PubMed

Chin Med. 2025 Jan 4;20(1):6. doi: 10.1186/s13020-024-01052-3.ABSTRACTBACKGROUND: Jianwei Xiaoshi oral liquid (JWXS), a classical traditional prescription comprising various edible medicinal plants, has demonstrated significant efficacy in treating paediatric indigestion. It originates from Jianpi Pill, which is developed in the Ming Dynasty and nourishes the spleen and regulates gastrointestinal function. However, the specific molecular mechanisms involved remain unclear.METHODS: To elucidate the material base of JWXS and its underlying mechanism in treating dyspepsia, the UHPLC-Q-Orbitrap HRMS method and network pharmacology were utilized. This was followed by pharmacological experiments, transcriptomics analyses and gut microbiota studies to further investigate the effects of JWXS on dyspepsia.RESULTS: A total of 105 compounds, mainly flavonoids, alkaloids, organic acids and cyclic peptides, were identified. According to the five principles of generic drug properties, 43 candidate compounds were screened out. Their efficacy was verified through gastric emptying and intestinal propulsion experiments. Transcriptomic analysis revealed that JWXS primarily alleviated dyspepsia symptoms by regulating the secretion of 8 key proteins in the pancreatic secretion pathway. The differences in the gut microbiota, as identified through 16S rRNA and ITS2 sequencing, were subsequently more pronounced than those observed in the bacterial microbiota of the model group. In total, 15 differential bacteria and 16 differential fungi were identified. Targeted metabolomics analysis of SCFAs revealed a significant decrease in valeric acid (VA), acetic acid (AA), and isovaleric acid (IVA) levels in the model group, which were restored to the corresponding levels after the administration of JWXS. Correlation analysis revealed that VA, AA, and IVA were positively correlated with Lactobacillus and Bacteroides, and negatively correlated with Aspergillus and Candida. This further suggested that JWXS might alleviate symptoms of indigestion by regulating the composition of the microbiota, increasing the variety and quantity of beneficial bacteria, reducing fungal contamination, and further increasing the levels of SCFAs in the body.CONCLUSION: JWXS improved functional dyspepsia in immature rats via a mechanism involving the regulation of the secretion of 8 key proteins in the pancreatic secretion pathway and the amelioration of flora disorders.PMID:39755683 | DOI:10.1186/s13020-024-01052-3

J Nanobiotechnology. 2025 Jan 5;23(1):7. doi: 10.1186/s12951-024-03073-4.ABSTRACTSelenium promotes plant growth and improves nutritional quality, and the role of nano-selenium in alfalfa in regulating nutritional quality is unknown. In this study, using the 15N labeling method, it was found that nano-selenium could promote plant nitrogen metabolism and photosynthesis by increasing the light energy capture capacity and the activities of key enzymes of the nitrogen metabolism process, leading to an increase in alfalfa nitrogen accumulation and dry matter content. The transcriptome and metabolome revealed that nano-selenium mainly affected the pathways of 'biosynthesis of amino acids', 'starch and sucrose metabolism', 'pentose and glucuronate interconversions', 'pentose phosphate pathway', and 'flavonoid biosynthesis'. At the early stage of nano-selenium treatment, the nitrogen metabolism, sugar metabolism, and flavonoid metabolism pathways were regulated by modulating the expression of genes such as NR, Nir, GS, GOGAT, E3.1.1.11, adh, CHS, FLS, etc., which increased the amount of L-glutamic, L-histidine, glycerone-P, coniferin, naringenin chalcone, and other beneficial substances, thus promoting the acceleration of nitrogen accumulation by plants. In summary, this study provides a better understanding of the mechanisms by which nano-selenium regulates key nitrogen metabolic pathways in alfalfa.PMID:39755664 | DOI:10.1186/s12951-024-03073-4

Reprod Biol Endocrinol. 2025 Jan 4;23(1):1. doi: 10.1186/s12958-024-01330-7.ABSTRACTBACKGROUND: A didelphic uterus represents a unique and infrequent congenital condition in which a woman possesses two distinct uteri, each with its own cervix. This anomaly arises due to partial or incomplete merging of the Müllerian ducts during the developmental stages in the womb. Accounting for uterine malformations, a didelphic uterus is a relatively rare condition, affecting approximately 0.5-2% of the population and is considered one of the more uncommon types of uterine abnormalities.METHODS: This case report aims to study the physical separation in uterine didelphys and its impact on endometrial microbiome and inflammation, and the patterns of endometrial receptivity observed.RESULTS: Endometrial receptivity analyses revealed a similar receptive state in both uteri, both in the early receptive phase. Differential markers of chronic endometritis, including CD138, and MUM1-positive cells, were observed when comparing endometrial biopsies from both uteri. The right uterus exhibited a higher prevalence of these positive cells. Regarding the microbiome, significant differences were found between the uteri, notably in the right uterus, a clear non-dominance of lactobacilli and the presence of genera such as Staphylococcus, Streptococcus, and Acinetobacter. Additionally, the right uterus presented a less 'favourable' microenvironment, a characteristic that was also reflected in the right cervix; both sites presenting less lactobacilli than the left side samples. A distinct metabolomic signature associated with the physical separation of the uteri contributed to the differences in endometrial milieu.CONCLUSIONS: Our study revealed that physical separation, among other factors in uterus didelphys, affects the endometrial microbiome, metabolome, and inflammatory state, with significant microbiome variation observed between the uteri, although similar endometrial receptivity patterns were noted.PMID:39755646 | DOI:10.1186/s12958-024-01330-7

J Hematol Oncol. 2025 Jan 4;18(1):2. doi: 10.1186/s13045-024-01655-1.ABSTRACTBACKGROUND: Targeting glucose uptake by glucose transporter (GLUT) inhibitors is a therapeutic opportunity, but efforts on GLUT inhibitors have not been successful in the clinic and the underlying mechanism remains unclear. We aim to identify the key metabolic changes responsible for cancer cell survival from glucose limitation and elucidate its mechanism.METHODS: The level of phosphorylated YAP was analyzed with Western blotting and Phos-tag immunoblotting. Glucose limitation-induced metabolic changes were analyzed using targeted metabolomics (600MRM). The anti-cancer role of metabolite was examined using colony formation assay and APCmin/+ mice. Co-immunoprecipitation, LS-MS, qRT-PCR, and immunofluorescence were performed to explore the underlying mechanisms.RESULTS: We found that D-Ribose-5-phosphate (D5P), a product of the pentose phosphate pathway connecting glucose metabolism and nucleotide metabolism, functions as a metabolic checkpoint to activate YAP under glucose limitation to promote cancer cell survival. Mechanistically, in glucose-deprived cancer cells, D5P is decreased, which facilitates the interaction between MYH9 and LATS1, resulting in MYH9-mediated LATS1 aggregation, degradation, and further YAP activation. Interestingly, activated YAP further promotes purine nucleoside phosphorylase (PNP)-mediated breakdown of purine nucleoside to restore D5P in a feedback manner. Importantly, D5P synergistically enhances the tumor-suppressive effect of GLUT inhibitors and inhibits cancer progression in mice.CONCLUSIONS: Our study identifies D5P as a metabolic checkpoint linking glucose limitation stress and YAP activation, indicating that D5P may be a potential anti-cancer metabolite by enhancing glucose limitation sensitivity.PMID:39755622 | DOI:10.1186/s13045-024-01655-1

BMC Oral Health. 2025 Jan 4;25(1):25. doi: 10.1186/s12903-024-05355-7.ABSTRACTBACKGROUND: Streptococcus mutans (S. mutans) contributes to caries. The biofilm formed by S. mutans exhibits greater resistance to drugs and host immune defenses than the planktonic form of the bacteria. The objective of this study was to evaluate the anti-biofilm effect of cordycepin from the perspective of metabolomics.METHODS: The minimum inhibitory concentration (MIC) was determined to evaluate the antimicrobial effect of cordycepin on planktonic S. mutans. The 24-h biofilm was treated with 128 µg/mL of cordycepin for 10 min at the 8- or 20-h time points. Biofilm biomass and metabolism were assessed using crystal violet and MTT assays and cordycepin cytotoxicity was evaluated in human oral keratinocytes (HOK) using CCK-8 assays. The live bacterial rate and the biofilm volume were assessed by confocal laser scanning microscopy. Metabolic changes in the biofilm collected at different times during with cordycepin were analyzed by metabolomics and verified by quantitative real-time PCR.RESULTS: The results showed that treatment with 128 µg/mL cordycepin reduced both the biomass and metabolic activity of the biofilm without killing the bacteria, and cordycepin at this concentration showed good biocompatibility. Metabolomics analysis showed that differentially abundant metabolites following cordycepin treatment were mainly related to purine and nucleotide metabolism. After immediate treatment with cordycepin, genes related to purine and nucleotide metabolism were downregulated, and the levels of various metabolites changed significantly. However, the effect was reversible. After continuing culture for 4 h, the changes in genes and most metabolites were reversed, although the levels of 2'-deoxyadenosine, 2'-deoxyinosine, and adenine remained significantly different.CONCLUSIONS: Cordycepin has the effect of anti-biofilm of S. mutans, mainly related to purine and nucleotide metabolism.PMID:39755609 | DOI:10.1186/s12903-024-05355-7

J Immunother Cancer. 2025 Jan 4;13(1):e009415. doi: 10.1136/jitc-2024-009415.ABSTRACTBACKGROUND: Immune checkpoint inhibitors (ICIs) in combination with antiangiogenic drugs have shown promising outcomes in the third-line and subsequent treatments of patients with microsatellite stable metastatic colorectal cancer (MSS-mCRC). Radiotherapy (RT) may enhance the antitumor effect of immunotherapy. However, the effect of RT exposure on patients receiving ICIs and targeted therapy remains unclear. This study aimed to investigate the association between RT exposure and clinical responses to fruquintinib (a highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor) plus sintilimab (an anti-programmed death 1 antibody; F&S) in previously treated patients with MSS-mCRC and to explore predictive biomarkers.METHODS: In this prospective observational study, patients with mCRC receiving F&S as third-line or subsequent treatment were enrolled. Eligible patients were divided into the RT cohort (RTC) and the non-RT cohort (NRTC) according to their RT history. The primary endpoint was the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Pretreatment fecal and serum samples were collected for microbiome analysis, metabolome analysis, and immune signatures to identify biomarkers for treatment.RESULTS: A total of 55 patients were included, of which 25 were in the RTC and 30 in the NRTC. Better ORR (28.0% vs 6.7%, p=0.048), DCR (80.0% vs 36.7%, p=0.002), median PFS (6.2 vs 2.7 months, p<0.001), and median OS (14.8 vs 5.9 months, p=0.019) were noted in patients with RTC than those with NRTC. The enrichment of Lactobacillus, Bifidobacterium, and PC(20:5(5Z,8Z,11Z,14Z,17Z)/20:3(8Z,11Z,14Z)) in RTC significantly predicted better DCR and PFS, whereas guanosine and interleukin-10 predominated in patients with NRTC were negatively correlated with PFS and OS.CONCLUSIONS: Patients with RT exposure benefited significantly from F&S in the third-line or subsequent treatment for MSS-mCRC. Gut microbiota, metabolites, and cytokines may help predict F&S outcomes for mCRC, which may be helpful in treatment decision-making.TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT05635149.PMID:39755582 | DOI:10.1136/jitc-2024-009415

Environ Pollut. 2025 Jan 2:125634. doi: 10.1016/j.envpol.2025.125634. Online ahead of print.ABSTRACTThe extensive presence of per-/polyfluoroalkyl substances (PFASs) in the environment and their adverse effects on organisms have garnered increasing concern. With the shift of industrial development from legacy to emerging PFASs, expanding the understanding of molecular responses to legacy and emerging PFASs is essential to accurately assess their risks to organisms. Compared with traditional toxicological approaches, omics technologies including transcriptomics, proteomics, metabolomics/lipidomics, and microbiomics allow comprehensive analysis of the molecular changes that occur in organisms after PFAS exposure. This paper comprehensively reviews the insights of omics approaches, especially the multi-omics approach, on the toxic mechanisms of both legacy and emerging PFASs in recent five years, focusing on hepatotoxicity, developmental toxicity, immunotoxicity, reproductive toxicity, neurotoxicity, and the endocrine-disrupting effect. PFASs exert various toxic effects via lipid and amino acid metabolism disruption, perturbations in several cell signal pathways, and binding to nuclear receptors. Notably, integrating multi-omics offers a thorough insight into the mechanisms of toxicity associated with PFASs. The gut microbiota plays an essential regulatory role in the toxic mechanisms of PFAS-induced hepatotoxicity. Finally, further research directions for PFAS toxicology based on omics technologies are prospected.PMID:39755359 | DOI:10.1016/j.envpol.2025.125634

Environ Pollut. 2025 Jan 2:125629. doi: 10.1016/j.envpol.2025.125629. Online ahead of print.ABSTRACTDifferentiated thyroid cancer (DTC) generally has a favorable prognosis, and radioactive iodine (RAI) therapy is typically used for metastatic DTC that continues to progress and poses life-threatening risks. However, resistance to RAI in metastatic DTC significantly impairs treatment effectiveness. This study aims to identify potential compounds that may influence RAI efficacy. We conducted untargeted metabolomics on pre-treatment serum samples from 42 RAI-refractory DTC (RAIR-DTC) patients and 52 RAI-sensitive patients. The results revealed significantly elevated levels of two per- and polyfluoroalkyl substances (PFAS), PFDA and PFNA, in RAI-resistant patients. This accumulation was significantly negatively correlated with the expression of the sodium-iodide symporter (NIS), which reflects the differentiation status and iodide uptake capability of thyroid cancer. Furthermore, high levels of PFDA and PFNA exposure were significantly associated with poor prognosis in patients undergoing RAI therapy. In vivo exposure simulations in a murine model showed that PFAS exposure significantly increased the malignant progression of thyroid cancer, reduced iodine uptake ability, and promoted dedifferentiation. Overall, these findings provide novel insights into the development of RAIR-DTC, highlighting the importance of continuous monitoring and control of PFAS exposure in cancer patients.PMID:39755358 | DOI:10.1016/j.envpol.2025.125629

Environ Pollut. 2025 Jan 2:125631. doi: 10.1016/j.envpol.2025.125631. Online ahead of print.ABSTRACTAllergic asthma is a significant international concern in respiratory health, which can be exacerbated by the increasing levels of non-allergenic pollutants. This rise in airborne pollutants is a primary driver behind the growing prevalence of asthma, posing a health emergency. Additionally, climatic risk factors can contribute to the onset and progression of asthma. Understanding the complex interplay between pollution, climate, and asthma induction is crucial to elucidate how environmental changes intensify asthma. In this study, we investigated the proteomic and metabolomic changes in the lungs of a mouse asthma model following co-exposure to carbon black nanoparticles and high humidity, which represent airborne and climatic factors, respectively. An asthma model was established using ovalbumin, and mice were intratracheally instilled with 15 or 30 μg/kg of carbon black and simultaneously exposed to either 70% or 90% relative humidity. Protein and metabolite profiles from the lung were used to analyze the most significantly changed clusters, and potential biomarkers and enriched pathways were identified to dissect the adverse effects of the two risk factors. The lung proteome and metabolome are significantly altered by the co-exposure, with the effects modulated by carbon black concentration and humidity level. This study proposes 10 proteins and 18 metabolites as candidate biomarkers. The significantly enriched KEGG pathways include one protein pathway (primary immunodeficiency) and six metabolic pathways (ABC transporters, nucleotide metabolism, Parkinson's disease, purine metabolism, choline metabolism in cancer, and biosynthesis of cofactors). A joint proteomic and metabolomic analysis identifies five common pathways across both omics, namely, ABC transporters, central carbon metabolism in cancer, EGFR tyrosine kinase inhibitor resistance, glioma, and NF-kappa B signaling pathway, disturbed by the co-exposure. We provide a multi-omic basis for the health risk assessment and management of co-exposures to environmental risk factors.PMID:39755354 | DOI:10.1016/j.envpol.2025.125631

J Hepatol. 2025 Jan 2:S0168-8278(24)02830-7. doi: 10.1016/j.jhep.2024.12.039. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Hepatocyte transplantation has shown promise for genetic diseases of the hepatocytes but to date has shown limited efficacy for non-genetic forms of severe liver injury. Limited cell engraftment and poor function of donor hepatocytes in recipient livers impacts the clinical utility of hepatocyte cell therapy. The mechanisms underpinning this are poorly understood. We explored this in a liver injury model, where predictable levels of injury and hepatocyte senescence was induced in AhCreMdm2fl/fl mice through genetic excision of hepatocyte Mdm2.METHODS: Freshly isolated mouse, or human cryopreserved hepatocytes were delivered via intrasplenic injection into AhCreMdm2fl/fl (immune competent and deficient strains) mice. Engraftment kinetics, donor cell engraftment and host liver function were assessed. Paired transcriptomic and proteomic analyses were performed on healthy vs senescent mouse hepatocytes.RESULTS: We found inhibition of host hepatocyte proliferation and liver injury is a requirement for donor hepatocyte engraftment and long-term repopulation, improving liver repair and function, but excessive senescence inhibited this process causing graft function decline due to transmission of senescence from host to donor cells. Paired proteomic and transcriptomic analysis of healthy vs senescent hepatocytes reveal a unique senescent signature associated with paracrine senescence. Modification of the host niche prior to transplantation with the senotherapeutic drug ABT737 improved donor cell proliferative capacity.CONCLUSIONS: The host niche impacts the initial engraftment and long-term function of transplanted hepatocytes. Targeting paracrine senescence may be a way to improve donor hepatocyte function, optimise therapy and guide translation into the clinics.IMPACT AND IMPLICATIONS: Hepatocyte transplantation has shown promise for genetic diseases but has limited efficacy for acute and severe liver injury. Poor engraftment and functionality inhibit wide-spread clinical application. We show that host senescence provides a required non-competitive niche for donor hepatocytes to repopulate the recipient liver, but can paradoxically, negatively impact donor function. These findings demonstrate a requirement for a clear understanding of the host niche prior to cell transfusion. This has significant implications not only for hepatocellular therapies, but also when developing and optimising any pre-clinical and clinical cell therapies.PMID:39755157 | DOI:10.1016/j.jhep.2024.12.039

Food Chem. 2024 Dec 26;470:142666. doi: 10.1016/j.foodchem.2024.142666. Online ahead of print.ABSTRACTSargassum polycystum (S. polycystum) is a brown macroalga with a high phytochemical content, making it a nutritious and bioactive food source. However, information on factors contributing to health benefits, like antioxidants and cytotoxicity, is less explored for Malaysian S. polycystum. In this study, three extracts of S. polycystum were characterized using a combination of analytical techniques. Despite similar carbohydrate content across all extracts, water extract exhibited the highest protein [21.90 ± 1.01 albumin equivalent (μg/mg)] and phenolic [7.73 ± 1.95 gallic acid equivalent (μg/mg)] contents. However, it displayed the lowest antioxidant and anticancer activities [half-maximal inhibitory concentration (IC50) of > 2000 μg/mL]. Interestingly, ethanolic extract demonstrated the strongest scavenging activity (IC50 of 397.90 ± 20.43 μg/mL) and selective anticancer activity against MCF7 breast cancer cells (IC50 of 338.63 ± 48.98 μg/mL). Untargeted metabolomic profiling confirmed the differences in the chemical composition of the extracts. Subsequently, correlation and docking analyses were used to identify the potential bioactive compounds within the extracts. The ethanolic extract is a rich source of these bioactive compounds with superior antioxidant and anticancer properties, highlighting the need for further research on its potential utility in the food industry.PMID:39755036 | DOI:10.1016/j.foodchem.2024.142666

Biomater Adv. 2024 Dec 7;169:214144. doi: 10.1016/j.bioadv.2024.214144. Online ahead of print.ABSTRACTThis study defines biochemical mechanisms that contribute to novel neural-regenerative activities we recently demonstrated for thiol-modified ManNAc analogs in human neural stem cells (hNSCs) by comparing our lead drug candidate for brain repair, "TProp," to a "size-matched" N-alkyl control analog, "But." These analogs biosynthetically install non-natural sialic acids into cell surface glycans, altering cell surface receptor activity and adhesive properties of cells. In this study, TProp modulated sialic acid-related biology in hNSCs to promote neuronal differentiation through modulation of cell adhesion molecules (integrins α6, β1, E-cadherin, and PSGL-1) and stem cell markers. By comparison, But elicited minimal change to these endpoints, indicating dependence on the chemical properties of the thiol group of non-natural sialic acids and not the size of this sugar's N-acyl group. Conversely, But elicited distinct intracellular responses including increased nestin expression (~6-fold) and the modulation of several metabolites identified through cell-wide screening. Metabolites up-regulated by But included dopamine and norfenenfrine, suggesting that this analog may be a drug candidate for treating neural damage associated with conditions such as Parkinson's disease. The metabolomics data also provided new insights into the neuroprotective effects of TProp when used to treat brain injury by upregulation of anti-inflammatory metabolites (e.g., α- & γ-linolenic acids) valuable for dampening injury- and treatment-related inflammation. Finally, these analogs modulate compounds that control proline (e.g., 1-pyrroline-2-carboxylate), a master regulator of many cellular activities. Overall, this study presents new mechanisms and pathways to exploit metabolic glycoengineering for neural repair and treatment of neurodegenerative diseases.PMID:39754871 | DOI:10.1016/j.bioadv.2024.214144

Neurochem Res. 2025 Jan 4;50(1):74. doi: 10.1007/s11064-024-04317-3.ABSTRACTEpilepsy (EP) is a neurological disorder characterized by abnormal, sudden neuronal discharges. Seizures increase extracellular glutamate levels, causing excitotoxic damage. Glutamate transporter type 1 (GLT-1) and its human homologue excitatory amino acid transporter-2 (EAAT2) clear 95% of extracellular glutamate. Studies on neurodegenerative diseases suggest that trichostatin A (TSA), a broad-spectrum histone deacetylase (HDAC) inhibitor, can increase GLT-1/EAAT2 transcription. However, the precise mechanism by which TSA modulates GLT-1/EAAT2 levels remains unclear. This research demonstrated that TSA increases GLT-1/EAAT2 expression through histone acetylation, exerting substantial antiepileptic effects. Our results identify a promising therapeutic strategy for EP involving the modulation of glutamate transporters to mitigate seizures. Future research should explore the specific mechanisms underlying the effects of TSA and its potential clinical applications. Acute and chronic EP models were induced using kainic acid (KA) to assess the effects of TSA on the seizure threshold and frequency. Electrophysiological recordings of the hippocampus were used to evaluate the impact of TSA on neuronal excitability. RNA-Seq was used to analyse changes in glutamate transporter-related gene expression. Western blot analysis and qRT‒PCR were used to assess the influence of TSA on HDAC expression. To validate the role of GLT-1/EAAT2 in the antiepileptic effects of TSA, the impact of the GLT-1/EAAT2 inhibitor dihydrokainic acid (DHK) on the effects of TSA was assessed. Glutamate release was measured, and microdialysis was used to determine the glutamate content in the cerebrospinal fluid. Finally, metabolomics analysis was used to explore changes in amino acid levels in the hippocampus following TSA treatment to further confirm the antiepileptic potential of TSA. TSA effectively inhibited seizures in both acute and chronic models. It reduced the amplitude of excitatory postsynaptic currents (PSCs) and the frequency of spontaneous excitatory PSCs in the hippocampus without affecting inhibitory PSCs. Transcriptome analysis was used to identify glutamate transmission-related targets and revealed significant upregulation of the GLT-1 and EAAT2 genes in the hippocampus, which was confirmed by qRT‒PCR and Western blotting. Acetylation-induced upregulation of GLT-1/EAAT2 was observed, and inhibition of these transporters by DHK reduced the seizure-mitigating effects of TSA, underscoring the role of GLT-1/EAAT2 in clearing glutamate and its contribution to the observed antiepileptic effects of TSA. Our findings highlight the crucial role of GLT-1/EAAT2 in mediating the impact of TSA on glutamatergic transmission and seizure activity. These insights pave the way for the development of novel therapeutic approaches for EP involving the modulation of glutamate transporters.PMID:39754645 | DOI:10.1007/s11064-024-04317-3

J Dent Res. 2025 Jan 3:220345241298219. doi: 10.1177/00220345241298219. Online ahead of print.ABSTRACTMissing teeth have been linked to incident cardiovascular disease, diabetes, and all-cause mortality. Our previous study revealed that signs of oral infections and inflammatory conditions (i.e., periodontal disease and dental caries) are associated with disadvantageous features of circulating metabolites. This study investigates whether missing teeth and tooth loss, the end points of these diseases, are associated with similar metabolic features. The 2 Finnish population-based studies Health-2000 (n = 6,197) and FINRISK-97 (n = 6,050) were included, as was Parogene (n = 465), a cohort of patients with an indication for coronary angiography. The number of teeth was recorded in clinical examinations. Serum concentrations of 157 metabolites were determined by a nuclear magnetic resonance spectroscopy-based method. Health-2000 participants (n = 3,371) provided follow-up serum samples, and 1,186 of them participated in a repeated oral examination 11 y after the baseline. Linear regression models adjusted for age, sex, smoking, body mass index, and diabetes were fitted to the number of teeth and metabolite measures. The results from the separate cohorts were combined in a fixed-effects meta-analysis. We also analyzed whether the number of teeth at baseline and tooth loss during follow-up were associated with changes in metabolite concentrations. Missing teeth were associated with increased very-low-density lipoprotein-related measures and triglyceride concentrations, as well as with decreased high-density lipoprotein parameters and small particle size. Missing teeth also had an association with low levels of unsaturated fatty acids (FAs), including omega-3 and omega-6 FAs, and elevated proportions of monounsaturated and saturated FAs. The number of teeth at baseline predicted changes in several concentrations, such as measures related to intermediate-density lipoprotein, low-density lipoprotein, and FAs, but no associations with tooth loss during the 11-y follow-up were observed. To conclude, missing teeth are associated with adverse metabolic features characterized by systemic inflammation and several risk factors for cardiometabolic diseases.PMID:39754308 | DOI:10.1177/00220345241298219

J Exp Clin Cancer Res. 2025 Jan 3;44(1):3. doi: 10.1186/s13046-024-03254-x.ABSTRACTBACKGROUND: Glioblastoma multiforme (GBM) exhibits a cellular hierarchy with a subpopulation of stem-like cells known as glioblastoma stem cells (GSCs) that drive tumor growth and contribute to treatment resistance. NAD(H) emerges as a crucial factor influencing GSC maintenance through its involvement in diverse biological processes, including mitochondrial fitness and DNA damage repair. However, how GSCs leverage metabolic adaptation to obtain survival advantage remains elusive.METHODS: A multi-step process of machine learning algorithms was implemented to construct the glioma stemness-related score (GScore). Further in silico and patient tissue analyses validated the predictive ability of the GScore and identified a potential target, CYP3A5. Loss-of-function or gain-of-function genetic experiments were performed to assess the impact of CYP3A5 on the self-renewal and chemoresistance of GSCs both in vitro and in vivo. Mechanistic studies were conducted using nontargeted metabolomics, RNA-seq, seahorse, transmission electron microscopy, immunofluorescence, flow cytometry, ChIP‒qPCR, RT‒qPCR, western blotting, etc. The efficacy of pharmacological inhibitors of CYP3A5 was assessed in vivo.RESULTS: Based on the proposed GScore, we identify a GSC target CYP3A5, which is highly expressed in GSCs and temozolomide (TMZ)-resistant GBM patients. This elevated expression of CYP3A5 is attributed to transcription factor STAT3 activated by EGFR signaling or TMZ treatment. Depletion of CYP3A5 impairs self-renewal and TMZ resistance of GSCs. Mechanistically, CYP3A5 maintains mitochondrial fitness to promote GSC metabolic adaption through the NAD⁺/NADH-SIRT1-PGC1α axis. Additionally, CYP3A5 enhances the activity of NAD-dependent enzyme PARP to augment DNA damage repair. Treatment with CYP3A5 inhibitor alone or together with TMZ effectively suppresses tumor growth in vivo.CONCLUSION: Together, this study suggests that GSCs activate STAT3 to upregulate CYP3A5 to fine-tune NAD⁺/NADH for the enhancement of mitochondrial functions and DNA damage repair, thereby fueling tumor stemness and conferring TMZ resistance, respectively. Thus, CYP3A5 represents a promising target for GBM treatment.PMID:39754188 | DOI:10.1186/s13046-024-03254-x

EMBO J. 2025 Jan 3. doi: 10.1038/s44318-024-00335-7. Online ahead of print.ABSTRACTMitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection against diet-induced obesity. In this study, we used temporal metabolomics on HeLa cells to show that MTCH2 deletion results in a high ATP demand, an oxidized cellular environment, and elevated utilization of lipids, amino acids, and carbohydrates, accompanied by a decrease in several metabolites. Lipidomics analysis revealed a strategic adaptive reduction in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, MTCH2 knockout cells showed an increase in mitochondrial oxidative function, which may explain the higher energy demand. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion prevents NIH3T3L1 preadipocytes from differentiating into mature adipocytes, an energy consuming reductive biosynthetic process. In summary, the loss of MTCH2 leads to increased mitochondrial oxidative activity and energy demand, creating a catabolic and oxidative environment that fails to fuel the anabolic processes required for lipid accumulation and adipocyte differentiation.PMID:39753955 | DOI:10.1038/s44318-024-00335-7

Sci Rep. 2025 Jan 3;15(1):632. doi: 10.1038/s41598-024-84840-z.ABSTRACTEndophytes are microorganisms residing in plant tissues without causing harm and their relevance in medicinal plants has grown due to their biomolecules used in pharmaceuticals. This study isolated two endophytic bacterial strains from the leaves of M. oleifera and P. betel collected from Junagadh Agricultural University. The isolates were characterized morphologically and physio-biochemically, confirming them as gram-positive or gram-negative rods and cocci. Identification using 16S rRNA gene sequencing identified isolates belonging to various genera, including Priestia aryabhattai and Kocuria rhizophila The SEM characterization of the five selected isolates revealed diverse morphological structures, including coccus and rod shapes, organized in various formations. Isolates varied in size, with N3 (Kocuria rhizophila) cocci and S5 (Priestia aryabhattai) rods. Metabolomic analysis using GC/MS and LC-MS revealed diverse metabolic profiles with key compounds like n-Hexadecanoic acid, Pyrrolo[1,2-a]pyrazine-1,4-dione, Dihydrocapsaicin, and β-Homoproline, highlighting the potential of these endophytic bacteria in agricultural applications due to their roles in membrane integrity, antioxidant properties, stress response, and antibacterial activity.PMID:39753876 | DOI:10.1038/s41598-024-84840-z

J Proteome Res. 2025 Jan 3. doi: 10.1021/acs.jproteome.4c00914. Online ahead of print.ABSTRACTMALDI-HiPLEX-IHC mass spectrometry imaging (MSI) represents a newly established workflow to map tens of antibodies linked to photocleavable mass tags (PC-MTs), which report the distribution of antigens in formalin-fixed paraffin-embedded (FFPE) tissue sections. While this highly multiplexed approach has previously been integrated with untargeted methods, the possibility of mapping target cell antigens and performing bottom-up spatial proteomics on the same tissue section has yet to be explored. This proof-of-concept study presents a novel workflow combining MALDI-HiPLEX-IHC with untargeted spatial proteomics to analyze a single FFPE tissue section, using clinical clear cell renal cell carcinoma (ccRCC) tissue as a model. Workflow implementation highlighted the need for an additional antigen retrieval step following antibody staining to aid antibody detachment and enhance tryptic digestion. Moreover, this approach enabled the stratification of histologically similar tumor cores of the same grade based on varying lymphocyte populations, particularly T regulatory cells. Finally, integration with untargeted spatial proteomics revealed proteomic alterations associated with these lymphocyte infiltration patterns. These findings demonstrate the potential of this workflow to map and characterize the molecular environment of tumor-infiltrating lymphocytes, offering insights into the molecular impact of immune cells within the tumor microenvironment.PMID:39753523 | DOI:10.1021/acs.jproteome.4c00914

Mol Oncol. 2025 Jan 3. doi: 10.1002/1878-0261.13791. Online ahead of print.ABSTRACTColorectal cancer (CRC) is a prevalent malignant tumor worldwide, with a high mortality rate due to its complex etiology and limited early screening techniques. This study aimed to identify potential biomarkers for early detection of CRC utilizing targeted metabolite profiling of platelet-rich plasma (PRP). Based on multiple reaction monitoring (MRM) mode, liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis identified metabolites in PRP collected from patients with CRC (n = 70) and healthy controls (n = 30). A total of 302 metabolites were identified and quantified in this study, including various categories such as lipids, lipid mediators, amino acids, and derivatives, organic acids and derivatives, nucleotides and derivatives, alkaloids, carbohydrates, vitamins and derivatives, and others. The differential analysis revealed that five carbohydrates and organic acids (lactose, glycerol-3-phosphate, 2-hydroxyglutaric acid, isocitric acid, and citric acid) involved in the carbohydrate metabolism pathway displayed consistent upregulation within PRP derived from patients with CRC. To further validate the abundance of differential metabolites, 10 pairs of CRC tissues, adjacent tissues, and matched PRP were collected. Ultimately, five carbohydrate metabolites were validated in PRP, and compared with carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA199), the five carbohydrate metabolites significantly improved the specificity of differentiating patients with CRC from healthy controls. Furthermore, the diagnostic efficacy of the combined five-carbohydrate metabolite panel was superior to that of individual metabolites, CEA and CA199. The sensitivity, specificity, and AUC of the metabolite panel in distinguishing patients with CRC from healthy controls were 90.00%, 96.67%, and 0.961 (95% CI 0.922-0.998), respectively. Collectively, metabolomics was used to identify and validate differential metabolites in the PRP of CRC, which may serve as potential early screening markers for patients with CRC.PMID:39753208 | DOI:10.1002/1878-0261.13791

J Hazard Mater. 2024 Dec 27;486:137024. doi: 10.1016/j.jhazmat.2024.137024. Online ahead of print.ABSTRACTPerfluorooctanoic acid (PFOA), an anthropogenic organic pollutant known for its persistence, resistance to degradation, and toxicity, has raised significant concerns about its potential ecological impacts. Zostera marina, a common submerged seagrass species in temperate offshore areas, is highly vulnerable to pollutant stressors. However, the impact of PFOA on Z. marina remains unclear. In this study, Z. marina was exposed to different concentrations of PFOA (0, 0.5, 1, 5, 10, and 20 μg/L) for 14 days. We subsequently assessed survival rates, growth patterns, physiological indices, transcriptomic profiles, and metabolomic characteristics. The results revealed dose-dependent PFOA accumulation in Z. marina tissues and significant growth inhibition. Furthermore, exposure to PFOA resulted in a significant reduction in photosynthetic pigment content (IBRv2 indices: 2.78-10.29) and elevated enzyme activity (IBRv2 indices: 2.90-8.96). Transcriptomic analysis identified 1511 differentially expressed genes associated with 11 KEGG pathways predominantly affected by PFOA exposure. Weighted gene co-expression network analysis highlighted the crucial role of the hydroxyphenylpyruvate reductase (hppr) gene in antioxidant defense mechanisms and detoxification processes against PFOA-induced stress. Metabolomics identified 412 differentially expressed metabolites, mainly consisting of flavonoids, organic acids, and lipids. In summary, PFOA exposure resulted in the down-regulation of gene expression related to photosynthesis and energy metabolism while also affecting metabolite synthesis. The response of Z. marina to PFOA stress involves modulation of the cytoskeletal dynamics and signal transduction pathways, as well as activation of a suite of genes and metabolites to initiate defense mechanisms.PMID:39752826 | DOI:10.1016/j.jhazmat.2024.137024