Search Results (24,334)

Background: The potent topoisomerase I inhibitor SN-38, the active metabolite of irinotecan, is limited in clinical application due to severe systemic toxicity. Prodrug strategies enabling selective activation in the tumor microenvironment offer a promising approach to improve its therapeutic index. This study aims to rationally design, synthesize, and systematically evaluate novel disulfide-based SN-38 prodrugs engineered for redox-responsive activation in hypoxic tumors. Methods: Two novel disulfide-based SN-38 prodrugs (SN-38-CSS and SN-38-LSS) were designed and synthesized; SN-38-CSS incorporates a constrained cis-piperazine-fused six-membered cyclic disulfide linker, while SN-38-LSS contains a linear disulfide tether, to differentially exploit the upregulated thioredoxin (Trx/TrxR) system in hypoxic tumor microenvironments. Results: Both prodrugs demonstrated high stability under physiological pH conditions and in human plasma, minimizing premature release. Crucially, they exhibited selective, rapid degradation in the presence of dithiol reductants (TCEP and DTT), mimicking Trx system activity, while remaining stable towards monothiols (GSH, L-Cys). In vitro cytotoxicity assays revealed that the prodrugs exhibited significantly reduced toxicity compared to SN-38 under normoxic conditions across most tested cell lines. However, under hypoxic conditions, their activity was significantly restored. Specifically, SN-38-CSS exhibited cytotoxicity comparable to SN-38 against MCF-7 and NCI-N87 cells, whereas SN-38-LSS showed lower activation efficiency. Conclusions: SN-38-CSS is identified as a promising redox and hypoxia dual-responsive prodrug candidate, highlighting the strategic use of cyclic disulfide linkers for achieving high selectivity and controlled drug release within the tumor microenvironment. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes and obesity, yet their actions extend beyond glycemic control and weight loss. This narrative review synthesizes current preclinical and clinical evidence examining the bidirectional relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and circadian biology. A structured literature search was conducted in PubMed using combinations of the terms ‘GLP-1,’ ‘circadian,’ ‘chronobiology,’ ‘sleep,’ ‘obesity,’ and ‘type 2 diabetes’ through January 2026. Accumulating evidence indicates that GLP-1 physiology is closely coupled to circadian timing systems and sleep–wake regulation. In this narrative review, we synthesize emerging data that reframe GLP-1RAs as chronometabolic modulators, acting at the intersection of metabolism, circadian biology, and sleep. We review circadian control of GLP-1 secretion by intestinal L-cells, emphasizing the role of core clock genes and the vulnerability of incretin rhythms to circadian misalignment from shift work, nocturnal light exposure, and sleep loss. We then examine GLP-1 receptor signaling within central and peripheral clock networks, including feedback effects on hypothalamic and hepatic circadian regulation. Emerging data suggest that GLP-1 signaling is under circadian regulation and may, in turn, influence central and peripheral clock systems. Comparative discussion of semaglutide, liraglutide, and tirzepatide highlights agent-specific pharmacokinetics and emerging clinical data linking GLP-1RA therapy to sleep outcomes, particularly obstructive sleep apnea. Finally, we outline translational opportunities for chronotherapy and precision medicine, positioning GLP-1RAs as integrative tools for metabolic and sleep-related disease rather than purely weight-centric therapies. We propose that GLP-1 receptor agonists may function as chronometabolic modulators, with potential implications for personalized chronopharmacological strategies in metabolic disease. Full article

Hyperuricemia, a common metabolic disorder characterized by elevated serum uric acid (UA) levels, can lead to severe complications such as gout and renal impairment. Conventional therapies, while effective, are frequently accompanied by significant adverse effects, underscoring the urgent need for safer therapeutic alternatives. Recent evidence identifies the intestine as a novel, pivotal regulator of UA homeostasis, presenting a promising therapeutic axis. This review delineates the intestinal mechanisms governing UA regulation and evaluates the therapeutic potential of natural active substances that target these pathways. We conducted a comprehensive review of recent preclinical studies focusing on intestinal mechanisms involved in UA metabolism, including the roles of gut microbiota, urate transport proteins, intestinal barrier function, and inflammation. Studies evaluating natural active substances—such as polyphenols, polysaccharides, peptides, and plant extracts—were systematically analyzed for their effects on gut-mediated UA regulation. Natural active substances have been shown to effectively alleviate hyperuricemia by modulating gut microbiota, enhancing UA intestinal excretion, reinforcing intestinal barrier function, and suppressing inflammatory pathways. Collectively, these findings demonstrate the multi-target efficacy of natural active substances within the intestines, offering a promising therapeutic strategy that warrants further investigation into nutrition-based intestinal interventions and novel pharmacological treatments for hyperuricemia. Full article

Lactic acid bacteria (LABs) produce bacteriocins, which are increasingly recognized as effective biopreservatives for smoked salmon. These bacteriocins may help solve the ongoing problem of controlling Listeria monocytogenes in the smoked salmon industry. L. monocytogenes is a psychrotolerant, salt-tolerant foodborne pathogen capable of surviving the refrigerated, low-oxygen conditions typical of smoked salmon processing. Its presence poses significant public health risks, particularly for immunocompromised individuals, and continues to drive costly product recalls and regulatory pressure. Conventional control strategies, including chemical preservatives and physical treatments, are increasingly limited by consumer demand for clean-label foods and the pathogen’s ability to persist in processing environments. The bacteriocins produced by LABs provide a precise and natural alternative to conventional preservatives. These antimicrobial peptides can inhibit L. monocytogenes through membrane disruption and metabolic interference while maintaining the sensory quality of smoked salmon. Their application in surface treatments, protective coatings, and active packaging has demonstrated strong potential to suppress pathogen growth during chilled storage. As the smoked salmon industry is seeking sustainable and effective biocontrol tools, bacteriocins represent a viable strategy to enhance product safety, extend shelf life, and reduce reliance on synthetic additives. Continued research into their stability, delivery systems, and synergistic combinations will be essential for integrating bacteriocins into modern smoked salmon preservation frameworks. Full article

Neuropeptides regulate diverse physiological and behavioural processes in parasites, yet their functional roles in the infective larval stages of Schistosoma mansoni remain poorly defined. In this study, we identified miracidia-derived putative neuropeptides and examined their roles in regulating miracidial behaviour. Peptidomic analysis revealed ten putative neuropeptides, including five whose proteomic identification in this life stage was previously unreported. Neuropeptide precursor proteins were evaluated for stage-specific expression and Schistosoma genus specificity to prioritise candidates with potential functional and biocontrol relevance. Protein–protein interaction analysis identified Smp_176700 as a highly connected neuropeptide precursor associated with proteins implicated in miracidial structure and infection. Eight putative neuropeptides derived from six precursor proteins were synthesised and externally applied to miracidia in acute (1 min) and prolonged (360 min) behavioural assays. During acute exposure, most peptides induced significant concentration-dependent behavioural changes at 3 mg/mL and 0.1 mg/mL, characterised by reduced swimming velocity and increased directional change, with no significant effects at 0.01 mg/mL. Prolonged exposure revealed peptide-specific effects, with ASLSYF-OH and FLLGLPPSLRQH-OH producing the most pronounced behavioural modulation. These findings demonstrate that S. mansoni miracidia express bioactive neuropeptides capable of modulating larval behaviour, providing insight into schistosome neurobiology and identifying potential targets for transmission-blocking interventions. Full article

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for more deaths than any other malignancy. Despite advances in treatment, it remains highly lethal, with 5-year survival rates showing minimal improvement over the past several decades, highlighting a critical unmet clinical need. Macrophage Migration Inhibitory Factor (MIF) is a multifunctional cytokine that contributes to inflammation and cancer, promoting tumor growth, progression, and metastasis through modulation of the tumor microenvironment, stimulation of angiogenesis, and regulation of immune responses. Polymorphisms in the promoter region of MIF, such as high-expression CATT repeats, influence MIF expression and susceptibility to a range of inflammatory, autoimmune, and malignant disorders, yet their role in lung cancer remains largely unexplored. Therapeutic strategies targeting MIF, including small-molecule inhibitors, antibodies, and peptide-based agents, have shown promise in preclinical models, although their clinical translation is still limited. This review discusses the dual role of MIF in inflammation and oncology, summarizes current therapeutic developments, and emphasizes the potential of MIF-targeted interventions in lung cancer. It discusses the significance of genetic predisposition, particularly high-expression MIF alleles, in guiding personalized treatment strategies for lung cancer and identifying patients who may derive benefit from MIF inhibition. Full article

Objective: CIGB-258 is a 3 KDa altered peptide ligand recognized for its anti-inflammatory activity. Herein, the effect of CIGB-258 was assessed against carboxymethyllysine (CML) and ethanol (Et-OH)-induced sepsis-like events in zebrafish (Danio rerio). Methodology: Adult zebrafish (n = 30/group) were intraperitoneally microinjected (10 μL) with CML (final 3 mM) + Et-OH (final 50%) or CML + Et-OH containing CIGB-258 (final 1 μM) and analyzed for swimming activity, abdominal bleeding and survivability. The zebrafish were sacrificed 180 min after injection, and blood and organs were processed for biochemical and histological evaluation. Results: The CML + Et-OH group showed the lowest survival, compromised swimming ability, and severe abdominal bleeding 60 min post-treatment, which were substantially improved by treatment with CIGB-258. The CML + Et-OH group showed the greatest extent of oxidization and the lowest antioxidant activity in plasma, while co-treatment with CIGB-258 resulted in a remarkable improvement in oxidative extent and antioxidant status. The CML + Et-OH group showed dyslipidemia and an atherogenic lipid profile, which were substantially prevented by the CIGB-258 treatment. The livers and kidneys of the CML + Et-OH group showed the greatest extent of inflammation and senescence, which were substantially ameliorated by treatment with CIGB-258. Similarly, the CML + Et-OH group exhibited severe intestinal bleeding, which decreased 2.2-fold following treatment with CIGB-258. H&E staining and Mason-trichrome staining revealed extreme disruption to intestinal microvillus cell morphology and severe fibrosis in the intestines of the CML + Et-OH group, which effects were mitigated by the treatment with CIGB-258. Conclusions: The CML + Et-OH treatment resulted in acute gastrointestinal bleeding, severe oxidative stress, and hepatic and renal damage, leading to acute septic shock-like death in zebrafish. However, treatment with CIGB-258 reduced these effects through antioxidant and anti-inflammatory actions and by increasing HDL-C levels. Full article

Widespread, sometimes careless use of antibiotics has accelerated the rise and spread of antibiotic-resistant pathogens. These resistant bacteria are now often found in animal-based foods like meat, milk, and eggs, as well as in plant-based foods such as fruits and vegetables. Contaminated food is a key way these bacteria travel through the food chain and eventually reach people. This review brings together global trends in antibiotic contamination, explains the molecular mechanisms underlying antimicrobial resistance, and examines current approaches to addressing this problem. It also highlights new technologies that could work alongside or improve on traditional antibiotics. Some promising options are antimicrobial peptides, natural bioactive compounds, nanomaterials, and monoclonal antibody-based therapies. Tackling antimicrobial resistance requires teamwork across fields such as microbiology, food science, pharmacology, environmental science, and public health. Future research should strengthen global surveillance, standardize resistance-assessment methods, expand studies on non-bacterial pathogens, and ensure rigorous evaluation of novel therapies for pharmacokinetics, toxicity, scalability, and regulatory compliance. Ongoing global cooperation and new scientific ideas are crucial to slow the spread of resistant microbes and protect food safety and human health. Full article

Functional seafoods derived from marine organisms, including fish, shellfish and algae, are gaining increasing attention due to their high content of bioactive compounds, such as omega-3 fatty acids, peptides, polysaccharides and antioxidants, which provide health benefits beyond basic nutrition. These marine-derived compounds exhibit a wide range of biological activities and have been investigated for their potential roles in the prevention and management of chronic diseases, including cardiovascular, neurodegenerative, cancer and gastrointestinal disorders. Their effects are largely mediated through anti-inflammatory, antioxidant and immunomodulatory mechanisms. Advances in biotechnology, including genetic engineering and improved extraction of bioactive compounds, have enhanced the nutritional quality and pharmacological relevance of functional seafoods. At the same time, sustainable aquaculture practices are being developed to reduce environmental impacts. Nevertheless, challenges such as regulatory inconsistencies, scalability issues and limited understanding of bioavailability and long-term effects still persist. These constraints should be considered when interpreting mechanistic and efficacy findings presented across different study designs and exposure conditions. Future perspectives highlight innovations in precision aquaculture, waste valorisation and traceability as key strategies to improve sustainability and strengthen consumer trust. This review summarizes current knowledge on functional seafoods, with emphasis on pharmacological mechanisms, clinical applications and the need for interdisciplinary research to optimize their health benefits and commercial potential. Full article

The gut–skin axis is increasingly implicated in psoriasis pathogenesis, yet the cross-compartment convergence of molecular programs remains incompletely defined. We constructed a conceptual “Triple-Hit” multi-omics framework by integrating five independent public datasets spanning gut microbial functional remodeling (shotgun metagenomics), systemic immune cell methylomes (PBMC and CD8+ T-cell EPIC 850K), and lesional skin regulatory layers (miRNA and bulk RNA-seq). In the gut compartment, functional profiles exhibited a selective reduction in microbial lipid catabolic potential, including decreased fatty acid degradation and a lowered composite lipid degradation score, alongside heterogeneous shifts across SCFA-associated metabolic pathways. Systemically, PBMC methylomes revealed widespread regional remodeling (45,396 DMRs) enriched for membrane-proximal signaling and cytoskeletal programs, while CD8+ T cells showed specific epigenetic alterations in lipid- and glycosphingolipid-associated loci, suggesting a systemic metabolic–epigenetic alignment. In the skin, we identified a compact miRNA signature (168 DE-miRNAs) and a mechanistically interpretable, directionality-constrained miRNA–mRNA bridge that aligns with an AMP-dominant inflammatory transcriptome, consistent with reduced post-transcriptional restraint. Collectively, these findings support a convergent multi-omics framework linking putative microbial metabolic remodeling, systemic immune priming, and cutaneous effector programs. This study provides a systems-level perspective on psoriasis pathogenesis, highlighting the metabolic–epigenetic–transcriptional convergence as a potential avenue for therapeutic intervention. Full article

Background/Objectives: Multidrug-resistant (MDR) Acinetobacter baumannii (Ab) has emerged as a significant bacterial pathogen responsible for nosocomial infections. The most common clinical manifestations of Ab infection include ventilator-associated pneumonia and catheter-related bloodstream/urinary infections. Given the extensive MDR phenotype of Ab, preventive vaccination strategies are crucial for protecting susceptible populations. Methods: We utilized immunoinformatics to identify candidate peptides containing both putative B- and T-cell epitopes from proteins associated with Ab pathogenesis. Subsequently, we designed novel Acinetobacter Multi-Epitope Vaccines (AMEVs), each comprising an Ab thioredoxin A (TrxA) leader protein, five to seven of the identified peptide antigens, and a C-terminal His(6x)-tag to facilitate protein purification. Results: Subcutaneous vaccination of C57BL/6 mice with AMEV1 or AMEV2, formulated with TiterMax adjuvant, conferred 60% and 80% protection, respectively, against intraperitoneal Ab challenge. AMEV vaccination induced a robust antibody response to each corresponding whole protein and most of its component peptides. We then constructed an improved vaccine, AMEV5, which included the Ab TrxA protein and seven confirmed B-cell epitope peptides. Subcutaneous immunization of BALB/c mice (n = 10 per group) with rAMEV5 emulsified in Adda03 adjuvant activated antigen-specific IL-5-secreting T cells and antibody-producing B cells. Evaluation of vaccine efficacy demonstrated that AMEV2- and AMEV5-immunized mice were protected from a lethal intraperitoneal Ab challenge, with survival rates of 70% and 90%, respectively. Conclusions: These study results provide insights into the application of reverse vaccinology to combat the rise of MDR Acinetobacter infection. Full article

The health risks associated with excessive alcohol consumption have emerged as a public health challenge, with alcohol-associated liver disease (ALD) and hyperuricemia (HUA) being particularly prominent health issues. Current treatments often have side effects, driving the need for safe, multi-target natural alternatives. Based on the dual barrier strategy of “metabolic regulation–antioxidant defense”, this study developed bioactive peptides from corn germ meal via enzymatic hydrolysis, which simultaneously activated alcohol dehydrogenase (ADH), inhibited xanthine oxidase (XOD), and exhibited antioxidative properties. The fraction <3 kDa emerged with stronger triple bioactivity while also demonstrating sensitivity to strong acids and enhanced activity under trypsin treatment in in vitro stability tests. A total of 841 unique peptides were obtained from purified peptide fractions. After computer-aided screening and molecular docking, three corn-derived peptides (LMFP, FEGLFR, and QLPSYR) were identified, which acted synergistically. Docking simulations revealed that they bind to ADH and XOD via hydrogen bonds and hydrophobic interactions, suggesting potential interactions with these enzymes that may influence their activity. The corn-derived bioactive peptides developed in this study may serve as potential resources for alleviating alcohol metabolism and hyperuricemia symptoms. Full article

Bladder cancer (BCa) is a major global urinary tract malignancy characterized by high incidence, frequent recurrence, and significant mortality. Early diagnosis is crucial for improving prognosis and minimizing invasive procedures; however, current standard techniques, cystoscopy and urine cytology, are limited by invasiveness, cost, low sensitivity, and subjectivity. This has spurred the development of non-invasive diagnostic strategies based on urine analysis. This review highlights five emerging approaches: AI-augmented urine cytology, genomic biomarker assays (e.g., PCR and NGS for mutations and copy-number variations), DNA methylation profiling, RNA biomarkers (mRNA, miRNA, lncRNA), and protein/peptide/metabolite detection utilizing ELISA, SERS, nanozymes, and mass spectrometry. We assess the diagnostic accuracy, innovations, and clinical potential of each, while addressing persisting issues such as lack of standardization, high costs, and insufficient sensitivity for early-stage lesions. Future directions include integrating multi-omics data with AI, advancing point-of-care devices, and conducting large-scale multicenter trials. Together, these developments promise to shift BCa management toward molecular-based early detection, enabling more precise, non-invasive, and personalized patient care. Full article

Background: Trastuzumab is a blockbuster monoclonal antibody that has revolutionized the treatment of HER2-positive breast and gastric cancers. With the increasing availability of biosimilar monoclonal antibodies in clinical practice, independent verification of biosimilarity using products sampled from a real-world supply chain is important to assure clinicians and the patients to use these products confidently. Objective: The aim of this study is to assess the biosimilarity of AryoTrust, a trastuzumab biosimilar, in comparison with the reference product Herceptin. AryoTrust and Herceptin products were randomly withdrawn from Iraqi hospitals to reflect medicines administered in real clinical settings. Methods: AryoTrust and Herceptin were compared using an extensive set of orthogonal analytical techniques which included SDS-PAGE, ion-exchange chromatography, capillary isoelectric focusing, peptide mapping, N-glycan profiling, circular dichroism, differential scanning calorimetry, and surface plasmon resonance. In addition to these teste, functional comparability was also tested using an HER2-dependent cell-based proliferation inhibition bioassay. Results: The results showed that both products have highly comparable profiles in all assessed attributes. The analysis showed similar molecular integrity and purity, identical primary structure, comparable charge heterogeneity, similar isoelectric points (pI) of the main isoform, close glycosylation patterns (mainly, by core-fucosylated complex-type glycans), similar higher-order structural features, and thermal stability. The receptor binding studies exhibited comparable binding affinities with Fcγ receptors and FcRn. Finally, the cell-based bioassay revealed comparable dose–response curves with similar EC₅₀ values and relative potency. Conclusions: The integrated analytical and functional data support the biosimilarity of AryoTrust to the reference product Herceptin, which has been marketed and used in Iraq. This study provides real-world scientific evidence supporting confidence in the quality and comparability of this trastuzumab biosimilar and reduces any doubt in the product and at the same time emphasizes the value of independent post-marketing biosimilarity assessments. Full article

Background: Tumor neoantigens are key targets for personalized vaccines and T-cell therapies, yet most pipelines focus on neoantigens derived from SNV/small indel and often yield a limited number of high-quality candidates. SVs are prevalent in tumors and can generate novel chimeric sequences and neopeptides, making them a promising additional source of neoantigens. However, SV-derived neoantigen prediction remains challenging due to breakpoint uncertainty, isoform-dependent coding inference, and limited integration of multi-dimensional evidence and reproducibility. Methods: We developed SVNeoPP (Structural Variant Neoantigen Prediction and Prioritization), an end-to-end workflow for SV-derived neoantigen analysis. SVNeoPP takes WGS and RNA-seq as inputs, performs SV calling and annotation, and reconstructs altered transcripts and coding sequences in a traceable, isoform-aware manner to generate candidate peptides. Candidates are prescreened by integrating antigen-processing features with HLA binding prediction, and then hierarchically filtered and prioritized based on transcript expression, LC–MS/MS proteomics evidence, immunogenicity predictions, and sequence similarity to experimentally validated neoantigen databases. SVNeoPP is implemented in Snakemake to enable modular extension, checkpoint-based restarts, and end-to-end reproducibility. Results: Using a hepatocellular carcinoma (HCC) multi-omics dataset as a proof of concept, we demonstrated the performance of SVNeoPP and obtained a high-priority shortlist of candidate peptides. Compared with other methods, SVNeoPP substantially expanded the candidate search space for SV-derived neoantigens and showed more favorable distributions of antigen-processing and HLA binding features. Conclusions: SVNeoPP provides a reusable, traceable, and interpretable multi-dimensional evidence-driven framework for SV-derived neoantigens. As a complementary module to SNV/small-indel pipelines, it broadens the neoantigen candidate repertoire and generates ranked candidates with interpretable evidence to facilitate downstream prioritization and decision-making. Full article