The dipeptidyl peptidase (DPP) family comprises enzymes with important metabolic and immunomodulatory properties. This narrative review summarizes recent clinical and experimental evidence on the role of DPP-1, DPP-4, DPP-9, and DPP-10 in pulmonary diseases. The strongest translational evidence currently supports DPP-1 inhibition in non-cystic fibrosis bronchiectasis, where brensocatib reduces exacerbations and prolongs time to first exacerbation, with additional DPP-1 inhibitors in development. By contrast, the roles of DPP-4, DPP-9, and DPP-10 are supported mainly by preclinical studies in pulmonary hypertension, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pulmonary fibrosis, asthma, non-small cell lung cancer (NSCLC), and nonsteroidal anti-inflammatory drugs (NSAIDs)/aspirin-exacerbated respiratory disease. Across these models, DPP inhibition modulates inflammation, protease activation, epithelial or endothelial mesenchymal transition, extracellular matrix (ECM) remodeling, and related signaling pathways. Overall, DPP-targeted interventions are promising in pulmonary medicine, but broader clinical translation will require well-designed prospective trials.

Background/Objectives: Ribosome-inactivating proteins (RIPs) are plant-derived enzymes with potent cytotoxic activity, widely studied as anticancer agents, particularly as toxic payloads in immunoconjugates. Despite numerous encouraging results reported, their clinical application has been limited by their immunogenicity. RIPs from edible plants have been proposed as potentially more suitable candidates due to their possible improved tolerability. However, this aspect still requires validation in vivo in animal models. This study investigated the cytotoxic activity, mechanisms of action and translational potential of sodin 5 (a recently characterized type 1 RIP derived from the edible plant Salsola soda L.) in human colon cancer models, comparing it to the well-known type 1 RIP saporin-S6. Methods: The effects of sodin 5 and saporin-S6 on cell viability, cell death mechanisms and epithelial barrier integrity were assessed on HT29 and Caco-2 cell lines. Sodin 5 cross-reactivity with other anti-type 1 RIP sera was evaluated by ELISA. Finally, its structural characteristics were analyzed. Results: Sodin 5 showed a cytotoxic effect comparable to that of saporin-S6 in HT29 and Caco-2 colon cancer cells, with time- and concentration-dependent reductions in viability. Both type 1 RIPs disrupted the integrity of the intestinal epithelial barrier in mono- and co-culture models and predominantly activated the apoptotic pathway, without inducing necrosis. Sodin 5 exhibited limited immunological cross-reactivity and a conserved catalytic core, supporting its potential relevance as a therapeutic payload for intestinal cancer therapy. Conclusions: Our results indicate that sodin 5 possesses promising characteristics for anticancer applications, particularly in the treatment of intestinal malignancies, where local exposure and repeated administration are often required.

Sarcopenia is an age-related skeletal muscle disorder characterized by reduced muscle mass, strength, and physical performance, as well as increased risk of disability, hospitalization, and mortality. Emerging evidence suggests that gut microbiota alterations may contribute to muscle decline via a microbiota–gut–muscle axis, acting as a context-dependent modulator rather than a primary causal driver. This narrative review synthesizes mechanistic, clinical, and translational evidence linking gut dysbiosis to sarcopenia. Preclinical studies show that microbiota modulation (e.g., antibiotics, probiotics, prebiotics, postbiotics, fecal microbiota transplantation) affects muscle mass, strength, and metabolism through pathways including inflammation, mitochondrial dysfunction, altered short-chain fatty acid production, and impaired anabolic signaling. In humans, observational studies associate lower microbial diversity and reduced short-chain fatty acid-producing taxa with poorer muscle outcomes, but findings are heterogeneous and non-causal. Interventional trials remain limited and characterized by small sample sizes, with effects more consistent for functional outcomes than muscle mass. Overall, the gut microbiota represents a modifiable contributor within the complex biology of sarcopenia. Future studies should integrate microbiome profiling and multi-omics approaches within well-designed clinical trials to identify responder phenotypes and define the role of microbiota-targeted strategies within multimodal interventions.

Background: The early detection of prostate and testicular tumors remains challenging as standard diagnostic tools often lack sensitivity and produce ambiguous results. Seminal fluid is a biologically rich medium that closely reflects the state of male reproductive tissues and has therefore emerged as a promising source of non-invasive molecular biomarkers. Objective: This study aimed to critically evaluate the evidence regarding cell-free DNA, RNA, proteins and metabolites in seminal fluid, and to assess their potential for improving the early detection of male reproductive cancers. Methods: A systematic review was performed according to PRISMA guidelines. Comprehensive searches of the PubMed and Scopus databases were conducted to identify original clinical studies analyzing molecular biomarkers in seminal fluid from patients with prostate or testicular tumors. For each study, data were extracted on biomarker types, cohort characteristics, analytical methods and diagnostic performance. Results: Forty-two eligible studies were included, covering multiple biomarker classes. Most were observational, single-center investigations classified as level 3b evidence. Across the different types of biomarkers, seminal fluid was associated with tumor-associated molecular changes. Alterations in the concentration, fragmentation and methylation patterns of cell-free DNA (e.g., GSTP1, RARβ2, LGALS3 and OCT3/4) distinguished malignant from benign conditions with sensitivities of up to 80–100%. RNA-based markers, including microRNAs, small non-coding RNAs, and tRNA fragments, showed improved performance in several studies, with multimarker models achieving areas under the curve (AUCs) of 0.85–0.93. Proteomic analyses identified high-specificity candidates such as TGM4, AMACR, PROS1 and DKK3. Metabolomic profiling further strengthened the diagnostic potential; reduced seminal citrate outperformed prostate-specific antigen (AUC 0.748 vs. 0.548), and reproducible shifts in amino acid and lipid profiles were observed in testicular tumors. However, substantial heterogeneity in study design, patient selection, and analytical platforms was observed. Risk of bias varied, and large prospective validation cohorts were lacking. Conclusions: Current evidence suggests that seminal fluid contains molecular signals associated with tumors that could be used for diagnosis. However, the available data are predominantly exploratory and methodologically heterogeneous. Before seminal fluid-based biomarkers can be considered for routine clinical implementation, robust prospective studies with standardized protocols are required.

Microbiome-based therapies are reshaping the therapeutic landscape for ulcerative colitis (UC), offering new avenues for disease management beyond conventional immunomodulatory and biologic treatments. UC remains a chronic, relapsing condition with significant unmet clinical needs, as many patients fail to achieve sustained remission or experience adverse effects with current therapies. The gut microbiome has emerged as a central contributor to UC pathogenesis, influencing epithelial barrier integrity, immune homeostasis, and metabolic signaling. Interventions such as fecal microbiota transplantation (FMT) and defined microbial consortia have demonstrated proof-of-concept efficacy in early-phase clinical trials, each leveraging distinct mechanistic strategies. FMT, as a broad ecological intervention, restores microbial diversity and functional redundancy, potentially addressing multiple pathogenic mechanisms simultaneously. In contrast, defined consortia enable precise targeting of specific metabolic and immunological pathways, including short-chain fatty acid production, bile-acid remodeling, epithelial barrier reinforcement, immune modulation, and succinate degradation. Recent clinical evidence suggests that consortia with broader mechanistic coverage may achieve more consistent biological activity than narrowly focused designs. This review synthesizes mechanistic and clinical insights across broad and defined microbial consortia, integrates evidence from randomized controlled trials and early-phase LBP studies, and outlines a precision-medicine framework to guide therapy selection. We highlight the importance of aligning therapeutic mechanisms with patient-specific microbial, metabolic, and immune profiles, and discuss future directions including biomarker-guided stratification, hybrid consortia, and adaptive trial designs. Advancing both broad and defined approaches, while incorporating ecological principles, mechanistic understanding, and patient stratification, will be essential to realizing the full therapeutic potential of microbiome-based therapies in UC.

Background/Objectives: CDKL5 deficiency disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy characterized by early onset refractory epilepsy and severe neurodevelopmental impairment with autistic features. Despite advances in genetic diagnosis, objective biomarkers reflecting disease mechanisms remain limited. Extracellular vesicles (EVs) circulating in the blood may contain disease-related proteins derived from the central nervous system. This study aimed to characterize the plasma EV proteome in CDD in a hypothesis-generating exploratory framework and identify the candidate molecular pathways associated with this disorder. Methods: Plasma samples from seven patients with genetically confirmed CDD and seven neurotypical developmental controls were analyzed. Extracellular vesicle-containing preparations (EVs-cp) were isolated via immunoprecipitation using antibodies against CD9, CD63, and CD81. Proteomic profiling was performed using data-independent mass spectrometry. Differentially expressed proteins were identified using Welch’s t-test with a false discovery rate correction. Functional enrichment, protein interaction network, and correlation analyses were performed using CDKL5 Clinical Severity Assessment (CCSA) scores. Results: In total, 5617 proteins were identified, of which 3510 were used for quantitative analysis. Compared to the controls, 2108 proteins were upregulated and 158 were downregulated in the CDD samples. Enrichment analysis revealed alterations in vesicle-mediated transport, cytoskeletal organization, and immune-related pathways. Several proteins were also correlated with clinical severity scores. Conclusions: Plasma EV proteomics revealed molecular alterations associated with CDD and provided a potential approach for biomarker discovery and mechanistic investigation.

Background: Translocation morphology renal cell carcinoma (tRCC) accounts for nearly half of all pediatric RCC cases. Biological study AREN14B4-Q aimed to characterize the molecular landscape of tRCC using samples acquired from patients enrolled in the Children’s Oncology Group Risk Classification and Biobanking study AREN03B2. Methods: From 2006 to 2014, patients <30 yr old with renal tumors were prospectively enrolled in AREN03B2, a Central IRB-approved biobanking study. All pediatric RCC cases underwent a detailed central pathology review and molecular diagnostics to accurately classify RCC subtypes. Samples with confirmed tRCC and appropriate informed consent were identified with adequate tissue for RNA and DNA extraction, along with germline DNA, for whole-genome sequencing (WGS), RNA sequencing, and DNA methylation analyses. Results: From 41 patients, high-quality samples allowed for 18 tumors and non-tumor DNA to be analyzed via WGS, 19 via DNA methylation, and 36 RNA samples via transcriptome sequencing. Consistent with and extending clinical cytogenetic findings, WGS and fusion transcript analyses confirmed very few additional mutations beyond the tRCC translocation. No recurrent genomic copy number gains/losses were found. RNA and WGS analyses enabled sub-classification of tRCC, closely aligning with the different TFE3 fusion partners. DNA methylation analyses demonstrated less tRCC sub-stratification compared with RNA analyses. Pathways activated in tRCC were involved in epithelial differentiation, extracellular matrix organization, apoptosis, immune regulation, signal transduction, and angiogenesis. Conclusions: Arrested epithelial differentiation is the overarching driver in tRCC and is strongly correlated with the specific subclasses of fusion transcript generated by the genetic translocation TFE fusion partner. Negative regulation of apoptosis, increased M2 macrophage expression, and enhanced angiogenesis also appear to be functional features of tRCCs, as are increased expression of matrix metalloproteinases, PI3K-AKT/mTOR/MAPK signaling, and mitochondrial metabolism, highlighting potential therapeutic options beyond direct targeting of the oncogenic driver fusions.

Objectives: Complex regional pain syndrome (CRPS) is a heterogeneous pain disorder with incompletely understood immunoinflammatory features. This study investigated whether autonomic receptor autoantibodies differentiate CRPS from other chronic pain conditions and healthy controls. Methods: We conducted a cross-sectional analysis of serum samples from patients referred with suspected CRPS. Patients were subsequently classified as having either CRPS or another chronic pain condition, based on the Budapest criteria. Healthy controls were included for comparison. Serum levels of autoantibodies targeting the muscarinic M2 receptor (M2R), β1-adrenergic receptor (β1AR), and the β2-adrenergic receptor (β2AR) were assessed using enzyme-linked immunosorbent assay. All analyses were performed blinded to group assignment. Results: Seventy participants were analyzed (CRPS = 22, other chronic pain = 25, healthy controls = 23). M2R autoantibody levels were higher in both CRPS and other chronic pain compared with healthy controls (mean difference [MD] = 0.37, 95%CI 0.22-0.51; and MD = 0.31 95%CI 0.19-0.44, respectively). β2AR levels were higher in other chronic pain compared with healthy controls (MD = 0.29, 95%CI 0.04-0.54), whereas no significant difference was observed in CRPS (MD = 0.21 95%CI -0.01-0.42). No meaningful differences were observed between CRPS and other chronic pain for any receptor. β1AR levels did not differ between groups. Seropositivity for any autoantibody was 55% in CRPS, 44% in other chronic pain, and 22% in healthy controls. Conclusions: Elevated autonomic receptor autoantibody levels were observed across chronic pain conditions but were not specific for CRPS.

Background: Bone metastasis is a major determinant of morbidity and therapeutic failure in advanced prostate cancer (PCa); however, the transcriptional programs and tumor microenvironmental alterations driving metastatic progression remain incompletely understood. This study aimed to systematically characterize transcriptomic differences between non-metastatic and bone-metastatic PCa and to identify key microenvironmental signaling pathways involved in tumor survival and chemoresistance. Methods: Bulk RNA sequencing was performed on 49 non-metastatic and 28 bone-metastatic PCa specimens. Differential expression analysis was integrated with weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis, and immune/stromal deconvolution. Key findings were validated using in vitro functional assays, including Transwell co-culture models, small interfering RNA (siRNA)-mediated gene silencing, cell viability, apoptosis, and docetaxel resistance analyses. Results: Transcriptomic profiling identified 574 differentially expressed genes. Bone-metastatic tumors were enriched in ribosome-related and translational pathways, whereas non-metastatic tumors displayed immune-associated signatures, including natural killer (NK) cell-mediated cytotoxicity and cytokine signaling. WGCNA revealed immune-related gene modules preferentially enriched in non-metastatic disease. Immune deconvolution demonstrated significantly higher infiltration of NK cells and endothelial cells in non-metastatic tumors. Chemokine-receptor analysis highlighted upregulation of the CXCL10-CXCR3 axis in non-metastatic PCa. In vitro, PCa cells expressed CXCR3, while endothelial cells markedly increased CXCL10 expression upon co-culture. Functional assays showed that endothelial-derived CXCL10 promoted PCa cell survival, suppressed apoptosis, and conferred resistance to docetaxel via CXCR3-dependent signaling; these effects were reversed by CXCL10 or CXCR3 knockdown. Conclusions: These findings uncover a context-dependent endothelial-immune chemokine network distinguishing non-metastatic from bone-metastatic PCa and identify the CXCL10-CXCR3 axis as a critical mediator of tumor survival and chemoresistance, suggesting a potential therapeutic vulnerability in advanced prostate cancer.

Background/Objectives: Non-variceal upper gastrointestinal bleeding (NVUGIB) remains a major clinical emergency, particularly among patients receiving antiplatelet or anticoagulant therapy, whose use has increased substantially in recent years. This study aimed to evaluate the clinical characteristics, endoscopic findings, risk stratification, and outcomes of NVUGIB in patients receiving antithrombotic therapy, and to compare the predictive performance of commonly used prognostic scores. Methods: This prospective cohort study included 89 patients receiving antithrombotic therapy who presented with NVUGIB at Beni-Suef University Hospitals between March 2023 and March 2025. Clinical presentation, laboratory findings, and endoscopic characteristics were recorded. Risk stratification was assessed using Glasgow-Blatchford (GBS), Rockall, Baylor, AIMS65, ABC, and PNED scores. The optimal cut-off values for prediction of rebleeding and mortality were determined using receiver operating characteristic (ROC) analysis and the Youden index. Area under the curve (AUC) values were reported with 95% confidence intervals. Results: Endoscopy revealed that peptic ulcers were the most common lesion (41/89, 46%), followed by erosive disease (27/89, 30%), with the stomach being the most frequently involved site (76.5%). Rebleeding occurred in 16 patients (18.0%), while mortality was observed in 2 patients (2.2%). The Glasgow-Blatchford score demonstrated the most consistent performance for predicting rebleeding, with an optimal cutoff value of 5.5 (derived using the Youden index), yielding 92.9% sensitivity and 78.8% specificity. For mortality prediction, AIMS65, ABC, and PNED scores showed very high AUC values, although these findings should be interpreted cautiously due to the small number of mortality events (n = 2). No statistically significant difference in rebleeding or mortality was observed between single and dual antithrombotic therapy, although patients receiving dual therapy required longer hospitalization and more transfusion units. Conclusions: In patients with antithrombotic-related GI bleeding, ulcers and erosions predominate, with minimal differences between single and dual therapy outcomes. Concomitant NSAID use trends toward higher mortality. Glasgow-Blatchford score offers optimal performance for both rebleeding and mortality prediction, with a cutoff of 5.5 providing excellent sensitivity (92.9%) and specificity (78.8%) for rebleeding risk assessment.