Search Results (7,518)

Background: The kidney is an organ rich in peroxisomes, which play a pivotal role in fatty acid oxidation and ROS decomposition. Importantly, peroxisomal dysfunction contributes to the development and progression of various renal diseases. Therefore, we aimed to elucidate whether peroxisomes affect renal damage and fibrosis over time using a unilateral ureteral obstruction (UUO) mouse model. Methods: Expression levels of peroxisome-related factors and ROS- and hypoxia-related genes in UUO mice were measured in a time-dependent manner. Results: UUO led to renal damage and fibrosis progression over time; it significantly increased the protein expression levels of ATG5 and ATG7, while it decreased PMP70 and PEX14 protein expression. In particular, UUO increased the protein expression level of pexophagy receptor NBR1. Although the number of peroxisomes decreased, the protein expression levels of peroxisomal biogenesis-related proteins such as PEX11b, PEX16, and PEX19 remained constant. Decreased lipid metabolism due to reductions in ACOX1, DBP, and catalase caused by UUO and increased ROS production through peroxisomal degradation and mitochondrial antioxidant enzyme dysfunction were observed. Additionally, HIF-1α protein levels gradually increased in the UUO mice, whereas those of HIF-2α initially increased and then decreased. Conclusions: UUO is characterized by a progressive, chronological reduction in peroxisomal markers. Our findings indicate that peroxisomal degradation and associated metabolic dysfunction are tightly correlated with the progression of kidney injury and fibrosis, suggesting a potential involvement of compromised peroxisomal homeostasis in renal pathogenesis rather than proving a direct causal mechanism. Maintaining peroxisomal quality control may nevertheless represent a potential therapeutic avenue for chronic kidney disease. Full article

Acute liver failure (ALF) is characterized by a rapid decline in liver function, leading to metabolic and organ failure. This study employed liver metabolomics, Nuclear Factor kappa-B (NF-κB) signaling pathway analysis, and inflammatory factor profiling to investigate the therapeutic mechanisms of xanthoxylin in ALF. Xanthoxylin administration led to increased antioxidant levels and reduced markers of inflammation and tissue damage. Xanthoxylin downregulated the messenger RNA (mRNA) expression of Nitric Oxide Synthase (NOS), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), NF-κB, Inhibitor of NF-κB α (IκBα), and Toll-like receptor 4 (TLR4), and inhibited the protein expression of p-p38 and p-p65 while upregulating B-cell CLL/Lymphoma 2 (Bcl-2) and B-cell Lymphoma-x (Bcl-xl). Metabolomic analysis identified 41 differentially expressed metabolites, 20 of which showed strong correlations with pharmacodynamic parameters. These 20 candidate metabolite signatures are involved in amino acid and carboxylic acid metabolic pathways, with potential links to glycolysis and the tricarboxylic acid (TCA) cycle. Together, these findings suggest that xanthoxylin exerts therapeutic effects against ALF by modulating the IκBα/NF-κB signaling pathway and related metabolic pathways, providing a scientific basis for understanding its multi-target mechanism. Full article

Nectin-4 has emerged as a clinically relevant target in muscle-invasive bladder cancer (MIBC), primarily because of its role in antibody–drug conjugate-based therapies. However, the broader biological context of Nectin-4 expression and its association with tumor-promoting signaling pathways in MIBC remain insufficiently characterized. In this single-institution study, Nectin-4 expression (H-score 0–300) was assessed by immunohistochemistry in two independent MIBC cohorts. Associations between Nectin-4 expression and key markers related to growth signaling, metabolic regulation, and inflammation were analyzed alongside clinicopathological characteristics. Nectin-4 expression was significantly higher in malignant tissue than in non-malignant tissue (p = 0.0016 and p = 0.0302, respectively). Nectin-4 expression was not associated with demographic or clinicopathological parameters; however, a trend toward lower expression in more advanced disease stages was observed. Significant positive correlations were identified between Nectin-4 expression and protein kinase B (p = 0.0004), cytoplasmic (p = 0.0115) and membranous somatostatin receptor 2 (p = 0.0125), insulin receptor substrate 1 (p = 0.03), and interleukin-1 receptor antagonist (IL-1RA; p = 0.0045). In contrast, a negative correlation was observed with the IL-1β/IL-1RA ratio (p = 0.0246). Although Nectin-4 expression was not significantly associated with cancer-specific or overall survival, a trend toward shorter relapse-free survival was observed in patients with lower Nectin-4 expression (p = 0.0531). In multivariate analysis, patient age, but not Nectin-4 expression, emerged as an independent prognostic factor. Although Nectin-4 expression does not appear to have independent prognostic value, its biological associations suggest that it reflects an integrated tumor-related signaling context. These findings support further investigation of Nectin-4 as part of rational, biology-driven therapeutic strategies in bladder cancer. Full article

Inflammatory bowel disease (IBD) poses a significant global health burden with rising incidence, particularly in Asia. This study employed an integrative network pharmacology approach combined with molecular docking to elucidate the therapeutic mechanism of ganoderic acid A (GAA) against IBD. Potential GAA targets were retrieved from pharmacogenomic databases, while IBD-related genes were curated from OMIM and GeneCards databases. Weighted gene co-expression network analysis of IBD transcriptomic datasets (GSE38713, GSE126124) identified disease-associated modules, with the yellow module exhibiting the strongest positive correlation. Functional enrichment analyses demonstrated significant involvement of overlapping targets in lipid metabolism, the inflammatory response, and the mitogen-activated protein kinase (MAPK) signaling cascade pathway. We identified 14 IBD-GAA-ferroptosis-related genes and 54 key module genes. Intersection analysis revealed 5 overlapping targets, including tumor necrosis factor-α(TNF-α), peroxisome proliferators-activated receptor γ (PPARγ), MAPK14, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic α (PIK3CA), and Caspase 3 (CASP3). Molecular docking confirmed high-affinity binding of GAA to these targets, with binding energies ranging from −7.3 to −10 kcal/mol. Crucially, experimental evaluation demonstrated the pivotal role of GAA in alleviating disease pathology. GAA treatment suppressed the significantly elevated levels of TNF-α and p-MAPK14 in the organoids using a cytokine/LPS-induced IBD model. These findings collectively suggest a potential involvement of GAA in pathways associated with ferroptosis regulation, although direct experimental evidence for ferroptosis markers remains to be established. The observed multi-target effects on immune regulation and cellular proliferation/differentiation provide a foundation for further mechanistic investigation. Full article

Background: Kidney transplantation is the preferred treatment for end-stage kidney disease (ESKD), but long-term outcomes remain limited by chronic allograft injury, infections, metabolic complications, and cardiovascular risk. Gut microbiota alterations and microbiota-derived metabolites may influence immune regulation, inflammation, drug metabolism, and graft outcomes through the gut–kidney axis. This review summarizes evidence on the gut microbiota in kidney transplantation, emphasizing immune tolerance, complications, cardiovascular risk, graft function, and perspectives. Methods: A structured search was conducted in PubMed, Scopus, and Web of Science to May 2026. Eligible publications included studies involving kidney transplant recipients (KTR), kidney disease or solid organ transplant populations, and mechanistic models. Evidence was synthesized narratively. Results: Gut microbiota alterations in KTR reflect pre-transplant dysbiosis and post-transplant exposures, including antibiotics, immunosuppression, infection, diet, hospitalization, and graft function. Dietary factors and nutrient-derived substrates may modulate microbial composition and production of relevant metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), tryptophan-derived compounds, bile acid derivatives, and uremic toxins. Microbiota-related pathways may involve barrier dysfunction, microbial translocation, innate immune activation, altered regulatory T cell/T helper 17 (Treg/Th17) balance, metabolite signaling, uremic toxin generation, and endothelial stress. Clinical studies associate dysbiosis and microbial metabolites with diarrhea, infections, delayed graft function (DGF), rejection-related shifts, tacrolimus variability, cardiovascular risk, graft dysfunction, graft failure, and mortality. Most findings need validation. Conclusions: Gut microbiota signatures and microbial metabolites are promising markers of transplant-related risk, but not established causal determinants or therapeutic targets. Clinical translation requires standardized methods, multi-omics integration, and prospective patient- and graft-centered trials. Full article

Bacterial infections pose a serious threat to human health, and antibiotics remain the first-line therapeutic agents in clinical practice. However, the vast majority of antibiotics lack the ability to penetrate cell membranes, which severely limits the number of clinically available options for treating intracellular bacterial infections. Developing efficient intracellular antibiotic delivery strategies is therefore of considerable clinical significance, both for reducing antibiotic dosage and for expanding the repertoire of drugs applicable to intracellular infections. To address this challenge, we constructed a protein-based delivery platform mediated by a cell-penetrating miniprotein for efficient intracellular antibiotic delivery. In this system, bovine serum albumin (BSA), which possesses broad antibiotic-binding capability, was employed as the drug carrier, while the cell-penetrating miniprotein ZF5.3, which is capable of endosomal escape, served as the transmembrane delivery mediator. ZF5.3 was conjugated to BSA via a bioorthogonal reaction, and ceftriaxone (CRO) was selected as the model antibiotic to construct a nanoscale delivery system. The binding interaction between CRO and BSA was characterized using UV-Vis, HPLC, and molecular docking techniques. The assembly of the ZF5.3–BSA delivery platform was confirmed by UV-Vis absorption spectroscopy and gel electrophoresis. Intracellular delivery efficiency was evaluated by confocal fluorescence imaging and flow cytometry, and the results demonstrated that ZF5.3 conjugation enhanced intracellular protein delivery efficiency by over 5-fold. Fluorescence co-localization analysis revealed that ZF5.3-mediated cargo is mainly distributed in the cytoplasm and does not completely co-localize with lysosomal markers, suggesting its ability to effectively escape from lysosomes. An intracellular infection model using Staphylococcus aureus was established. Colony-forming unit (CFU) counting experiments confirmed that the delivery system significantly enhanced the intracellular antibacterial activity of ceftriaxone. CCK8 cytotoxicity assays confirmed that the system is non-toxic to cells. Full article

Neurodegeneration and oxidative stress are central drivers of immune-mediated neuropathies. Capsaicin, the active ingredient in chili pepper and a direct agonist of the transient receptor potential vanilloid (TRPV1) channel, is used clinically to treat neuropathic pain. We previously demonstrated immunomodulatory and antioxidative effects of capsaicin in experimental autoimmune neuritis in vivo and Schwann cells (SC) in vitro. However, the molecular mechanisms underlying the maintenance of axonal integrity in dorsal root ganglion (DRG) and SC homeostasis remain unclear. In this study, we described the effects of capsaicin on DRG and SC in vitro under both naïve and S-Nitroso-N-acetyl-DL-penicillamine (SNAP)-induced oxidative stress conditions. Capsaicin induced an upregulation of the antioxidative cascade involving Nrf2, Ho-1, and Nqo1 in naïve DRG neurons and restored axonal growth under preventive and therapeutic settings. Preventive treatment enhanced catalase expression, whereas treatment increased regeneration-associated Gap43 and Atf3. Inhibition of TRPV1 with capsazepine partly attenuated the protective effect of axonal outgrowth, indicating TRPV1-mediated neuroprotection. In SC, capsaicin increased mitochondrial ATP production and spare respiratory capacity, inducing a transient Nrf2-dependent antioxidant response. Capsaicin suppressed expression of myelination markers under basal conditions but promoted expression of myelination- and repair-associated markers under oxidative stress. The findings support capsaicin as a regulator of neuronal and Schwann cell oxidative stress adaptation. Full article

Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases—including Parkinson’s disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes—gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson’s disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a “sixth vital sign” reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology. Full article

Prostate cancer (PCa) is among the highest incidence malignancies in men, with high rates of inevitable resistance development, relapse, and mortality. Castration-resistant prostate cancer (CRPC) continued to pose substantial therapeutic challenges, highlighting the urgent need for effective treatment options. This study assessed the marine cembranoid sarcophine activity against the progression and recurrence of the metastatic CRPC (mCRPC) in mouse xenograft models. Protein and phosphorylation levels were assessed by immunoblotting and mRNA expression by qPCR and RNA sequencing. The in vivo efficacy was evaluated through tumor progression over 3 weeks followed by primary tumor excision and recurrence monitoring over an 8-week course. Sarcophine significantly reduced the mCRPC CWR-R1ca tumor volume by 74.1% and suppressed the epigenetic regulators EZH2 and SMYD2; lineage plasticity factors ASCL1 and BRN2; Wnt/stemness signaling markers β-catenin and LGR6; AKT total expression and activation; and invasion-associated proteins TRPC4 and MMP2 in primary tumors. Sarcophine effectively prevented the mCRPC locoregional recurrence, as well as lung and spleen distant recurrences, and effectively reduced recurrence in other organs. Transcriptomics-RNA-Seq analysis of primary tumors identified 2697 downregulated and 3534 upregulated genes, indicating broad transcriptional reprogramming following sarcophine treatments. These findings demonstrate coordinated suppression of multi-oncogenic pathways and validate the therapeutic potential of sarcophine to control mCRPC. Full article

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy characterized by variable clinical behavior and diverse molecular phenotypes. Although immune checkpoint inhibitors and targeted therapies have transformed the treatment landscape of advanced RCC, clinically validated biomarkers capable of improving risk stratification, therapeutic-decision making and disease monitoring remain lacking. Kidney injury molecule-1 (KIM-1), also known as hepatitis A virus cellular receptor-1 (HAVCR1) or T-cell immunoglobulin and mucin domain-containing protein-1 (TIM-1), has emerged as a biologically compelling investigational biomarker e because of its close relationship to proximal tubular epithelial injury and renal carcinogenesis. KIM-1 is a transmembrane glycoprotein minimally expressed in normal kidney tissue but markedly upregulated in dedifferentiated proximal tubular epithelial cells following injury, and in clear cell RCC, where its extracellular domain can be shed into plasma and urine. Beyond its role as a marker of tubular injury, KIM-1 participates in immune regulation, phagocytosis, inflammatory signaling and tissue remodeling, supporting its potential relevance to tumor biology. Clinical studies have demonstrated associations between elevated circulating KIM-1 levels and RCC diagnosis, recurrence risk, and survival outcomes, particularly in localized and postoperative disease settings. KIM-1 has additionally been investigated as a therapeutic target through antibody–drug conjugate approaches. Despite promising translational data, important limitations yet remain. Current evidence is predominantly prognostic rather than predictive, and substantial analytical and biological challenges continue to limit implementation. Assay standardization, clinically meaningful cutoffs, specimen selection, timing of sampling, and confounding by chronic kidney disease or nonmalignant renal injury remain incompletely resolved. Furthermore, evidence supporting incremental value beyond established clinicopathologic models remains limited. This review critically evaluates the biological rationale, analytical considerations and clinical evidence supporting KIM-1 in RCC. Particular emphasis is placed on distinguishing prognostic, predictive, pharmacodynamic, and therapeutic applications, as well as defining the evidentiary gaps that must be addressed before clinical implementation. Current evidence is derived predominantly from retrospective and exploratory analyses, and important limitations remain regarding assay standardization, biological specificity, chronic kidney disease-related confounding, and prospective validation. The review concludes with a summary of the evolving landscape of KIM-1-directed biomarker strategies in RCC, which may ultimately contribute to improved biologic risk stratification and biomarker-driven clinical investigation in RCC. Full article

Plant-derived compounds have recently attracted considerable scientific attention due to their potential therapeutic applications, which are largely attributed to their antioxidant properties. Tert-butyl hydroperoxide (t-BHP) is a potent inducer of intracellular oxidative stress, generating reactive free radicals, which significantly contribute to hepatic and renal damage. Micromeria frivaldszkyana (M. frivaldszkyana), a Bulgarian endemic species, contains high levels of phenolic compounds, including linarin, rosmarinic acid (RA), chlorogenic acid, rutin, quercetin, naringenin, and apigenin. In this study, male Wistar rats received oral treatment for 5 days comprising saline, 250, 400, or 500 mg/kg of M. frivaldszkyana methanolic extract, 100 mg/kg RA, or 125 mg/kg silymarin. On the final day, 0.5 mmol/kg of t-BHP was injected intraperitoneally, and blood and liver tissue samples were collected 18 h later for biochemical and histological analysis. Liver and kidney function was evaluated using biochemical markers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine (Cr), uric acid (UA)), indicators of oxidative stress (malondialdehyde (MDA), 8-hydroxy-2′-deoxyguanosine (8-OHdG), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT)), and histopathology. Exposure to t-BHP resulted in significant hepatic and renal damage, including elevated serum markers, increased lipid peroxidation, and deoxyribonucleic acid (DNA) damage. Administration of 500 mg/kg M. frivaldszkyana markedly lowered elevated serum ALT and AST levels. The extract also significantly mitigated t-BHP-induced increases in serum Cr and UA. However, no significant increase in the levels of the antioxidant enzymes SOD and CAT or in GSH was observed at all tested doses. Malondialdehyde and 8-OHdG levels increased markedly following t-BHP exposure, whereas pretreatment with M. frivaldszkyana at all tested doses significantly ameliorated these oxidative alterations. These findings suggest that the methanolic extract of M. frivaldszkyana confers protective effects against t-BHP-induced toxicity, potentially through stabilisation of cell membranes, inhibition of lipid peroxidation, and reduction in DNA damage. The extract may therefore serve as a potential natural therapeutic agent against injuries caused by oxidative stress. Full article

Background: Solriamfetol, a dopamine and norepinephrine reuptake inhibitor widely used in narcolepsy management, has not been thoroughly investigated for its anti-fibrotic and anti-inflammatory properties. Herein, we investigated its potential therapeutic applications and underlying mechanisms in both cellular and murine models of pulmonary fibrosis. Methods: To induce fibrosis, C57BL/6 male mice (six-week-old) were administered bleomycin via the intratracheal route. These animals subsequently received solriamfetol orally once per day at dosages of 3 or 10 mg/kg. Histological and immunohistochemical techniques were employed to evaluate inflammatory cell infiltration, collagen accumulation, and α-smooth muscle actin (α-SMA) expression in bronchoalveolar lavage samples and lung tissue sections. Cytokine levels were measured by ELISA, and gene/protein expression of pro-fibrotic markers, A_2A/A_2B adenosine receptors (ARs), adenylate cyclases (ACs), Epac, K_Ca3.1, and adenosine deaminase (ADA) were assessed via quantitative PCR and Western blot. Electrophysiological recordings evaluated K_Ca3.1 channel activity. Purified ADA and normal human lung fibroblasts (NHLFs) were treated with solriamfetol to assess effects on ADA activity and levels of cAMP and adenosine, respectively. Results: Solriamfetol significantly reduced inflammatory cell infiltration, collagen accumulation, and α-SMA expression in fibrotic lungs. Solriamfetol restored downregulated A_2AAR, A_2BAR, ACs, and Epac, while suppressing ADA expression and activity, resulting in elevated extracellular adenosine and intracellular cAMP. The intervention potentiated Epac signaling and inhibited fibroblast activation. Solriamfetol inhibited the K_Ca3.1 current in fibroblasts and reduced K_Ca3.1 protein expression levels in TGFβ-treated fibroblasts and lung tissues from bleomycin-challenged mice. Notably, these effects were abolished by A_2AAR or A_2BAR antagonists, implying that they occur through AR-mediated pathways. Conclusions: Solriamfetol inhibits ADA and reinforces adenosine–cAMP signaling, suppressing pathological fibroblast activation. These findings suggest its therapeutic utility as a novel anti-fibrotic compound for various fibrotic diseases, including pulmonary fibrosis. Full article

Neuroinflammation is a key hallmark of both neurodegenerative and neurospecific autoimmune diseases, including multiple sclerosis (MS), where immune dysregulation contributes to cellular stress, autophagy, and disease progression in Alzheimer’s disease (AD), Parkinson’s disease (PD), and MS. Emerging evidence suggests a shared mechanism behind MS, AD, and PD, driven by chronic interaction between the peripheral immune system and the central nervous system (CNS). While MS was traditionally viewed as a primary autoimmune condition, recent research indicated that all three disorders involve a breakdown of the blood–brain barrier (BBB). This structural failure enables peripheral immune cells and cytokines to enter the brain, causing sustained neuroinflammation and accelerating disease progression. Here, we propose an end-to-end framework for identification of the diagnostic and therapeutic cell-specific protein markers commonly regulated in mild–moderate AD (MMAD), early-stage PD (ESPD), and MS within peripheral blood mononuclear cells (PBMCs). PBMC markers were first identified based on shared differential protein expression, followed by filtering for BBB permeability. Subsequently, sorted cell markers were mapped to disease-specific neural cell types. Our analysis suggests that PBMC-derived cells, including astrocyte- and monocyte-like populations, share overlapping transcriptional signatures and functional similarity with macrophages and neuroglial cells, indicating potential transcriptional similarity or functional convergence. Furthermore, intra- and inter-cellular pathway analysis suggested both shared and disease-specific signaling mechanisms, with kinase–integrin interactions emerging as key regulatory factors. Selected potential seed markers, primarily kinases and immunoglobulins, were further analyzed through evolutionary sequence–structure space to identify druggable structural features. Next, protein moonlighting possibilities were tested to enhance the temporal functional trajectory of the markers for precise therapeutic impact. Hence, the framework provides a robust strategy to identify immune-based disease-specificcandidate diagnostic andpotential therapeutic targets. Full article

Introduction: The uric acid-to-albumin ratio (UAR) is a novel cardiovascular biomarker, but its prognostic value in patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) remains unknown. Materials and Methods: This retrospective study enrolled 1513 consecutive patients who underwent successful CTO-PCI at a single center from February 2011 to December 2023. Patients were stratified by baseline UAR tertiles. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), and the secondary endpoint was all-cause mortality. Multivariable Cox regression and restricted cubic spline (RCS) analyses were performed. Results: During a median follow-up of 810 days, patients in the highest UAR tertile had significantly higher rates of MACCE (18.5%, 10.1%, and 7.5% across tertiles; p < 0.001) and all-cause mortality (10.7%, 3.8%, and 2.0%; p < 0.001). After multivariable adjustment, each one-unit increase in UAR was associated with a 6% higher risk of MACCE (HR 1.06; 95% CI 1.02–1.10; p = 0.002) and a 9% higher risk of all-cause mortality (HR 1.09; 95% CI 1.04–1.14; p < 0.001). Patients in the highest UAR tertile had significantly increased risks of MACCE (HR 1.90; 95% CI 1.25–2.90; p = 0.003) and all-cause mortality (HR 3.40; 95% CI 1.62–7.12; p = 0.001) compared with those in the lowest UAR tertile. RCS analysis showed significant overall associations between UAR and both MACCE and all-cause mortality, with no significant evidence of nonlinearity. Conclusions: Elevated baseline UAR was independently associated with long-term MACCE and all-cause mortality after successful CTO-PCI. These findings support UAR as a readily available prognostic marker but do not establish causality or support UAR-guided therapeutic decision-making. Prospective studies are needed for validation. Full article

This study elucidates the multi-targeted antineoplastic mechanisms of Parkia speciosa empty pod extract (PSET) against HCT-116 and HT-29 colorectal cancer (CRC) cells through integrated transcriptomic and proteomic analyses. Phytochemical profiling indicates that PSET is rich in bioactive metabolites, notably quercetin, rutin, and pyrogallol, which orchestrate its profound ability to inhibit tumor proliferation, migration, and invasion. Transcriptomic data revealed that PSET profoundly suppresses the oncogenic Wnt/β-catenin signaling axis while simultaneously activating p53-mediated cell cycle arrest. Complementary proteomic profiling uncovered critical metabolic vulnerabilities, demonstrating that PSET abrogates the Warburg effect by disrupting key glycolytic enzymes (e.g., ENO1, GAPDH, LDHA), thereby inducing metabolic starvation. Furthermore, the extract precipitated a catastrophic collapse of the cytoskeletal architecture and downregulated epithelial–mesenchymal transition (EMT) markers, effectively paralyzing the cells’ metastatic machinery. The integrated transcriptomic and proteomic signatures also highlighted an irrecoverable state of cellular stress, characterized by an overwhelming unfolded protein response and dysregulated RNA splicing, ultimately driving the cells toward apoptosis. In conclusion, this integrated omics approach provides robust molecular validation that PSET systemically dismantles colorectal cancer survival networks, highlighting its strong potential as a natural, multi-targeted therapeutic agent. Full article