PubMed

J Pers Med. 2024 Dec 19;14(12):1157. doi: 10.3390/jpm14121157.ABSTRACTChronic kidney disease (CKD) is a major worldwide health concern because of its progressive nature and complex biology. Traditional diagnostic and therapeutic approaches usually fail to account for disease heterogeneity, resulting in low efficacy. Precision medicine offers a novel approach to studying kidney disease by combining omics technologies such as genomics, transcriptomics, proteomics, metabolomics, and epigenomics. By identifying discrete disease subtypes, molecular biomarkers, and therapeutic targets, these technologies pave the way for personalized treatment approaches. Multi-omics integration has enhanced our understanding of CKD by revealing intricate molecular linkages and pathways that contribute to treatment resistance and disease progression. While pharmacogenomics offers insights into expected responses to personalized treatments, single-cell and spatial transcriptomics can be utilized to investigate biological heterogeneity. Despite significant development, challenges persist, including data integration concerns, high costs, and ethical quandaries. Standardized data protocols, collaborative data-sharing frameworks, and advanced computational tools such as machine learning and causal inference models are required to address these challenges. With the advancement of omics technology, nephrology may benefit from improved diagnostic accuracy, risk assessment, and personalized care. By overcoming these barriers, precision medicine has the potential to develop novel techniques for improving patient outcomes in kidney disease treatment.PMID:39728069 | DOI:10.3390/jpm14121157

J Pers Med. 2024 Dec 5;14(12):1141. doi: 10.3390/jpm14121141.ABSTRACTChronic kidney disease (CKD) is a chronic disorder characterized by kidney fibrosis and extracellular matrix accumulation that can lead to end-stage kidney disease. Epithelial-to-mesenchymal transition, inflammatory cytokines, the TGF-β pathway, Wnt/β-catenin signaling, the Notch pathway, and the NF-κB pathway all play crucial roles in the progression of fibrosis. Current medications, such as renin-angiotensin-aldosterone system inhibitors, try to delay disease development but do not stop or reverse fibrosis. This review emphasizes the growing need for tailored antifibrotic medications for CKD treatment. Precision medicine, which combines proteomic, metabolomic, and genetic data, provides a practical way to personalize treatment regimens. Proteomic signatures, such as CKD273, and genetic markers, such as APOL1 and COL4A5, help in patient stratification and focused therapy development. Two recently developed antifibrotic medications, nintedanib and pirfenidone, have been proven to diminish fibrosis in preclinical animals. Additionally, research is being conducted on the efficacy of investigational drugs targeting CTGF and galectin-3 in the treatment of kidney fibrosis.PMID:39728054 | DOI:10.3390/jpm14121141

J Pers Med. 2024 Nov 27;14(12):1121. doi: 10.3390/jpm14121121.ABSTRACTPharmacogenomics (PGx) has revolutionized personalized medicine by empowering the tailoring of drug treatments based on individual genetic profiles. However, the complexity of drug response mechanisms necessitates the integration of additional biological and environmental factors. This article explores integrating epigenetics, nutrigenomics, microbiomes, protein interactions, exosomes, and metabolomics with PGx to enhance personalized medicine. In addition to discussing these scientific advancements, we examine the regulatory and ethical challenges of translating multi-omics into clinical practice, including considerations of data privacy, regulatory oversight, and equitable access. By framing these factors within the context of Medication Adherence, Medication Appropriateness, and Medication Adverse Events (MA3), we aim to refine therapeutic strategies, improve drug efficacy, and minimize adverse effects, with the goal of improving personalized medicine. This approach has the potential to benefit patients, healthcare providers, payers, and the healthcare system as a whole by enabling more precise and effective treatments.PMID:39728034 | DOI:10.3390/jpm14121121

Curr Issues Mol Biol. 2024 Dec 18;46(12):14270-14290. doi: 10.3390/cimb46120855.ABSTRACTDendrobium devonianum is an important medicinal plant, rich in flavonoid, with various pharmacological activities such as stomachic and antioxidant properties. In this study, we integrated metabolome and transcriptome analyses to reveal metabolite and gene expression profiles of D. devonianum, both green (GDd) and purple-red (RDd) of semi-annual and annual stems. A total of 244 flavonoid metabolites, mainly flavones and flavonols, were identified and annotated. Cyanidin and delphinidin were the major anthocyanidins, with cyanidin-3-O-(6″-O-p-Coumaroyl) glucoside and delphinidin-3-O-(6″-O-p-coumaroyl) glucoside being the highest relative content in the RDd. Differential metabolites were significantly enriched, mainly in flavonoid biosynthesis, anthocyanin biosynthesis, and flavone and flavonol biosynthesis pathways. Transcriptomic analysis revealed that high expression levels of structural genes for flavonoid and anthocyanin biosynthesis were the main reasons for color changes in D. devonianum stems. Based on correlation analysis and weighted gene co-expression network analysis (WGCNA) analysis, CHS2 (chalcone synthase) and UGT77B2 (anthocyanidin 3-O-glucosyltransferase) were identified as important candidate genes involved in stem pigmentation. In addition, key transcription factors (TFs), including three bHLH (bHLH3, bHLH4, bHLH5) and two MYB (MYB1, MYB2), which may be involved in the regulation of flavonoid biosynthesis, were identified. This study provides new perspectives on D. devonianum efficacy components and the Dendrobium flavonoids and stem color regulation.PMID:39727983 | DOI:10.3390/cimb46120855

Curr Issues Mol Biol. 2024 Nov 21;46(12):13296-13310. doi: 10.3390/cimb46120793.ABSTRACTHepatocellular carcinoma (HCC) is the most common form of liver cancer in humans, with an increasing incidence worldwide. The current study aimed to explore the molecular mechanisms that inhibit the proliferation of HepG2 cells, a hepatoblastoma-derived cell line. MSC-derived exosomes (UC-MSCs) were prepared with a median particle size (N50) of 135.8 nm. Concentrations of UC-MSCs ranging from 10 μg/mL to 1000 μg/mL were applied to HepG2 cell cultures and compared to untreated and anticancer drug-treated HepG2 cells. A combined approach was employed, integrating a proteomic analysis of UC-MSCs, metabolomic analysis of HepG2 cells, and transcriptomic profiling of HepG2 cells to decipher the inhibitory mechanisms of UC-MSC exosomes on HepG2 cell growth. Treatment with a high concentration of UC-MSCs led to a notable reduction in HepG2 cell viability, with survival decreasing by 65%. A proteomic analysis of UC-MSCs revealed enriched degranulation processes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in addition to the known exosomal pathways. Transcriptomic profiling showed distinct changes in the expression of genes related to hepatocellular diseases in UC-MSC-treated HepG2 cells, contrasting with changes observed in HepG2 cells treated with the chemotherapeutic agent doxorubicin (DOX). Combined with a metabolomic analysis, the detailed GO and KEGG pathway analyses indicated that pathways associated with neutrophil extracellular trap formation played a critical role in mediating protein degradation and suppressing central carbon metabolism in cancer cells. Our results revealed that the UC-MSC treatment mimicked molecular mechanisms similar to those involved in neutrophil extracellular trap formation, exhibiting effects on HepG2 cell growth suppression that differed from those of chemical cancer drugs. Notably, the UC-MSC treatment demonstrated that protein degradation in HepG2 cells was regulated through canonical signaling pathways activated by bacterial peptides in neutrophils. This research has provided valuable insights into the potential of MSC-derived exosomes as a therapeutic approach for cancer treatment in the future.PMID:39727921 | DOI:10.3390/cimb46120793

J Inherit Metab Dis. 2025 Jan;48(1):e12840. doi: 10.1002/jimd.12840.ABSTRACTShort-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare genetic disorder caused by biallelic pathogenic variants in the ECHS1 gene. ECHS1D is characterised by severe neurological and physical impairment that often leads to childhood mortality. Therapies such as protein and single nutrient-restricted diets show poor efficacy, whereas the development of new treatments is hindered by the low prevalence of the disorder and a lack of model systems for treatment testing. Here, we report on the establishment of a Drosophila model of ECHS1D. Flies carrying mutations in Echs1 (CG6543) were characterised for their physical and metabolic phenotypes, and dietary intervention to improve fly model health was explored. The Echs1 null larvae recapitulated human ECHS1D phenotypes including poor motor behaviour and early mortality and could be rescued by the expression of a human ECHS1 transgene. We observed that both restriction of valine in isolation, or all branched-chain amino acids (BCAAs-leucine, isoleucine and valine) together, extended larval survival, supporting the idea that reducing BCAA pathway catabolic flux is beneficial in this disorder. Further, metabolic profiling revealed substantial changes to carbohydrate metabolism, suggesting that Echs1 loss causes widespread metabolic dysregulation beyond valine metabolism. The similarities between Drosophila and human ECHS1D suggest that the fly model is a valuable animal system in which to explore mechanisms of pathogenesis and novel treatment options for this disorder.PMID:39727068 | DOI:10.1002/jimd.12840

J Anim Physiol Anim Nutr (Berl). 2024 Dec 27. doi: 10.1111/jpn.14087. Online ahead of print.ABSTRACTFood leftovers can be used as alternative feed ingredients for monogastric to replace human-competing feedstuffs, such as cereals, recycle a waste product, reduce the feed-food competition and keep nutrients and energy in the feed-food chain. Among food leftovers, former food products (FFPs) are no more intended for human but still suitable for animal consumption. However, the metabolic impact of FFP has never been investigated. In this study, we evaluated the impact of replacing 30% of conventional cereals with FFP on abdominal fat quality and plasma metabolome modulation in postweaning piglets. Thirty-six Large White × Landrace postweaning piglets (28 days old) were randomly assigned to three dietary groups for 42 days: control (CTR), 30% replacement of CTR with salty FFP (SA), 30% replacement of CTR with sugary FFP (SU). Body weight and feed intake were measured to calculate average daily gain, average daily feed intake and feed conversion ratio. The fatty acid profile of the diets and the abdominal adipose tissue was determined and a mass spectrometry-based untargeted metabolomics investigation was performed on plasma samples. The growth performance was not significantly affected by SA and SU diets. Despite the different fatty acid profile of the diets, the fatty acid profile of the adipose tissue was rebalanced in piglets. The plasma metabolome was more affected by the time factor rather than the treatment factor. Six metabolites were significantly altered in SA and SU groups compared to CTR: caffeine, theobromine, proline-betaine, dipalmitoyl-phosphatidylcholine (PC 32:0), spermidine and l-tryptophan. Caffeine and glycerophospholipid pathways were significantly different between CTR and SA and SU groups, although no impact on other metabolic pathways was observed. Overall, the limited impact of FFP on the abdominal fat, plasma metabolome and related pathways in postweaning piglets demonstrated the value of FFP as innovative and sustainable feed ingredients to replace human-competing feedstuffs.PMID:39727062 | DOI:10.1111/jpn.14087

Physiol Plant. 2025 Jan-Feb;177(1):e70028. doi: 10.1111/ppl.70028.ABSTRACTThe classic plant growth-promoting phytohormone cytokinin has been identified and established as a mediator of pathogen resistance in different plant species. However, the resistance effect of structurally different cytokinins appears to vary and may regulate diverse mechanisms to establish resistance. Hence, we comparatively analysed the impact of six different adenine- and phenylurea-type cytokinins on the well-established pathosystem Nicotiana tabacum-Pseudomonas syringae. The efficiency of resistance effects was evaluated based on impacts on the host plant defence response by scoring infection symptoms and the direct impact on the pathogen by assessment of proliferation in planta. To identify common and cytokinin-specific components involved in resistance effects, transcriptome profiling and targeted metabolomics were conducted in leaves treated with the different cytokinins. We observed clearly different potentials of the tested cytokinins in either suppressing infection symptoms or pathogen proliferation. Gene regulation and metabolite analyses revealed cytokinin-type specific impacts on defence components, such as salicylic acid and related signalling, expression of PR proteins, and regulation of specialised metabolism. Cytokinins also strongly affected plant cell physiological parameters, such as a remarkable decrease in amino acid pools. Hence, this study provides comparative information on the efficiency of diverse cytokinins in mediating resistance in one well-studied pathosystem and insights into the specific regulation of resistance effects mediated by different cytokinin molecules. This is particularly relevant for studies on the function of cytokinins or other phytohormones and compounds interacting with cytokinin activities in the context of pathogen infections and other stress scenarios, considering the diverse cytokinins present in plants.PMID:39727031 | DOI:10.1111/ppl.70028

Front Microbiol. 2024 Dec 12;15:1468627. doi: 10.3389/fmicb.2024.1468627. eCollection 2024.ABSTRACTAs one of the three major food crops in the world, maize plays a significant role in alleviating the food crisis. Maize stalk rot can reduce maize yield and mechanical harvesting efficiency. In addition, mycotoxins such as Deoxynivalenol (DON) and Zearalenone (ZEN) produced by maize stalk rot pathogens can also harm livestock and human health. Maize stalk rot is an infection of the whole growth period, and there are no effective control measures at present. Therefore, it is of great significant to study the pathogenesis and control mechanism of stalk rot from multiple perspectives. In the present study, root and rhizosphere soil of disease-resistant inbred line Y853 and disease-susceptible inbred line Q478 were collected at the dough stage (R4) and maturity stage (R6) of maize, respectively. The effects of resistant/susceptible inbred line on soil microorganisms were analyzed by amplicon sequences and metabolomics. The results showed that there was different microbial community composition from different inbred lines in different growth stages. Specifically, the abundance of Arthrobacter, Streptomyces and Bacillus in R4 rhizosphere soil was higher than that of R6, while the rhizosphere fungal composition of LR853 was significantly different from that of the other three compartments. Co-occurrence network analysis showed that the pathogen Fusarium had the highest degree centrality and closeness centrality in the DR478. Moreover, metabolomics analysis showed that four main metabolic pathways were significantly enriched, and 15 metabolites were upgrade in resistant inbred line. Furthermore, microbes, especially fungi, also were related to these 15 metabolites. Our results revealed that maize resistance to stalk rot is closely related to root-associated microbiota and rhizospheric metabolites, which would be a new perspective of phytopathogenic biocontrol.PMID:39726971 | PMC:PMC11669678 | DOI:10.3389/fmicb.2024.1468627

In Silico Pharmacol. 2024 Dec 24;13(1):6. doi: 10.1007/s40203-024-00287-0. eCollection 2025.ABSTRACTVisceral Leishmaniasis, caused by Leishmania donovani, is the second most deadly parasitic disease, causing over 65,000 deaths annually. Synthetic drugs available in the market, to combat this disease, have numerous side effects. In this backdrop, we aim to find safer antileishmanial alternatives with minimal side effects from mushrooms, which harbour various secondary metabolites with promising efficacy. Robust screening of sixteen extracts from eight different wild mushrooms reveals that the hydroalcoholic extract of Amanita princeps has outstanding antileishmanial activity against Leishmania donovani. Metabolomic profiling of this lead extract identifies 50 bioactive mycocompounds and among them, 10 were selected for in-silico study against five major targets-arginase, spermidine synthase, ornithine decarboxylase, trypanothione reductase and SOD, crucial for thiol-redox balance in parasites in the polyamine synthesis pathway. Molecular docking analysis against our prioritised targets identified two mycompounds Ergosterol and Taraxacolide 1-O-b-D-glucopyranoside from Amanita princeps having the highest binding affinity of -15.8 and -11.8 kcal/mol respectively against the ornithine decarboxylase of polyamine synthesis pathway. However, MD simulations and free energy calculation using MM-GBSA analysis revealed the better stability of ergosterol with PASP receptors suggesting its promising role as an anti-leishmanial compound. Further results of in vitro arginase, SOD, and NO enzyme assays also corroborated with in-silico findings, reinforcing the anti-leishmanial efficacy of the Amanita princeps extract. Thus, both in silico and in vitro analyses suggest the efficacy of both Ergosterol and Taraxacolide 1-O-b-D-glucopyranoside compounds resourced from Amanita princeps as potent antileishmanial agents.PMID:39726904 | PMC:PMC11668711 | DOI:10.1007/s40203-024-00287-0

Front Nutr. 2024 Dec 11;11:1447878. doi: 10.3389/fnut.2024.1447878. eCollection 2024.ABSTRACTHigh sugar, high-fat diets and unhealthy lifestyles have led to an epidemic of obesity and obesity-related metabolic diseases, seriously placing a huge burden on socio-economic development. A deeper understanding and elucidation of the specific molecular biological mechanisms underlying the onset and development of obesity has become a key to the treatment of metabolic diseases. Recent studies have shown that the changes of bile acid composition are closely linked to the development of metabolic diseases. Bile acids can not only emulsify lipids in the intestine and promote lipid absorption, but also act as signaling molecules that play an indispensable role in regulating bile acid homeostasis, energy expenditure, glucose and lipid metabolism, immunity. Disorders of bile acid metabolism are therefore important risk factors for metabolic diseases. The farnesol X receptor, a member of the nuclear receptor family, is abundantly expressed in liver and intestinal tissues. Bile acids act as endogenous ligands for the farnesol X receptor, and erroneous FXR signaling triggered by bile acid dysregulation contributes to metabolic diseases, including obesity, non-alcoholic fatty liver disease and diabetes. Activation of FXR signaling can reduce lipogenesis and inhibit gluconeogenesis to alleviate metabolic diseases. It has been found that intestinal FXR can regulate hepatic FXR in an organ-wide manner. The crosstalk between intestinal FXR and hepatic FXR provides a new idea for the treatment of metabolic diseases. This review focuses on the relationship between bile acids and metabolic diseases and the current research progress to provide a theoretical basis for further research and clinical applications.PMID:39726876 | PMC:PMC11669848 | DOI:10.3389/fnut.2024.1447878

Front Nutr. 2024 Dec 12;11:1523842. doi: 10.3389/fnut.2024.1523842. eCollection 2024.ABSTRACTFood allergies manifest as systemic or digestive allergic responses induced by food allergens, and their progression has been demonstrated to be intimately associated with the host's gut microbiota. Our preceding investigation has revealed that the probiotic strains Lactiplantibacillus plantarum CCFM1189 and Limosilactobacillus reuteri CCFM1190 possess the capability to mitigate the symptoms of food allergy in mice. However, the underlying mechanisms and material foundations through which these probiotic strains exert their effects remain enigmatic. Here, we initially compared the ameliorative effects of these two probiotic strains on food allergy mice subjected to antibiotic cocktail (ABX) treatment. It is indicated that ABX treatment was ineffective in alleviating weight loss, diarrhea, and allergic symptoms in mice, and it also inhibited the reduction of histamine and T helper cell 2 (Th2) cytokines mediated by effective strains, suggesting that effective strains must operate through the gut microbiota. Then, building upon the outcomes of prior non-targeted metabolomics studies, by quantifying the content of indoleacrylic acid (IA) in single-strain fermentation of probiotic strains and mouse feces, it was ascertained that effective strains do not synthesize IA themselves but can augment the concentration of IA in the gut by modulating the gut microbiota. Ultimately, we discovered that direct intervention with IA could mitigate diarrhea, allergic symptoms, and intestinal damage by modulating immunoglobulin E (IgE) levels, histamine, Th2 cytokines, and tight junction proteins, thereby corroborating that IA is a pivotal metabolite for the alleviation of food allergies. These observations underscore the significance of gut microbiota and metabolites like IA in the management of food allergies and hold potential implications for the development of novel therapeutic strategies.PMID:39726866 | PMC:PMC11670748 | DOI:10.3389/fnut.2024.1523842

Cureus. 2024 Nov 26;16(11):e74528. doi: 10.7759/cureus.74528. eCollection 2024 Nov.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a poor prognosis. This poor prognosis is largely attributed to a late-stage diagnosis. Recent advancements in metabolomics have emerged as a promising avenue for biomarker discovery in PDAC. This systematic review evaluates the potential of metabolite biomarkers for early detection of PDAC. Four studies meeting the inclusion criteria were analyzed, encompassing experimental, case-control, and prospective cohort designs. Key findings include the identification of distinct metabolic subtypes in PDAC with varying sensitivities to metabolic inhibitors. A biomarker signature comprising nine metabolites plus CA19-9 showed high accuracy in distinguishing PDAC from chronic pancreatitis, outperforming CA19-9 alone. Another study identified a five-metabolite signature demonstrating high diagnostic accuracy for pancreatic cancer, differentiating it from type 2 diabetes mellitus. A two-metabolite model (isoleucine and adrenic acid) showed superior performance in detecting stage-I PDAC compared to CA19-9. These studies consistently demonstrate altered metabolic pathways in PDAC patients compared to healthy controls and those with benign pancreatic conditions. Integrating metabolomic data with other molecular profiling approaches has become a powerful strategy for improving diagnostic accuracy. However, challenges remain, including the influence of confounding factors, the need for large-scale validation studies, and the standardization of metabolomic methods. The potential of artificial intelligence in interpreting complex metabolomic data offers promising avenues for future research. This review highlights the significant potential of metabolite biomarkers in early PDAC detection while emphasizing the need for further validation and refinement of these approaches.PMID:39726485 | PMC:PMC11671176 | DOI:10.7759/cureus.74528

Front Plant Sci. 2024 Dec 12;15:1496691. doi: 10.3389/fpls.2024.1496691. eCollection 2024.ABSTRACTConsiderable biological decline of continuously cropped alfalfa may be tightly linked to rhizosphere metabolism. However, plant-soil feedbacks and age-related metabolic changes in alfalfa stands remain unexplored. The aim of this study was to identify the linkages of rhizosphere and root metabolites, particularly autotoxins and prebiotics, to alfalfa decline under continuous cropping. We performed liquid chromatography-mass spectrometry for non-targeted metabolomic profiling of rhizosphere soils and alfalfa roots in 2- and 6-year-old stands. Differentially abundant metabolites that responded to stand age and associated metabolic pathways were identified. Compared with bulk soils, rhizosphere soils were enriched with more triterpenoid saponins (e.g., medicagenic acid glycosides), which showed inhibitory effects on seed germination and seedling growth. These autotoxic metabolites were accumulated in the old stand age, and their relative abundances were negatively correlated with plant growth, yield, and quality traits, as well as soil total nitrogen and alkali-hydrolyzable nitrogen concentrations. In contrast, prebiotic metabolites, represented by glycerolipids (e.g., glycerophosphocholine) and fatty acyls (e.g., colnelenic acid), were depleted in rhizosphere soils in the old stand. The relative abundances of glycerolipids and fatty acyls were positively correlated with plant traits and soil available phosphorus and alkali-hydrolyzable nitrogen concentrations. Age-induced changes in the rhizosphere metabolome mirrored the reprogramming patterns of root metabolome. The pathways of terpenoid backbone biosynthesis and plant hormone signal transduction, as well as metabolism of galactose, glycerophospholipid, and ɑ-linolenic acid in alfalfa roots were affected by stand age. The upregulation of terpenoid backbone biosynthesis in alfalfa roots of old plants, which stimulated triterpenoid saponin biosynthesis and exudation. Rhizosphere accumulation of autotoxins was accompanied by depletion of prebiotics, leading to soil degradation and exacerbating alfalfa decline. This research aids in the development of prebiotics to prevent and manage continuous cropping obstacles in alfalfa.PMID:39726426 | PMC:PMC11670254 | DOI:10.3389/fpls.2024.1496691

Am J Physiol Cell Physiol. 2024 Dec 26. doi: 10.1152/ajpcell.00880.2024. Online ahead of print.ABSTRACTCellular senescence has been implicated in the aging-related dysfunction of satellite cells, the resident muscle stem cell population primarily responsible for the repair of muscle fibres. Despite being in a state of permanent cell cycle arrest, these cells remain metabolically active and release an abundance of factors that can have detrimental effects on the cellular microenvironment. This phenomenon is known as the senescence-associated secretory phenotype (SASP), and its metabolic profile is poorly characterized in senescent muscle. In the present investigation, we examined the intracellular and extracellular metabolome of C2C12 myoblasts using a bleomycin-mediated model of DNA damage-induced senescence. We also evaluated the relationship between the senescent metabolic phenotype and SASP signalling through molecular and network-based analyses. Senescent myoblasts exhibited a significantly altered extracellular metabolome (i.e. exometabolome), including increased secretion of several aging-associated metabolites. Four of these metabolites - trimethylamine-N-oxide (TMAO), xanthine, choline, and oleic acid - were selected for individual dose-response experiments to determine if they could drive the senescence phenotype. While most of the tested metabolites did not independently alter senescence markers, oleic acid treatment of healthy myoblasts significantly upregulated the SASP genes Ccl2, Cxcl12, and Il33 (p<0.05). A gene-metabolite interaction network further revealed that oleic acid was one of the most interconnected metabolites to key senescence-associated genes. Notably, oleic acid interacted with several prominent SASP genes, suggesting a potential epigenetic effect between this monounsaturated fatty acid and SASP regulation. In summary, the exometabolome, particularly oleic acid, is implicated in SASP signalling within senescent myoblasts.PMID:39726265 | DOI:10.1152/ajpcell.00880.2024

BMC Bioinformatics. 2024 Dec 26;25(1):391. doi: 10.1186/s12859-024-06016-w.ABSTRACTAs a heterogeneous disease, prostate cancer (PCa) exhibits diverse clinical and biological features, which pose significant challenges for early diagnosis and treatment. Metabolomics offers promising new approaches for early diagnosis, treatment, and prognosis of PCa. However, metabolomics data are characterized by high dimensionality, noise, variability, and small sample sizes, presenting substantial challenges for classification. Despite the wide range of applications of deep learning methods, the use of deep learning in metabolomics research has not been extensively explored. In this study, we propose a hybrid model, TransConvNet, which combines transformer and convolutional neural networks for the classification of prostate cancer metabolomics data. We introduce a 1D convolution layer for the inputs to the dot-product attention mechanism, enabling the interaction of both local and global information. Additionally, a gating mechanism is incorporated to dynamically adjust the attention weights. The features extracted by multi-head attention are further refined through 1D convolution, and a residual network is introduced to alleviate the gradient vanishing problem in the convolutional layers. We conducted comparative experiments with seven other machine learning algorithms. Through five-fold cross-validation, TransConvNet achieved an accuracy of 81.03% and an AUC of 0.89, significantly outperforming the other algorithms. Additionally, we validated TransConvNet's generalization ability through experiments on the lung cancer dataset, with the results demonstrating its robustness and adaptability to different metabolomics datasets. We also proposed the MI-RF (Mutual Information-based random forest) model, which effectively identified key biomarkers associated with prostate cancer by leveraging comprehensive feature weight coefficients. In contrast, traditional methods identified only a limited number of biomarkers. In summary, these results highlight the potential of TransConvNet and MI-RF in both classification tasks and biomarker discovery, providing valuable insights for the clinical application of prostate cancer diagnosis.PMID:39725937 | DOI:10.1186/s12859-024-06016-w

BMC Pregnancy Childbirth. 2024 Dec 26;24(1):868. doi: 10.1186/s12884-024-07097-4.ABSTRACTBACKGROUND: Delivery mode has been linked to child health, e.g., allergic disease. However, it remains unclear whether protein and metabolite differences across different delivery modes may underlie child development.METHODS: A cohort comprising 16 spontaneous onset vaginal delivery (VD), 16 prelabor cesarean delivery on maternal request (CS), and 8 intrapartum cesarean section (Intra_CS) women were analyzed using label-free proteomic and untargeted metabolomics assays on amniotic fluid and cord blood samples, respectively. We used weighted gene co-expression network analyses (WGCNA) to identify modules of highly correlated proteins or metabolites that associated with delivery modes and related clinical traits. KEGG enrichment analyses were performed to investigate the biological function of the identified modules. Integrative multiomics analysis was employed to examine the biological interplay between proteomic and metabolic interactions.RESULTS: Compared to the CS group, the proteomic and metabolomic profiles were similar between the Intra_CS and VD groups in our study. We did not identify any enriched protein or metabolite pathways related to immune development that could influence the risk of allergic diseases in offspring across different delivery modes. However, we identified seven protein modules correlated with the duration from the rupture of the membranes to full dilation of the cervix, with the actin cytoskeleton module significantly enriched. A metabolic module in cord blood that correlated with VD was enriched in subclasses including C21 steroids, steroid sulfates, and oxysterols. Integrative analysis of proteomic and metabolomic data suggested pathways related to mode of delivery and duration of labor, encompassing the actin cytoskeleton, NADP metabolic process, nicotinate, and nicotinamide metabolism in amniotic fluid, and the steroid hormone biosynthesis pathway in cord blood.CONCLUSIONS: Differences in steroid hormones and the actin cytoskeleton pathway according to proteomics and metabolomics in amniotic fluid and cord blood were more indicative of the labor process. These findings could guide future studies on delivery-associated biochemical pathways.PMID:39725908 | DOI:10.1186/s12884-024-07097-4

Invest New Drugs. 2024 Dec 27. doi: 10.1007/s10637-024-01489-1. Online ahead of print.ABSTRACTAntiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Patients were eligible if they had disease progression after standard therapies, adequate hematologic, hepatic and renal function, and no contraindications to bevacizumab. ME-344 was administered intravenously on days 1, 8 and 15 and bevacizumab on days 1 and 15 of 28-day cycles until disease progression or intolerance. The primary efficacy endpoint was progression-free survival (PFS) at week 16. In the 23 patients enrolled, the median age was 58 years, median number of prior lines of therapy was 4, and median interval from last therapy was 3 months. The most common adverse events (all grades/grade ≥ 3) were fatigue (48%/13%), abdominal pain (35%/4%), diarrhea (30%/4%) and constipation (30%/0%). No patient had an objective response; 9 patients (39%) achieved stable disease. The 16-week PFS was 30.6% (95% confidence interval [CI]: 12.2-51.3), the median PFS was 1.9 months (95% CI: 1.6-4.7), and the median overall survival was 6.7 months (95% CI: 3.4-not reached). ME-344 plus bevacizumab was well tolerated. Disease control was limited in this heavily pretreated patient population. Additional investigations in earlier lines are indicated, and extended-release ME-344 formulations may provide longer drug exposure to maximize benefit. (Trial registration number ClinicalTrials.gov NCT05824559. Registration date 22 March 2022).PMID:39725778 | DOI:10.1007/s10637-024-01489-1

Gut Microbes. 2025 Dec;17(1):2446391. doi: 10.1080/19490976.2024.2446391. Epub 2024 Dec 26.ABSTRACTResveratrol (RSV), a natural polyphenol, has been suggested to influence glucose and lipid metabolism. However, the underlying molecular mechanism of its action remains largely unknown due to its multiple biological targets and low bioavailability. In this study, we demonstrate that RSV supplementation ameliorates high-fat-diet (HFD)-induced gut microbiota dysbiosis, enhancing the abundance of anti-obesity bacterial strains such as Akkermansia, Bacteroides and Blautia. The critical role of gut microbiota in RSV-mediated anti-obesity effects was confirmed through antibiotic-induced microbiome depletion and fecal microbiota transplantation (FMT), which showed that RSV treatment effectively mitigates body weight, histopathological damage, glucose dysregulation and systematic inflammation associated with HFD. Metabolomics analysis revealed that RSV supplementation significantly increases the levels of the gut microbial flavonoid catabolite 4-hydroxyphenylacetic acid (4-HPA). Notably, 4-HPA was sufficient to reverse obesity and glucose intolerance in HFD-fed mice. Mechanistically,4-HPA treatment markedly regulates SIRT1 signaling pathways and induces the expression of beige fat and thermogenesis-specific markers in white adipose tissue (WAT). These beneficial effects of 4-HPA are partially abolished by EX527, a known SIRT1 inhibitor. Collectively, our findings indicate that RSV improve obesity through a gut microbiota-derived 4-HPA-SIRT1 axis, highlighting gut microbiota metabolites as a promising target for obesity prevention.PMID:39725607 | DOI:10.1080/19490976.2024.2446391

Lett Appl Microbiol. 2024 Dec 26:ovae116. doi: 10.1093/lambio/ovae116. Online ahead of print.ABSTRACTLactic acid bacteria are considered the safest alternative to antibiotics and have a broad range of applications in animal husbandry. Enterococcus faecalis is a primary component of the chicken gut microbiota; it is known for its ability to regulate intestinal microbial balance and its probiotic functions. In this study, E. faecalis strain AQ10 from isolated from was the chicken cecum and used a combination of whole-genome sequencing and phenotypic analyses to investigate its probiotic properties. Whole-genome sequencing revealed that the genome length of E. faecalis AQ10 is 2.98 Mbp, with an average guanine-cytosine content of 38.12%, and includes 2832 protein-coding genes. Genome mining tools were used to identify an antimicrobial compound gene cluster. Additionally, E. faecalis AQ10 exhibited probiotic characteristics in vivo and antibacterial effects in vitro, with organic acids potentially contributing to its anti-Klebsiella pneumoniae activity. Metabolomics analyses revealed that the supernatant of E. faecalis AQ10 contained seven organic acids. In conclusion, E. faecalis AQ10 demonstrates significant probiotic potential and may be a suitable candidate for use in livestock and poultry breeding.PMID:39725445 | DOI:10.1093/lambio/ovae116