Search Results (170)

Chronic kidney disease (CKD) is a heterogeneous condition with various etiologies, including type 2 diabetes mellitus (T2D), hypertension, and autoimmune disorders. Both diabetic CKD (CKD_T2D) and non-diabetic CKD (CKD_nonT2D) share overlapping clinical features, but understanding the molecular mechanisms underlying each subtype and distinguishing diabetic from non-diabetic forms remain poorly defined. To identify differentially expressed genes (DEGs) and enriched biological pathways between CKD_T2D and CKD_nonT2D cohorts, including autoimmune (CKD_nonT2D_AI) and hypertensive (CKD_nonT2D_HT) subtypes, through integrative transcriptomic analysis. Publicly available gene expression datasets from human glomerular and tubulointerstitial kidney tissues were curated and analyzed from GEO and ArrayExpress. Differential expression analysis and Gene Set Enrichment Analysis (GSEA) were conducted to assess cohort-specific molecular signatures. A considerable overlap in DEGs was observed between CKD_T2D and CKD_nonT2D, with CKD_T2D exhibiting more extensive gene expression changes. Hypertensive-CKD shared greater transcriptomic similarity with CKD_T2D than autoimmune-CKD. Key DEGs involved in fibrosis, inflammation, and complement activation—including Tgfb1, Timp1, Cxcl6, and C1qa/B—were differentially regulated in diabetic samples, where GSEA revealed immune pathway enrichment in glomeruli and metabolic pathway enrichment in tubulointerstitium. The transcriptomic landscape of CKD_T2D reveals stronger immune and metabolic dysregulation compared to non-diabetic CKD. These findings suggest divergent pathological mechanisms and support the need for tailored therapeutic approaches. Full article

Calendula officinalis L. is a widely used medicinal plant whose secondary metabolism and morphology are influenced by light. This study evaluated the effects of 2 and 4 h end-of-day (EOD) red/far-red (R:FR) and green (G) light on the growth, physiology, and phytochemical profile of hydroponically grown C. officinalis under a constant red/blue light background, compared with a red/blue control without EOD treatment. Morphological, physiological (gas exchange, chlorophyll fluorescence), biochemical (chlorophyll, anthocyanin), and chemical composition (attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and Gas Chromatography-Mass Spectrometry (GC-MS)) were evaluated. EOD G 2 h enhanced photosynthetic pigments, anthocyanins, and biomass, while control plants showed higher phenolic content. EOD R:FR induced stem elongation but reduced pigment and metabolite accumulation. GC-MS revealed organ-specific metabolic specialization, with flowers displaying greater chemical diversity than leaves. EOD G favored sesquiterpene diversity in flowers, while EOD R:FR increased nitrogen-containing compounds and unsaturated fatty acids. Vibrational data supported these shifts, with spectral signatures of esters, phenolics, and lipid-related structures. Bioactive compounds, including α-cadinol and carboxylic acids, were identified across treatments. These findings demonstrate that EOD light modulates physiological and metabolic traits in C. officinalis, highlighting EOD G as an enhancer of biomass and phytochemical richness for pharmaceutical applications under controlled conditions. Full article

This study aimed to investigate the tyrosine kinase inhibitor Nintedanib and its potential role in reversing epithelial–mesenchymal transition (EMT) induced by transforming growth factor beta 2 (TGF-β2) in retinal pigment epithelial (RPE) cells, along with its therapeutic potential using a mouse model of subretinal fibrosis. We hypothesized that the blockade of angiogenesis promoting and fibrosis inducing signaling using the receptor tyrosine kinase inhibitor Nintedanib (OfevTM) can prevent or reverse EMT both in vitro and in our in vivo model of subretinal fibrosis. Primary human retinal pigment epithelial cells (phRPE) and adult retinal pigment epithelial cell line (ARPE-19) cells were treated with TGF-β210 ng/mL for two days followed by four days of Nintedanib (1 µM) incubation. Epithelial and mesenchymal phenotypes were assessed by morphological examination, quantitative real-time polymerase chain reaction(qPCR) (ZO-1, Acta2, FN, and Vim), and immunocytochemistry (ZO-1, vimentin, fibronectin, and αSMA). Metabolites were measured using luciferase-based assays. Extracellular acidification and oxygen consumption rates were measured using the Seahorse XF system. Metabolic-related genes (GLUT1, HK2, PFKFB3, CS, LDHA, LDHB) were evaluated by qPCR. A model of subretinal fibrosis using the two-stage laser-induced method in C57BL/6J mice assessed Nintedanib’s therapeutic potential. Fibro-vascular lesions were examined 10 days later via fluorescence angiography and immunohistochemistry. Both primary and ARPE-19 RPE stimulated with TGF-β2 upregulated expression of fibronectin, αSMA, and vimentin, and downregulation of ZO-1, consistent with morphological changes (i.e., elongation). Glucose consumption, lactate production, and glycolytic reserve were significantly increased in TGF-β2-treated cells, with upregulation of glycolysis-related genes (GLUT1, HK2, PFKFB3, CS). Nintedanib treatment reversed TGF-β2-induced EMT signatures, down-regulated glycolytic-related genes, and normalized glycolysis. Nintedanib intravitreal injection significantly reduced collagen-1+ fibrotic lesion size and Isolectin B4+ neovascularization and reduced vascular leakage in the two-stage laser-induced model of subretinal fibrosis. Nintedanib can induce Mesenchymal-to-Epithelial Transition (MET) in RPE cells and reduce subretinal fibrosis through metabolic reprogramming. Nintedanib can therefore potentially be repurposed to treat retinal fibrosis. Full article

Peri- and postmenopausal women often experience unexplained weight gain despite maintaining consistent dietary and lifestyle habits. While the biological mechanisms underlying this phenomenon remain poorly understood, physiological and pathophysiological changes during the menopausal transition are likely contributors. Proteomic profiling holds potential for revealing key molecular pathways involved in the pathogenesis of obesity in this population. This review synthesizes current evidence on proteomic alterations linked to overweight and obesity in peri- and postmenopausal women. A structured literature search was performed across Ovid MEDLINE^®, EMBASE, the Cochrane Library, and Scopus for studies published between October 2010 and March 2025. Eligible studies included original research involving overweight or obese peri- or postmenopausal women that reported proteomic data. Extracted information encompassed study design, participant characteristics, sample types, and proteomic findings. Identified proteins were cross-referenced with a prior review of consistently dysregulated proteins in obesity. Five studies met the inclusion criteria, collectively revealing consistent proteomic patterns associated with inflammation, metabolic dysfunction, and endothelial dysregulation. These included C-reactive protein, Tissue necrotic factor-alpha, interleukins, adiponectin, and endocan. Notably, one study demonstrated that weight loss led to reductions in IL-6, IL-1 receptor antagonist, and CRP, suggesting that obesity-related inflammation may be at least partially reversible. This review provides preliminary evidence linking chronic inflammation, metabolic dysregulation, and vascular stress to obesity in peri- and postmenopausal women. These proteomic signatures enhance understanding of menopausal weight gain and highlight the potential of proteomics to guide personalized interventions. However, larger, well-designed prospective studies are needed to confirm these associations and clarify causal pathways. Full article

Background: BCR-ABL inhibitors such as imatinib and nilotinib exhibit multi-kinase activity that extends beyond oncology, offering significant potential for drug repurposing. Objectives: This study aims to systematically evaluate and prioritize the repurposing potential of BCR-ABL inhibitors, particularly imatinib and nilotinib. Methods: An integrated pharmacoinformatics framework was applied to analyze seven BCR-ABL inhibitors. Structural clustering, cheminformatics analysis, and transcriptomic profiling using the Connectivity Map were employed to evaluate structural relationships, target profiles, and gene expression signatures associated with non-oncology indications. Results: Structurally, imatinib and nilotinib clustered closely, while HY-11007 exhibited distinct features. Nilotinib’s high selectivity correlated with strong transcriptional effects in neurodegeneration-related pathways (e.g., HSP90 and LYN), whereas imatinib’s broader kinase profile (PDGFR and c-KIT) was linked to fibrosis and metabolic regulation. Connectivity Map analysis identified more than 30 non-cancer indications, including known off-target uses (e.g., imatinib for pulmonary hypertension) and novel hypotheses (e.g., nilotinib for Alzheimer’s via HSPA5 modulation). A substantial portion of these predictions aligned with the existing literature, underscoring the translational relevance of the approach. Conclusions: These findings highlight the importance of integrating structure–activity relationships and transcriptomic signatures to guide rational repurposing. We propose prioritizing nilotinib for CNS disorders and imatinib for systemic fibrotic diseases, supporting their advancement into preclinical and clinical evaluation. More broadly, this framework offers a versatile platform for uncovering hidden therapeutic potential across other drug classes with complex polypharmacology. Full article

Aerobic exercise mitigates age-related intestinal senescence through gut microbiota modulation, but the underlying mechanism has remained unclear. In this study, we performed 16S rRNA sequencing of gut contents from young, old, and old exercise C57BL/6J mice to assess exercise-induced alterations in microbiota community structure. Differential taxa analyses were applied to reveal age-associated bacterial signatures, gut barrier integrity, and systemic inflammation. Additionally, untargeted metabolomic profiling was employed to characterize gut metabolic profiles and reveal the key pathways through differential metabolite enrichment analyses. Aging significantly exacerbated the senescence-associated secretory phenotypes and the overgrowth of pathogenic bacteria in mice. However, aerobic exercise ameliorated these age-related deteriorations, restored gut microbial homeostasis, and reduced intestinal permeability. Notably, exercise intervention led to a significant increase in Akkermansia abundance in feces, establishing this mucin-degrading bacterium as a prominent exercise-responsive microbe. Metabolomic profiling identified eicosanoid metabolism as the most significantly perturbed pathway, and chronic exercise was found to regulate 14,15-Dhet levels. Our multi-omics integration confirmed that exercise is a potent modulator of the gut–microbiota–metabolite axis during aging. Elucidating the “Akkermansia–eicosanoid signaling” axis provided mechanistic insights into how exercise promotes healthy aging, identifying novel targets for anti-aging strategies via microbiota. Full article

Background/Objective: The expression of human steroid sulfatase (STS) is upregulated in castration-resistant prostate cancer (CRPC) and is associated with resistance to anti-androgen drugs, such as enzalutamide (Enza) and abiraterone (Abi). Despite the known link between STS overexpression and therapeutic unresponsiveness, the mechanism by which STS confers this phenotype remains incompletely understood. In this study, we sought to understand how STS induces treatment resistance in advanced prostate cancer (PCa) cells by exploring its role in altering mitochondrial activity. Methods: To examine the effects of increased STS expression on mitochondrial respiration and programming, we performed RNA sequencing (RNA-seq) analysis, the Seahorse XF Mito Stress Test, and a mitochondrial Complex I enzyme activity assay in STS-overexpressing cells (C4-2B STS) and in enzalutamide-resistant CPRC cells (C4-2B MDVR). We employed SI-2, the specific chemical inhibitor of STS, on C4-2B STS and C4-2B MDVR cells and evaluated STS activity inhibition on mitochondrial molecular pathways and mitochondrial respiration. Lastly, we examined the effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on C4-2B STS organoids. Results: We present evidence from the transcriptomic profiling of C4-2B STS cells that there are enriched metabolic pathway signatures involved in oxidative phosphorylation, the electron transport chain, and mitochondrial organization. Moreover, upon STS inhibition, signaling in the electron transport chain and mitochondrial organization pathways is markedly attenuated. Findings from the Seahorse XF Mito Stress Test and mitochondrial Complex I enzyme activity assay demonstrate that STS overexpression increases mitochondrial respiration, whereas the inhibition of STS by SI-2 significantly reduces the oxygen consumption rate (OCR) and Complex I enzyme activity in C4-2B STS cells. Similarly, an increased OCR and electron transport chain Complex I enzymatic activity are observed in C4-2B MDVR cells and a decreased OCR upon SI-2 inhibition. Lastly, we show that STS overexpression promotes organoid growth upon DHEAS treatment. Conclusions: Our study demonstrates STS as a key driver of metabolic reprogramming and flexibility in advanced prostate cancer. Disrupting enhanced mitochondrial respiration via STS presents a promising strategy in improving CRPC treatment. Full article

Traumatic brain injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the NanoString Neuropathology Panel to test the hypothesis that idebenone post-treatment mitigates TBI-pathology-associated acute gene expression changes by moderating the pro-inflammatory microglial response to injury. Controlled cortical impact to adult male mice increased the microglial activation signature in the peri-lesional cortex at 24 h post-TBI. Unexpectedly, several microglial signature genes upregulated by TBI were further increased by post-injury idebenone administration. However, idebenone significantly attenuated TBI-mediated perturbations to gene expression associated with behavior, particularly in the gene ontology–biological process (GO:BP) pathways “ephrin receptor signaling” and “dopamine metabolic process”. Gene co-expression analysis correlated levels of microglial complement component 1q (C1q) and the neurotrophin receptor gene Ntrk1 to large (>3-fold) TBI-induced decreases in dopamine receptor genes Drd1 and Drd2 that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, the results suggest that idebenone may enhance TBI-induced microglial number within the first 24 h of TBI and identify ephrin-A and dopamine signaling as novel idebenone targets. Full article

Background/Objectives: Individuals with childhood obesity exhibit significant metabolic heterogeneity, necessitating precise biomarkers for risk stratification and assessment. This multi-omics investigation characterizes metabolic and microbial signatures underlying divergent metabolic phenotypes in the context of pediatric obesity. Methods: We analyzed 285 Chinese children (5–7 years) stratified into five groups: wasting (WAS, n = 55), metabolically healthy/unhealthy and normal weight (MHWH, n = 54; MUWH, n = 67), and metabolically healthy/unhealthy obesity (MHO, n = 36; MUO, n = 73). Untargeted metabolomics (Orbitrap ID-X Tribrid™) and 16S rRNA sequencing were integrated with multivariate analyses (OPLS-DA with VIP > 1, FDR < 0.05; Maaslin 2 with TSS normalization and BH correction, FDR < 0.10). Results: Analysis identified 225 differential metabolites and 12 bacterial genera. The proportion of steroids and their derivatives among differential metabolites in the MUO/MHO group was significantly lower than that in the OVOB/NOR and OVOB/WAS groups (2.12% vs. 7.9–14.1%). MUO displayed elevated C17 sphinganine and LysoPC (O-18:0) levels but reduced PI (16:0/14:1) levels. In contrast, OVOB showed upregulated glycerol phospholipids (LPCs and PSs) and downregulated PE species (e.g., PE(16:0/16:0)) as well as gut microbiota dysbiosis characterized by a higher Firmicutes/Bacteroidetes (F/B) ratio (2.07 vs. 1.24 in controls, p = 0.009) and reduced α diversity (Ace index, Chao1 index, and Shannon index values were lower in the OVOB group, Shannon index: 2.96 vs. 3.45, p = 0.03). SCFA-producing genera were negatively correlated with the OVOB group, while positively associated with PE(16:0/16:0). Internal validation showed differential metabolites had potential predictive efficacy for MUO/MHO (AUC = 0.967) and OVOB/NOR (AUC = 0.888). Conclusions: We identified distinct lipid disruptions characterizing obesity subtypes, including steroid/terpene deficits and sphingolipid/ether lipid dysregulation in the MUO/MHO groups as well as phospholipid imbalance (↑LPC/PS↓PE) in the OVOB/NOR groups. The gut microbiota exhibited a profile characterized by low diversity, an increased F/B ratio, and a reduced abundance of SCFA-producing genera. These findings suggest potential biomarkers for childhood obesity stratification, though further validation is warranted. Full article

The objective of this study was to elucidate the proteomic and transcriptomic alterations within the cartilage in Kashin–Beck disease (KBD) compared to a normal control. We conducted a comparison of the expression profiles of proteins, mRNAs, and lncRNAs via data-independent acquisition (DIA) proteomics and transcriptome sequencing in six KBD individuals and six normal individuals. To facilitate the functional annotation enrichment analysis of the differentially expressed (DE) proteins, DE mRNAs, and DE lncRNAs, we employed bioinformatic analysis utilizing Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we conducted integration analysis of multi-omics datasets using mixOmics. We revealed a distinct proteomic signature, highlighting 53 DE proteins, with notable alterations in the pathways related to tryptophan metabolism and microbial metabolism. Additionally, we identified 160 DE mRNAs, with the functional enrichment analysis uncovering pathways related to RNA metabolism and protein splicing. Furthermore, our analysis of the lncRNAs demonstrated biological processes involved in protein metabolism and cellular nitrogen compound metabolic processes. The integrative analysis uncovered significant correlations, including the positive correlation between superoxide dismutase 1 (SOD1) and mitochondrial import receptor subunit TOM6 homolog (TOMM6), and the negative correlation between C-X9-C motif-containing 1 (CMC1) and succinate–CoA ligase [GDP-forming] subunit beta, mitochondrial (SUCLG2). Our results provide novel insights into the molecular mechanisms underlying KBD. Full article

Clear cell renal cell carcinoma (ccRCC) is distinguished by metabolic irregularities and unique immunological profiles. Nevertheless, the comprehensive examination of immune and metabolic attributes within the tumor microenvironment of ccRCC remains inadequately elucidated. In this study, we identified two distinct molecular subtypes (C1 and C2) of ccRCC using the non-negative matrix factorization (NMF) algorithm. Utilizing univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, we developed a prognostic signature comprising eight immune- and metabolism-related genes (IMRGs) associated with the tumor microenvironment. The validation of this signature was performed using both testing and entire datasets. A nomogram was developed using IMRGs prognostic signature and various clinical parameters, including age and TNM stage. We also performed the in vitro experiments to validate the carcinogenic role of PYCR1 in ccRCC cells. Subtype C1 exhibited a more favorable prognosis and higher levels of immune cell infiltration compared to subtype C2. The AUCs of the nomogram at 1-, 3-, and 5-year intervals (AUC = 0.874, 0.820, and 0.794) were slightly higher than those of the IMRGs signature alone (AUC = 0.773, 0.755, and 0.764). The association between risk score and immune checkpoint expressions, immunophenoscore (IPS), and microsatellite instability (MSI) collectively predicted treatment efficacy accurately. Additionally, in vitro experiments confirmed the involvement of PYCR1 in promoting the aggressive behaviors of ccRCC cells, as evidenced by reduced proliferation, invasion, and enhanced apoptosis upon PYCR1 knockdown. In conclusion, the IMRGs signature shows promise in predicting prognostic risk, assessing the effectiveness of immunotherapy, and tailoring treatment for ccRCC patients. Full article

The neurobehavioral changes in food allergy mice have not been comprehensively studied, and the mechanism underlying them remains unclear. Our study aims to fully investigate neurobehavioral changes in OVA (ovalbumin)-sensitized food allergy mice and explore the potential mechanism via the gut microbiota–brain axis. We established the food allergy mouse (C57BL/6J male) model with OVA, evaluating the anaphylactic symptoms and the levels of Th2 signature cytokine and allergy-related antibodies in serum. Using behavioral tests, we measured anxiety, depression, social behavior, repetitive behavior, attention, and spatial memory in control and OVA mice. In addition, we analyzed the prefrontal cortex for measuring inflammation-related indicators and gathered serum for untargeted metabolomics analysis and feces for 16S rDNA sequencing. OVA mice exhibited anaphylactic symptoms and significantly elevated serum IgE and Th2 signature cytokine levels. In addition to anxiety-like, depression-like, and repetitive behaviors, OVA mice also displayed less social interest and damaged attention. TNF-α, IL-1β, and IL-6 levels and the activation of microglia in the prefrontal cortex of OVA mice were significantly increased, which might explain the neuronal damage. Using multi-omics technology, amino acid metabolism disruption, particularly carboxylic acids and derivatives, was observed in OVA mice, which was remarkably correlated with the altered abundance of gut microbiota related to food allergy. Behaviors in OVA-induced food allergy mice were extensively impaired. The disruption of amino acid metabolism associated with gut microbiota dysbiosis in OVA mice might play a pivotal role in impairing neural immune homeostasis and neuronal damage, which could be responsible for behavioral abnormalities. Full article

Background: Rose processing faces critical challenges in preserving bioactive compounds and aroma profiles during thermal treatments, particularly given the growing demand for natural ingredients in the food and cosmetic industries. Methods: Using widely targeted metabolomics, we first characterized volatile profiles of four major commercial cultivars (Hetian, Damask, Bulgarian, and Fenghua; n = 6 replicates per cultivar), identifying terpenoids as dominant components (p < 0.05). Subsequent thermal optimization focused on Hetian rose, where WGCNA and K-means analyses revealed temperature-dependent dynamics (40–55 °C, triplicate drying trials per temperature). Results: Hetian rose exhibited significantly higher accumulation (p < 0.05) of a unique sesquiterpene marker, 4-(1,5-dimethyl-1,4-hexadienyl)-1-methyl-cyclohexene. Systematic drying optimization identified 50 °C as the thermal threshold for optimal color, bioactive retention, and sensory quality. Mechanistic analysis identified 193 temperature-responsive metabolites (VIP > 1, FC < 0.25 or >4, p < 0.01), with terpenoid biosynthesis (MVA/MEP pathways) and esterification dynamics emerging as critical control points. Conclusions: This study establishes the first cultivar-specific processing framework for roses, demonstrating that metabolic signature-guided drying improves product quality. The findings advance our understanding of thermal impacts on aroma biochemistry while providing actionable protocols for natural product industries. Full article

Background: Brown algae from the order Dictyotales are known to produce specialized metabolites with a wide array of biological activities. Studying these compounds is important for understanding their ecological roles, exploring biomedical potential and developing biotechnological applications. Methods: To evaluate the metabolic diversity of brown algae from the shallow habitats of the northern region of San Andrés Island (Colombia, SW Caribbean), a metabolic profiling approach was employed, based on ¹H-NMR spectra taken from organic extracts. Four sampling expeditions were conducted to collect the most abundant species, taking into account the taxonomic identity, growth substrate and collection date. Results: Five species were found and identified as Canistrocarpus crispatus, Stypopodium zonale, Dictyopteris delicatula, Padina gymnospora and Dictyota spp. Multivariate analyses applied to these spectra revealed that S. zonale and C. crispatus differentiated from the other samples mainly due to the signals for meroditerpenes and diterpenes, respectively. S. zonale had differential metabolic production observed when comparing algae collected in rocky bottoms with thalli growing on dead coral. This difference was attributed to changes in concentrations of the meroditerpene atomaric acid (1). Meanwhile, the major metabolite found in C. crispatus samples was dictyol B acetate (2). Conclusions: NMR metabolomics of San Andrés brown algae differentiated species based on lipid content and metabolic complexity. Notably, prenylated-guaiane diterpenes characterized C. crispatus, and meroditerpenoid concentrations varied in S. zonale. Temporal lipid variations were observed in P. gymnospora, while juvenile Dictyota spp. presented a less complex metabolic signature. Full article

In this work, metabolite profiling of seeds and antioxidant analysis of fragments of two marine seagrasses, Posidonia oceanica and Cymodocea nodosa, were carried out to identify metabolite signature involved in seed viability and to evaluate the potential of fragments as a source of bioactive compounds. Using HILIC/QTOF-MS, UHPLC-MS and spectrophotometric analysis, seed metabolites and polyphenols and antioxidant activities, such as those of radical scavenging (RSA), reduction (FRAP, CUPRAC) and complexation (CCA), of rhizome fragments were evaluated. Metabolite comparison between seeds revealed differences across development stages (germinated and non-germinated) and seed types (dormant and non-dormant), providing insights into metabolic activity potentially associated with germination processes and seed viability. Furthermore, polyphenol analysis showed the highest content of caffeic acid in mature leaves (17.00 ± 0.02 μg g⁻¹ dw for P. oceanica and 98.00 ± 0.03 μg g⁻¹ dw for C. nodosa). Total phenolic content was correlated with flavonoids and with reduction and complexation activities. The combination of radical scavenging activity and t_1/2 was higher in P. oceanica than C. nodosa and also surpassed the commercial synthetic antioxidant BHA. We conclude P. oceanica and C. nodosa exhibit distinct seed metabolite profiles related to germination and type of seeds, and that fragments are rich in antioxidants, with potential as sustainable sources of bioactive compounds. Full article