regorafenib's metabolic reprogramming effects in liver cancer. Metabolic enzyme expression was assessed by WB, immunohistochemical and immunofluorescence assays. Ultimately, mendelian randomization (MR) analysis was utilized to investigate the potential causality of sphingolipid metabolism in hepatic cancer.KEY FINDINGS: Regorafenib was observed to inhibit hepatoma cell proliferation and cell cycle progression at G0/G1 phase, resulting in significant alterations in sphingolipid levels. It promoted the significant accumulation of 16:0 dihydroceramide (16:0 dhCer) by upregulating ceramide synthase 6 (CERS6) expression and inhibiting dihydroceramide desaturase 1 (DEGS1) activity. The MR analysis revealed that DEGS1 was a risk factor for the development and progression of liver cancer, while cumulative 16:0 dhCer was a protective factor.SIGNIFICANCE: Sphingolipids, particularly dhCer and regulatory enzymes, may be potential sensitive markers of regorafenib in the treatment of liver cancer, providing new insights for enhancing the treated efficacy of regorafenib in liver cancer.PMID:39447728 | DOI:10.1016/j.lfs.2024.123165

J Ethnopharmacol. 2024 Oct 22:118976. doi: 10.1016/j.jep.2024.118976. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Modified Ma-Xing-Shi-Gan decoction (MMXSGD), a classic prescription from Treatise on Febrile Disease in China, is commonly used to treat Klebsiella pneumoniae (KP) infections in clinical settings.MATERIALS AND METHODS: The aim of this study is to assess the efficacy of MMXSGD in the treatment of pneumonia and investigate its underlying mechanism of action. UHPLC-MS/MS was established to identify the main chemical components of serum after intragastric administration with MMXSGD. A mouse model of pneumonia caused by KP was used to evaluate the therapeutic potential of MMXSGD. The macrophage polarization was analyzed by immunohistochemistry. The cytokine profile was assessed using Luminex assay. Lung transcript and metabolite levels were assessed by transcriptomics and non-targeted metabolomics to analyze potential anti-pneumonia mechanisms and targets.RESULTS: 22 major blood-entry components and 274 MMXSGD-pneumonia-related targets were identified. Compared with the model group, the mortality rate of mice in different dosage groups of MMXSGD was significantly reduced, and pathological lung damage was significantly alleviated. Among them, the low dose of MMXSGD treatment had the best protective effect. Further, MMXSGD treatment could regulates M1/M2 polarization in macrophages and inhibits the production of pro-inflammatory cytokines. The data from transcriptome and metabolome analysis indicate that MMXSGD could regulate inflammation-related pathways (PI3K/AKT, HIF-1, NF-κB pathway) and metabolites to modulate pulmonary inflammation. The results demonstrate that MMXSGD enhances the antibacterial effect in vivo by suppressing inflammation and regulating immunity rather than directly antibacterial effect.CONCLUSION: These findings provide a further assessment of MMXSGD, suggesting that MMXSGD has good therapeutic efficacy in bacterial infectious diseases.PMID:39447714 | DOI:10.1016/j.jep.2024.118976

J Ethnopharmacol. 2024 Oct 22:118988. doi: 10.1016/j.jep.2024.118988. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng saponin (PNS) has a variety of biological activities, such as improvement of myocardial ischemia, improvement of learning and memory, hypolipidemia, and immunomodulation. However, its protective mechanism on the central nervous system (CNS) is not clear.AIM OF THE STUDY: The present study initially evaluated the possible mechanism of PNS to improve cognitive dysfunction due to chronic sleep deprivation (CSD).MATERIALS AND METHODS: In the present study, we used a modified multi-platform aquatic environment sleep deprivation method to induce a cognitively impaired rat model, and explored the mechanism of action of PNS by integrating serum metabolomics and network pharmacology, which was further verified by molecular docking and experiments.RESULTS: The results showed that PNS significantly shortened the escape latency, increased the target quadrant time and the number of traversing platforms, and attenuated the inflammatory damage in the hippocampal Cornu Ammonis 1 (CA1) region in CSD rats. The non-targeted metabolomics results indicated that 35 biomarkers significantly altered following PNS therapy intervention, with metabolic pathways enriched for the effects of One carbon pool by folate, Riboflavin metabolism, Glycerophospholipid metabolism, Sphingolipid metabolism, Glycerolipid metabolism, Arachidonic acid metabolism, and Tryptophan metabolism. In addition, network pharmacology identified 234 potential targets for PNS intervention in CSD with cognitive impairment. Metabolite-response-enzyme-gene network was constructed by MetaScape and matched with the network pharmacology results to identify a total of five shared targets (LPL, GPAM, HSD11B1, HSD11B2, and SULT2A1) and two metabolic pathways (Sphingolipid metabolism and Steroid hormone biosynthesis). The results of molecular docking revealed that the five active ingredients had good binding ability with the five core targets. qPCR analysis confirmed the ability of PNS to modulate the above five targets.CONCLUSIONS: The combination of metabolomics and network analysis provides a scientific basis for promoting the clinical application of PNS in cognitive impairment.PMID:39447711 | DOI:10.1016/j.jep.2024.118988

Planta Med. 2024 Oct 24. doi: 10.1055/a-2420-0270. Online ahead of print.ABSTRACTThis exploratory study was designed to identify factors implicating microbial influence on medicinal plant metabolomes. Utilizing a whole-microbiome approach, amplicon sequencing was used to identify the makeup of fungal and bacterial assemblages from endophytic (interior) and epiphytic (external) environments in two different sets of congeneric host-plant pairs, with collection of multiple samples of two medicinal plant species (Actaea racemosa, Rhodiola rosea) and two generic analogs (Actaea rubra, Rhodiola integrifolia). Diversity analysis of microbial assemblages revealed the influence of three primary factors driving variance in microbial community composition: host-plant taxonomy, the compartmentalization of microbial communities within discrete plant parts, and the scale of distance (microhabitat heterogeneity) between sampling locations. These three factors accounted for ~ 60% of variance within and between investigated microbiomes. Across all our collections, bacterial populations were more diverse than fungi (per compartment), and microbial density in epiphytic compartments (aerial parts, rhizosphere) were higher than those of endophytes (leaf and root). These comparative data point to key loci associated with variation between congeneric pairs and plant genera, providing insight into the complex and contrasting relationships found within this multi-kingdom coevolutionary relationship. Although reflective of only a limited set of botanical source materials, these data document the richness of a relatively unexplored component of the plant world and highlight the relevance of a whole-microbiome ecology-driven approach to botanical research and directed natural product investigations.PMID:39447601 | DOI:10.1055/a-2420-0270

Med. 2024 Oct 17:S2666-6340(24)00378-7. doi: 10.1016/j.medj.2024.09.011. Online ahead of print.ABSTRACTBACKGROUND: Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS.METHODS: Global metabolomics was performed in an observational cohort of people with MS, followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2 g/day) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory, and gut microbiome parameters.FINDINGS: In the observational cohort, higher primary bile acid levels at baseline predicted slower whole-brain atrophy, brain substructure atrophy, and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not differ significantly between arms (p = 0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naive cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted between the two groups.CONCLUSIONS: Bile acid metabolism in MS is linked to brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable, and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.FUNDING: National MS Society grant RG-1707-28601 to P.B., R01 NS082347 from the National Institute of Neurological Disorders and Stroke to P.A.C., and National MS Society grant RG-1606-08768 to S.S.PMID:39447576 | DOI:10.1016/j.medj.2024.09.011

Int Immunopharmacol. 2024 Oct 23;143(Pt 2):113438. doi: 10.1016/j.intimp.2024.113438. Online ahead of print.ABSTRACTType A aortic dissection (TAAD) is an acute onset disease with a high mortality rate. TAAD is caused by a tear in the aortic intima and subsequent blood infiltration. The most prominent characteristics of TAAD are aortic media degeneration and inflammatory cell infiltration, which disturb the structural integrity and function of nonimmune and immune cells in the aortic wall. However, to date, there is no systematic evaluation of the interactions between nonimmune cells and immune cells and their effects on metabolism in the context of aortic dissection. Here, multiomics, including bulk RNA-seq, single-cell RNA-seq, and lipid metabolomics, was applied to elucidate the comprehensive TAAD lipid metabolism landscape. Normally, monocytes in the stress response state secrete a variety of cytokines. Injured fibroblasts lack the ability to degrade lipids, which is suspected to contribute to a high lipid environment. Macrophages differentiate into fatty acid binding protein 5-positive (FABP5+) macrophages under the stimulation of metabolic substrates. Moreover, the upregulation of Fabp5+ macrophages were retrospectively validated in TAAD model mice and TAAD patients. Finally, Fabp5+ macrophages can generate a wide range of proinflammatory cytokines, which possibly contribute to TAAD pathogenesis.PMID:39447410 | DOI:10.1016/j.intimp.2024.113438

Poult Sci. 2024 Oct 11;103(12):104395. doi: 10.1016/j.psj.2024.104395. Online ahead of print.ABSTRACTNitrites in meat products are important food additives with coloring, antibacterial and antioxidant effects, but excessive intake of nitrites can pose health risks, including an increased risk of cancer due to the formation of carcinogenic nitrosamines. In the present study, Limosilactobacillus fermentum CGMCC 1.7434 was screened and the effects of it and Debaryomyces hansenii GDMCC 2.149 and their combination on nitrite degradation were investigated. It was found that the co-culture of L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 significantly enhanced nitrite degradation (99.58%). The findings on salt and ethanol tolerance suggest suitability for application in meat fermentation processes. Scanning electron microscopy and additional data indicate that D. hansenii GDMCC 2.149 facilitates the growth, acid production, adhesion, secretion of AI-2 signaling molecules, and biofilm formation of L. fermentum CGMCC 1.7434. Metabolomics analysis suggests that these microorganisms reduce nitrite levels by converting NH3 derived from nitrite into L-glutamine, which is further transformed into N-nitroso compounds and their downstream derivatives through the ABC transporter pathway, the TCA cycle, and the amino acid metabolism pathway. Microbial community analyses showed that L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 were successfully inoculated into air-dried ducks, becoming dominant strains and effectively inhibiting the growth of pathogenic bacteria. Furthermore, during the processing of air-dried duck, the combination of ultrasonic cavitation (250 W, 4 min, 30°C, 40 kHz) with the co-fermentation of L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 effectively reduced nitrite content (84.55%) and TVB-N levels in the meat, without compromising color or TBARS values. This is crucial for understanding the mechanism of nitrite degradation by LAB in synergy with yeast and for the advancement of low-nitrite air-dried duck products.PMID:39447333 | DOI:10.1016/j.psj.2024.104395

Poult Sci. 2024 Oct 10;103(12):104404. doi: 10.1016/j.psj.2024.104404. Online ahead of print.ABSTRACTIntramuscular fat (IMF) content is an important indicator of livestock and poultry meat quality. Enhancing IMF deposition can significantly improve meat quality. Focusing on the core process of IMF deposition, this study used the Jingxing Yellow (JXY) chickens as a model organism and employed multi-omics approaches, including RNA-sequencing (RNA-seq), Whole-genome bisulfite sequencing (WGBS), and metabolomics, to identify the key genes influencing IMF deposition in chickens during development. The results indicated that the contents of triglycerides (TG) and phospholipids (PLIP) exhibited an upward trend. The TG content did not differ significantly between day 1 (D1) and day 7 (D7), but increased significantly after 35 days (D35) of age. The WGBS results revealed that CpG methylation was the predominant methylation type in the breast muscle tissue of JXY chickens. Integrative analysis of RNA-seq and WGBS identified 50 genes, including PLA2G4F, PALMD, PLSCR5, ARHGEF26, LUM, DCN, TNRC6B, CACNA1C, ROBO1, and MBTPS2, whose methylation levels were significantly negatively correlated with their expression levels. In addition, the combined Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differentially-expressed metabolites (DEM) and differentially-expressed genes (DEG) converged on the glycerophospholipid metabolism pathway, which was significantly enriched in DEGs such as PLA2G4F, PLA2G15, LPIN1, MBOAT2, DGKH, AGPAT2, and CHKA, as well as DEM like glycerophosphocholine and phosphocholine. Notably, PLA2G4F was identified as a DEG by DNA methylation, suggesting that PLA2G4F could be a key candidate gene influencing IMF deposition during chicken development. These findings are expected to provide a solid theoretical foundation for improving meat quality through targeted genetic and epigenetic interventions.PMID:39447331 | DOI:10.1016/j.psj.2024.104404

Biochem Biophys Res Commun. 2024 Oct 16;736:150843. doi: 10.1016/j.bbrc.2024.150843. Online ahead of print.ABSTRACTThe aim of this study was to clarify the transcriptional and metabolic characteristics of C2C12 myoblasts cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 20 % chicken serum (CHS) (C2C12-CHS cells) compared with C2C12 myoblasts cultured in DMEM containing 20 % fetal bovine serum (FBS) (C2C12-FBS cells). After 3 days of culture, C2C12-CHS cells showed a marked accumulation of lipid droplets, accompanied by increased expression levels of brown adipocyte-related genes (i.e., Bmp7, Prdm16, Ucp1, Cidea, Pgc1α, Cox7a1, Cox8, and β3-adorenoceptor). Furthermore, stimulation of β3-adorenoceptor by its selective agonist, mirabegron, increased the mRNA expression of Ucp1 and Pgc1α in C2C12-CHS cells. Wide-targeted metabolomic analysis performed by gas chromatography-tandem mass spectrometry revealed that the metabolic profile of C2C12-CHS cells was obviously different to that of C2C12-FBS cells. Additionally, the metabolomic analysis indicated that β3-adrenoceptor stimulation by mirabegron upregulated energy metabolism in C2C12-CHS cells as seen in brown adipocytes. These results suggest that C2C12-CHS cells may differentiate into brown adipocyte-like cells, accompanied by increased functional β3-adrenoceptor.PMID:39447277 | DOI:10.1016/j.bbrc.2024.150843

Food Chem. 2024 Oct 18;464(Pt 2):141717. doi: 10.1016/j.foodchem.2024.141717. Online ahead of print.ABSTRACTPseudomonas fragi and Pseudomonas lundensis are key spoilage microorganisms in aerobically stored chilled meat, which had co-spoilage effect on chilled pork. However, the mechanism of co-spoilage interaction of P. fragi and P. lundensis has not been elucidated. The metabolism of nutrients in pork by mixed bacteria may differ from that by single strains. This study applied metabolomics and in vitro metabolite utilization experiment to assess the mechanism of that co-metabolize raw pork during storage. Results showed that co-spoilage group had 104 differential metabolites (histamine, N-methylhydantoin and D-gluconic acid, etc.) and 78 differential metabolites (putrescine, uracil acid and uracil, etc.) compared to P. fragi and P. lundensis group, respectively. These differential metabolites were mainly related to histidine metabolism, arginine biosynthesis, and purine. The co-spoilage effect of P. fragi and P. lundensis was related to the promotion of deamination and decarboxylation of histidine to produce histamine, the promotion of α-ketoglutarate and glutamate-mediated transamination, and the full utilization of the arginine deiminase pathway by the co-culture bacteria in the degradation of arginine to produce putrescine. In vitro experiment, co-cultures of these strains resulted in greater consumption of glucose, higher utilization activity, and promoted deamination and decarboxylation of amino acids. These findings reveal the complex and competitive interactions of co-culture of P. fragi and P. lundensis, providing insight into microbial spoilage mechanisms in chilled pork.PMID:39447269 | DOI:10.1016/j.foodchem.2024.141717

Mult Scler Relat Disord. 2024 Oct 16;92:105946. doi: 10.1016/j.msard.2024.105946. Online ahead of print.ABSTRACTBACKGROUND: Multiple sclerosis (MS) is characterized by extensive tissue damage leading to a range of complex symptoms, including physical disability and cognitive dysfunction. Recent work has indicated the clinical relevance of bioactive lipid mediators (LMs), which are known to orchestrate inflammation and its resolution and are deregulated in MS. However, it is unknown whether LM profiles relate to white matter (WM) damage.OBJECTIVES: To investigate the potential association between plasma-derived LMs and MRI-quantified WM damage using fractional anisotropy (FA) and grey matter (GM) atrophy in dimethyl fumarate-treated relapsing remitting MS (RRMS) patients.METHODS: Severity of FA-based WM damage and GM atrophy was determined in RRMS patients (n = 28) compared to age- and sex-matched controls (n = 31) at treatment initiation (baseline) and after 6 months. Plasma LMs were assessed using HPLC-MS/MS and baseline LMs were correlated to changes in FA and brain volumes.RESULTS: We observed significant WM damage in RRMS patients (mean age 41.4 [SD 9.1]) at baseline and follow-up (z-score=-0.33 and 0.31, respectively) compared to controls (mean age 41.9 [SD 9.5]; p < 0.001 for both comparisons). Patients with severe WM damage showed a decline of thalamic volume (p = 0.02), and this decline correlated (r = 0.51, p < 0.001) with lower baseline levels of 9-HODE. This LM also predicted FA worsening (beta = 0.14, p < 0.001) over time at 6 months.CONCLUSION: Despite the relatively small sample size, lower baseline levels of the LM 9-HODE correlated with more thalamic atrophy and predicted subsequent worsening of WM damage in RRMS patients.PMID:39447246 | DOI:10.1016/j.msard.2024.105946

Phytomedicine. 2024 Oct 15;135:156158. doi: 10.1016/j.phymed.2024.156158. Online ahead of print.ABSTRACTBACKGROUND: Alzheimer's disease (AD), an escalating global health issue, lacks effective treatments due to its complex pathogenesis. YangXue QingNao Wan (YXQNW) is a China Food and Drug Administration (CFDA)- approved TCM formula that has been repurposed in clinical Phase II for the treatment of AD. Identifying YXQNW's active ingredients and their mechanisms is crucial for developing effective AD treatments.PURPOSE: This study aims to elucidate the anti-AD effects of YXQNW and to explore its potential therapeutic mechanisms employing an endophenotype network strategy.METHODS: Herein we present an endophenotype network strategy that combines active ingredient identification in rat serum, network proximity prediction, metabolomics, and in vivo experimental validation in two animal models. Specially, utilizing UPLC-Q-TOF-MS/MS, active ingredients are identified in YXQNW to build a drug-target network. We applied network proximity to identify potential AD pathological mechanisms of YXQNW via integration of drug-target network, AD endophenotype gene sets, and human protein interactome, and validated related mechanisms in two animal models. In a d-galactose-induced senescent rat model, YXQNW was administered at varying doses for cognitive and neuronal assessments through behavioral tests, Nissl staining, and transmission electron microscopy (TEM). Metabolomic analysis with LC-MS revealed YXQNW's influence on brain metabolites, suggesting therapeutic pathways. Levels of key proteins and biochemicals were measured by WB and ELISA, providing insights into YXQNW's neuroprotective mechanisms. In addition, 5×FAD model mice were used and administered YXQNW by gavage for 14 days at two doses. Amyloid-β levels, transporter expression, and cerebral blood flow have been detected by MRI and biochemical assays.RESULTS: The network proximity analysis showed that the effect of YXQNW on AD was highly correlated with amyloid β, synaptic function, glucose metabolism and mitochondrial function. The results of metabolomics combined with in vivo experimental validation suggest that YXQNW has the potential to ameliorate glucose transport abnormalities in the brain by upregulating the expression of GLUT1 and GLUT3, while further enhancing glucose metabolism through increased O-GlcNAcylation and mitigating mitochondrial dysfunction via the AMPK/Sirt1 pathway, thereby improving d-galactose-induced cognitive deficits in rats. Additionally, YXQNW treatment significantly decreased Aβ1-42 levels and enhanced cerebral blood flow (CBF) in the hippocampus of 5×FAD mice. while mechanistic findings indicated that YXQNW treatment increased the expression of ABCB1, an Aβ transporter, in 5×FAD model mice to promote the clearance of Aβ from the brain and alleviate AD-like symptoms.CONCLUSIONS: This study reveals that YXQNW may mitigate AD by inhibiting Aβ deposition and ameliorating mitochondrial dysfunction and glucose metabolism, thus offering a promising therapeutic approach for AD.PMID:39447228 | DOI:10.1016/j.phymed.2024.156158

PLoS One. 2024 Oct 24;19(10):e0307157. doi: 10.1371/journal.pone.0307157. eCollection 2024.ABSTRACTThe well-characterized edible and medicinal bamboo mushroom is Phallus indusiatus, a Chinese bamboo mushroom with long white indusium (skirt). To date, scientists have found more than five species of bamboo mushrooms in Thailand, containing bamboo mushrooms with long white, short white, and several colored skirts. Still, most of them are unidentified species and lack metabolic profile data. Hence, this study aims to evaluate the species of the long white-skirt Chinese bamboo mushroom-like (CH-isolate) and short white-skirt (TH-isolate) bamboo mushrooms isolated from a local farm in northern Thailand. External morphology and molecular identification were used to identify the species. Nutritional and metabolic studies were conducted to determine the nutrients and metabolites from both isolates. Our morphological and evolutionary phylogenetic analyses suggested that CH- and TH-isolates were different species. Interestingly, the CH-isolate, which has a similar morphology to P. indusiatus, clearly demonstrated the difference in species. In addition, the nutritional and metabolomic analysis revealed that CH- and TH-isolate contain different nutritional constituents and metabolic profiles. Our study reports the two new species of bamboo mushrooms that were suspected to be found in Thailand and their metabolic profiles that could be beneficially used in further studies. However, definitive confirmation of the novel species will be made in the future.PMID:39446827 | DOI:10.1371/journal.pone.0307157

Mol Cell Biochem. 2024 Oct 24. doi: 10.1007/s11010-024-05139-1. Online ahead of print.ABSTRACTAtherosclerosis (AS) is a chronic inflammatory disease characterized by lipid deposition within the arterial intima, as well as fibrous tissue proliferation and calcification. AS has long been recognized as one of the primary pathological foundations of cardiovascular diseases in humans. Its pathogenesis is intricate and not yet fully elucidated. Studies have shown that AS is associated with oxidative stress, inflammatory response, lipid deposition, and changes in cell phenotype. Unfortunately, there is currently no effective prevention or targeted treatment for AS. The rapid advancement of omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, has opened up novel avenues to elucidate the fundamental pathophysiology and associated mechanisms of AS. Here, we review articles published over the past decade and focus on the current status, challenges, limitations, and prospects of omics in AS research and clinical practice. Emphasizing potential targets based on omics technologies will improve our understanding of this pathological condition and assist in the development of potential therapeutic approaches for AS-related diseases.PMID:39446251 | DOI:10.1007/s11010-024-05139-1

Mol Neurobiol. 2024 Oct 24. doi: 10.1007/s12035-024-04538-1. Online ahead of print.ABSTRACTGliomas are intricate tumors with numerous metabolic and genetic abnormalities contributing to their aggressive phenotypes and poor prognoses. The study aims at identifying the key molecular metabolic as well as gene expressional variations that could be used to differentiate between different grades of glioma to obtain deeper insights the about metabolic status of glioma that may serve as good candidates of diagnosis in future. In the present study, the metabolomic profiling along with clinical and expressional analyses of glioma biopsies (n = 52; patients comprising both of benign and malignant lesions) was analyzed. The biopsies were subjected to gene/protein expressional analysis using RT-PCR and western blotting and also were subjected to metabolite analyses. The results of the gene/protein expressional analysis exhibited elevated levels of carnitine palmitoyltransferase, monoglyceride lipase, human phosphofructokinase, and isocitrate dehydrogenase in higher grades of glioma when compared to those of control. Our study suggested that the metabolites and gene/protein expressional levels were found to be discriminative among the grades of glioma. The study is deemed as a provider of deeper insights that are essential for differential therapeutic approaches that specifically target the dysregulated metabolome to the benefit of patients.PMID:39446218 | DOI:10.1007/s12035-024-04538-1

Food Funct. 2024 Oct 24. doi: 10.1039/d4fo03844d. Online ahead of print.ABSTRACTEpigallocatechin gallate (EGCG) has demonstrated potential effects on obesity-induced precocious puberty, but the underlying mechanisms remain unclear. Female mice were randomly assigned into control (CON), EGCG-treated (EGCG), high-fat diet (HFD), and HFD with EGCG treatment (HFDEGCG) groups. Key measurements included body weight, vaginal opening time, and serum sex hormone levels. The gut microbiota was analyzed through 16S rRNA sequencing, fecal metabolites were assessed via metabolomics, and the hypothalamic transcriptome was examined using RNA sequencing. EGCG mitigated weight gain and delayed vaginal opening in mice with obesity-induced precocious puberty. Additionally, it reduced serum estradiol levels and decreased the number of mature ovarian follicles in the HFDEGCG group compared to the HFD group. EGCG treatment partially reversed HFD-induced dysbiosis by increasing the abundance of beneficial bacteria such as Akkermansia. Metabolomic analysis revealed significant alterations in tryptophan metabolism, while transcriptome analysis identified genes involved in metabolic pathways. Correlation analyses underscored the importance of the gut-brain axis in mediating EGCG's effects. Overall, EGCG prevents obesity-induced precocious puberty by modulating the gut microbiota, altering metabolic pathways, and regulating hypothalamic gene expression.PMID:39445911 | DOI:10.1039/d4fo03844d

Appl Environ Microbiol. 2024 Oct 24:e0160324. doi: 10.1128/aem.01603-24. Online ahead of print.ABSTRACTFungi generate a diverse array of bioactive compounds with significant pharmaceutical applications. However, the chemical diversity of natural products in fungi remains largely unexplored. Here, we present a paradigm for specifically discovering diverse and bioactive compounds from fungi by integrating genome mining with building block molecular network and coculture analysis. Through pangenome and sequence similarity network analysis, we identified a rare type I polyketide enzyme from Penicillium sp. ZJUT-34. Subsequent building block molecular network and coculture strategy led to the identification and isolation of a pair of novel polyketides, (±)-peniphenone E [(±)-1], three known polyketides (2-4), and three precursor compounds (5-7) from a combined culture of Penicillium sp. ZJUT-34 and Penicillium sp. ZJUT23. Their structures were established through extensive spectroscopic analysis, including NMR and HRESIMS. Chiral HPLC separation of compound 1 yielded a pair of enantiomers (+)-1 and (-)-1, with their absolute configurations determined using calculated ECD methods. Compound (±)-1 is notable for its unprecedented structure, featuring a unique 2-methyl-hexenyl-3-one moiety fused with a polyketide clavatol core. We proposed a hypothetical biosynthetic pathway for (±)-1. Furthermore, compounds 2, 5, and 6 exhibited strong antioxidant activity, whereas (-)-1, (+)-1, 3, and four exhibited moderate antioxidant activity compared to the positive control, ascorbic acid. Our research demonstrates a pioneering strategy for uncovering novel polyketides by merging genome mining, metabolomics, and cocultivation methods. This approach addresses the challenge of discovering natural compounds produced by rare biosynthetic enzymes that are often silent under conventional conditions due to gene regulation.IMPORTANCEPolyketides, particularly those with complex structures, are crucial in drug development and synthesis. This study introduces a novel approach to discover new polyketides by integrating genomics, metabolomics, and cocultivation strategies. By combining genome mining, building block molecular networks, and coculturing techniques, we identified and isolated a unique polyketide, (±)-peniphenone E, along with three known polyketides and three precursor compounds from Penicillium sp. ZJUT-34 and Penicillium sp. ZJUT23. This approach highlights the potential of using combined strategies to explore fungal chemical diversity and discover novel bioactive compounds. The successful identification of (±)-peniphenone E, with its distinctive structure, demonstrates the effectiveness of this integrated method in enhancing natural product discovery and underscores the value of innovative approaches in natural product research.PMID:39445804 | DOI:10.1128/aem.01603-24

Diabetes Res Clin Pract. 2023 Nov;205:110986. doi: 10.1016/j.diabres.2023.110986. Epub 2023 Oct 28.ABSTRACTAIMS: To explore the clinical factors and urinary metabolites that predict biopsy-confirmed diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM).METHODS: Data from the medical records of 126 patients with T2DM who underwent kidney biopsy between January 2010 and October 2020 at a single-center were retrospectively reviewed to investigate the clinical factors that predict DN. Urine samples were collected to perform urine metabolomics in patients with T2DM divided by biopsy-confirmed DN, immunoglobulin A, and membranous nephropathy, and a control group of healthy participants. Each group comprised 11 age- and sex-matched participants. A prediction model was developed using a combination of clinical factors and urinary metabolites, and a multivariate receiver operating characteristic (ROC) analysis was conducted.RESULTS: Age, presence of proliferative diabetic retinopathy, T2DM duration, and hemoglobin A1c levels were clinical factors predictive of DN. Four urinary metabolites (alanine, choline, N-phenylacetylglycine, and trigonelline) had variable importance in projection scores > 1 and were predictive of DN. When conducting multivariate ROC analysis with a combination of clinical factors and urinary metabolites, the area under the curve was 1.000.CONCLUSIONS: The combination of clinical factors and urinary metabolites is highly valuable for predicting biopsy-confirmed DN in patients with T2DM.PMID:39445434 | DOI:10.1016/j.diabres.2023.110986

Front Plant Sci. 2024 Oct 9;15:1466493. doi: 10.3389/fpls.2024.1466493. eCollection 2024.ABSTRACTINTRODUCTION: Alfalfa (Medicago sativa L.) is a globally important legume crop with high nutritional and ecological value. Drought poses a serious threat to alfalfa acreage and yields. Spermine (Spm) has been shown to protect plants from drought damage. The aim of this study was to clarify the mechanism of exogenous Spm to improve drought resistance of alfalfa.METHODS: In this study, we root applied 0.1, 0.5, and 1 mM Spm to Gannong No. 3 (G3) alfalfa under drought stress, and then determined their physiological and metabolic changes.RESULTS: The results showed that exogenous Spm increased chlorophyll content, chlorophyll fluorescence parameters and gas exchange parameters, enhanced antioxidant enzymes activity, improved ascorbic acid-glutathione (AsA-GSH) cycle, increased osmoregulatory substances content, reduced hydrogen peroxide and superoxide anion levels, and inhibited malondialdehyde accumulation in alfalfa under drought stress, thereby increasing plant height and leaf relative water content and enhancing drought tolerance of alfalfa. The redundancy analysis of the above physiological indicators showed that the addition of the optimal Spm to improve drought tolerance of alfalfa under drought stress was mainly achieved by increasing catalase activity and improving the ASA-GSH cycle. In addition, metabolomics analysis revealed that exogenous Spm increased the content of oxobutanedioic acid, citric acid, fumaric acid and malic acid to enhance the tricarboxylic acid cycle. Meanwhile, exogenous Spm increased endogenous Spm and proline (Pro) content to resist drought stress by enhancing Spm and Pro metabolism. Moreover, exogenous Spm increased the accumulation of the signaling substance abscisic acid.DISCUSSION: In conclusion, exogenous Spm enhanced drought resistance of alfalfa leaves under drought stress.PMID:39445141 | PMC:PMC11496139 | DOI:10.3389/fpls.2024.1466493