Search Results (4,441)

Background: We aimed to explore the mechanism by which extracellular-5′-nucleotidase (NT5E) regulates macrophage polarization via regenerating islet-derived protein 3 beta (Reg3β) and other plasma proteins that mediate immune-cell effects on myocarditis. Methods: The involvement of NT5E in Reg3β-induced macrophage polarization was first analyzed using RNA sequencing, Western blotting, and quantitative polymerase chain reaction. Mendelian randomization was employed to identify NT5E and various plasma proteins as potential therapeutic targets for myocarditis. Mediation analysis, enrichment analysis, protein–protein interaction network analysis, drug prediction, molecular docking, and single-cell RNA sequencing were integrated to further evaluate the biological functions and pharmacological potential of the identified targets. Finally, phenome-wide association studies were conducted to assess the safety of targeting these proteins. Results: NT5E expression was elevated in Reg3β-stimulated M2 macrophages. The expression of Arg-1, a marker of M2 macrophages, decreased upon NT5E knockdown, suggesting that NT5E is involved in the Reg3β-mediated polarization of macrophages to the M2 phenotype. Mendelian randomization analysis identified NT5E and 80 other plasma proteins as being causally associated with myocarditis. Mediation analysis revealed 12 immune-cell types were mediators of the effects of plasma protein on myocarditis progression. Drug prediction identified candidates such as ICN 1229 and chrysin, which showed strong binding affinities in molecular docking analyses. These findings may contribute to the development of effective treatments for myocarditis. Conclusions: NT5E plays a dual role in Reg3β-induced macrophage polarization and in interacting with plasma proteins that influence the onset and progression of myocarditis through immune-cell pathways. Full article

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article

Female cancers such as breast and gynaecological cancers contribute to a significant global health burden and are a leading cause of fatality among women. With current treatment options often limited by resistance to cytotoxic drugs, side effects and lack of specificity to the cancer, there is a pressing need for alternative treatments. Recent research has highlighted the promising role of non-coding RNAs (ncRNA) in regulating these issues and providing more targeted approaches to suppressing key cancer pathways. This review explores the involvement of the various types of non-coding RNAs in regulating key oncogenic pathways, namely, the MAPK, PI3K/Akt/mTOR, Wnt/β-catenin and p53 pathways, in a range of female cancers such as breast, cervical, ovarian and endometrial cancers. Evidence from a multitude of studies suggests that non-coding RNAs function as double-edged swords, serving as both oncogenes and tumour suppressors, depending on their expression and cellular interactions. By mapping and investigating these regulatory interactions, this review demonstrates the complexity and dual functionality of ncRNAs in cancer. Understanding these complex mechanisms is essential for the development of new and effective ncRNA-based diagnostic methods and targeted therapies in female cancer treatment. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal degeneration, and gliosis. Its pathophysiology involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation, ultimately leading to progressive neurodegeneration and functional decline. Although significant advances have been made in disease-modifying therapies (DMTs), many patients continue to experience disease progression and unmet therapeutic needs. Drug repurposing—the identification of new indications for existing drugs—has emerged as a promising strategy in MS research, offering a cost-effective and time-efficient alternative to traditional drug development. Several compounds originally developed for other diseases, including immunomodulatory, anti-inflammatory, and neuroprotective agents, are currently under investigation for their efficacy in MS. Repurposed agents, such as selective sphingosine-1-phosphate (S1P) receptor modulators, kinase inhibitors, and metabolic regulators, have demonstrated potential in promoting neuroprotection, modulating immune responses, and supporting remyelination in both preclinical and clinical settings. Simultaneously, artificial intelligence (AI) is transforming drug discovery and precision medicine in MS. Machine learning and deep learning models are being employed to analyze high-dimensional biomedical data, predict drug–target interactions, streamline drug repurposing workflows, and enhance therapeutic candidate selection. By integrating multiomics and neuroimaging data, AI tools facilitate the identification of novel targets and support patient stratification for individualized treatment. This review highlights recent advances in drug repurposing and discovery for MS, with a particular emphasis on the emerging role of AI in accelerating therapeutic innovation and optimizing treatment strategies. Full article

Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient management, avoid drug combinations that can negatively affect patient care, and exploit potential synergistic combinations to improve current therapies in women’s healthcare. Methods: A DDI prediction model was built to describe relevant drug combinations affecting reproductive treatments. Approved drug features (chemical structure of drugs, side effects, targets, enzymes, carriers and transporters, pathways, protein–protein interactions, and interaction profile fingerprints) were obtained. A unified predictive score revealed unknown DDIs between reproductive and commonly used drugs and their associated clinical effects on reproductive health. The performance of the prediction model was validated using known DDIs. Results: This prediction model accurately predicted known interactions (AUROC = 0.9876) and identified 2991 new DDIs between 192 drugs used in different female reproductive conditions and other drugs used to treat unrelated conditions. These DDIs included 836 between drugs used for in vitro fertilization. Most new DDIs involved estradiol, acetaminophen, bupivacaine, risperidone, and follitropin. Follitropin, bupivacaine, and gonadorelin had the highest discovery rate (42%, 32%, and 25%, respectively). Some were expected to improve current therapies (n = 23), while others would cause harmful effects (n = 11). We also predicted twelve DDIs between oral contraceptives and HIV drugs that could compromise their efficacy. Conclusions: These results show the importance of DDI studies aimed at identifying those that might compromise or improve their efficacy, which could lead to personalizing female reproductive therapies. Full article

Colchicine is a potent alkaloid with well-established anti-inflammatory properties. It shows significant promise in treating classic immune-mediated inflammatory diseases, as well as associated cardiovascular diseases, including atherosclerosis. However, its clinical use is limited by a narrow therapeutic window, dose-limiting systemic toxicity, variable bioavailability, and clinically significant drug–drug interactions, partly mediated by modulation of P-glycoprotein and cytochrome P450 3A4 metabolism. This review explores advanced delivery strategies designed to overcome these limitations. We critically evaluate lipid-based systems, such as solid lipid nanoparticles, liposomes, transferosomes, ethosomes, and cubosomes; polymer-based nanoparticles; microneedles; and implants, including drug-eluting stents. These systems ensure targeted delivery, improve pharmacokinetics, and reduce toxicity. Additionally, we discuss chemical derivatization approaches, such as prodrugs, codrugs, and strategic ring modifications (A-, B-, and C-rings), aimed at optimizing both the efficacy and safety profile of colchicine. Combinatorial nanoformulations that enable the co-delivery of colchicine with synergistic agents, such as glucocorticoids and statins, as well as theranostic platforms that integrate therapeutic and diagnostic functions, are also considered. These innovative delivery systems and derivatives have the potential to transform colchicine therapy by broadening its clinical applications while minimizing adverse effects. Future challenges include scalable manufacturing, long-term safety validation, and the translation of research into clinical practice. Full article

Traditional anti-inflammatory medications—such as corticosteroids, biological agents, and non-steroidal anti-inflammatory drugs—are commonly employed to mitigate inflammation, despite their potential for debilitating side effects. There is a growing need for alternative next-generation therapies for symptomatic, unchecked, and/or detrimental inflammation with more favorable adverse effect profiles. The long history of use of gold salts as anti-inflammatory agents and the more recent exploration of gold nanoparticle (AuNP) formulations for clinical indications suggest that the targeted delivery of nanoparticles to inflammatory sites may be a promising approach worth investigating. Coupled with peptides that specifically target immune cells, AuNPs could potently counteract inflammation. Here, we provide an overview of the selective infiltration of AuNPs into immune cells and summarize their interactions with and impact on these cells. Additionally, we provide a comprehensive mechanistic summary of how AuNPs exert their anti-inflammatory effects. Full article

Fasciola hepatica remains a global health and economic concern, and treatment still relies heavily on triclabendazole. At the parasite–host interface, F. hepatica calcium-binding proteins (FhCaBPs) have a unique EF-hand/DLC-like domain fusion found only in trematodes. This makes it a parasite-specific target for small compounds and vaccinations. To enable novel therapeutic strategies, we report the first elevated-resolution structure of a full-length FhCaBP4. The apo structure was determined at 1.93 Å resolution, revealing a homodimer architecture that integrates an N-terminal, calmodulin-like, EF-hand pair with a C-terminal dynein light chain (DLC)-like domain. Structure-guided in silico mutagenesis identified a flexible, 16-residue β4–β5 loop (LTGSYWMKFSHEPFMS) with an FSHEPF core that demonstrates greater energetic variability than its FhCaBP2 counterpart, likely explaining the distinct ligand-binding profiles of these paralogs. Molecular dynamics simulations and AlphaFold3 modeling suggest that EF-hand 2 acts as the primary calcium-binding site, with calcium coordination inducing partial rigidification and modest expansion of the protein structure. Microscale thermophoresis confirmed calcium as the major ligand, while calmodulin antagonists bound with lower affinity and praziquantel demonstrated no interaction. Thermal shift assays revealed calcium-dependent stabilization and a merger of biphasic unfolding transitions. These results suggest that FhCaBP4 functions as a calcium-responsive signaling hub, with an allosterically coupled EF-hand–DLC interface that could serve as a structurally tractable platform for drug targeting in trematodes. Full article

Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as a cleavage agent and ion-pairing reagent, respectively, resulting in peptides being obtained as TFA salts. Although TFA has excellent properties for peptide production, numerous studies highlight the negative impact of using peptides from TFA⁻ salts in biological assays. Methods: Investigated peptides were synthesized via SPPS and the TFA⁻ counterion was exchanged for Cl⁻ via freeze-drying in different concentrations of HCl. Detection and quantification of residual TFA⁻ were carried out via FT-IR, ¹⁹F-NMR, and HPLC using an evaporative light-scattering detector (ELSD). A liposomal fluorescence assay was used to test for the influence of the counterion on the peptides’ passive membrane permeability. Results: All TFA⁻ detection methods were successfully validated according to ICH guidelines. TFA⁻ removal with 10 mM HCl was determined to be the optimal condition. No impact on peptide purity was observed at all HCl concentrations. Influences on permeability coefficients depending on peptide sequence and salt form were found. Conclusions: This study presents a systematic investigation of the removal of TFA⁻ counterions from synthetic peptides and their replacement with Cl⁻ counterions. Detected counterion contents were used to understand the impact of sequence differences, especially positive charges, on the amount and potential localization of counterions. Our findings emphasize the importance of counterion quantification and specification in assays with synthetic peptides. Full article

Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers. Full article

This study explores how aristolochic acid I (AAI) drives hepatocellular carcinoma (HCC). We first employ network toxicology and machine learning to map the key molecular target genes. Next, our research utilizes molecular docking to evaluate how AAI binds to these targets, and finally confirms the stability and dynamics of the resulting complexes through molecular dynamics simulations. We identified 193 overlapping target genes between AAI and HCC through databases such as PubChem, OMIM, and ChEMBL. Machine learning algorithms (SVM-RFE, random forest, and LASSO regression) were employed to screen 11 core genes. LASSO serves as a rapid dimension-reduction tool, SVM-RFE recursively eliminates the features with the smallest weights, and Random Forest achieves ensemble learning through decision trees. Protein–protein interaction networks were constructed using Cytoscape 3.9.1, and key genes were validated through GO and KEGG enrichment analyses, an immune infiltration analysis, a drug sensitivity analysis, and a survival analysis. Molecular-docking experiments showed that AAI binds to each of the core targets with a binding affinity stronger than −5 kcal mol⁻¹, and subsequent molecular dynamics simulations verified that these complexes remain stable over time. This study determined the potential molecular mechanisms underlying AAI-induced HCC and identified key genes (CYP1A2, ESR1, and AURKA) as potential therapeutic targets, providing valuable insights for developing targeted strategies to mitigate the health risks associated with AAI exposure. Full article

Boron-containing compounds (BCCs) have emerged as potential drugs. Their drug-like effects are mainly explained by their mechanisms of action in enzymes. Nowadays, some experimental data support the effects of specific BCCs on GPCRs, provided there are crystal structures that show them bound to G protein-coupled receptors (GPCRs). Some BCCs are recognized as potential ligands of GPCRs—the drug targets of many diseases. Objective: The aim of this study was to collecte up-to-date data on the interactions of BCCs with GPCRs. Methods: Data were collected from the National Center of Biotechnology Information, PubMed, Global Health, Embase, the Web of Science, and Google Scholar databases and reviewed. Results: Some experimental reports support the interactions of BCCs with several GPCRs, acting as their labels, agonists, or antagonists. These interactions can be inferred based on in silico and in vitro results if there are no available crystal structures for validating them. Conclusions: The actions of BCCs on GPCRs are no longer hypothetical, as the existing evidence supports BCCs’ interactions with and actions on GPCRs. Full article

Cardiovascular disease (CVD) is the leading cause of death worldwide, with pathophysiological mechanisms often involving platelet activation and chronic inflammation. While antiplatelet agents targeting adenosine diphosphate (ADP)-mediated pathways are well established in CVD management, less is known about drug interactions with the platelet-activating factor (PAF) pathway, a key mediator of inflammation. This study aimed to evaluate the effects of several commonly used cardiovascular and anti-inflammatory drug classes—including clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin II receptor blockers (ARBs), β-blockers, and analgesics—on platelet function via both the ADP and PAF pathways. Using human platelet-rich plasma (hPRP) from healthy donors, we assessed platelet aggregation in response to these two agonists in the absence and presence of graded concentrations of each of these drugs or of their usually prescribed combinations. The study identified differential drug effects on platelet aggregation, with some agents showing pathway-specific activity. Clopidogrel and NSAIDs demonstrated expected antiplatelet effects, while some (not all) antihypertensives exhibited additional anti-inflammatory potential. These findings highlight the relevance of evaluating pharmacological activity beyond traditional targets, particularly in relation to PAF-mediated inflammation and thrombosis. This dual-pathway analysis may contribute to a broader understanding of drug mechanisms and inform the development of more comprehensive therapeutic strategies for the prevention and treatment of cardiovascular, hypertension, and inflammation-driven diseases. Full article

Diabetes mellitus (DM) is one of the leading causes of death and disability worldwide and its prevalence continues to rise. Chronic hyperglycemia exposes patients to severe complications. Among these, diabetic vascular lesions are the most destructive. Their primary driver is the synergistic interaction between hyperglycemia-induced oxidative stress and chronic inflammation. This review systematically elucidates how multiple pathological pathways—namely, metabolic dysregulation, mitochondrial dysfunction, endoplasmic reticulum stress, and epigenetic reprogramming—cooperate to drive oxidative stress and inflammatory cascades. Confronting this complex pathological network, natural products, unlike conventional single-target synthetic drugs, exert multi-target synergistic effects, simultaneously modulating several key pathogenic networks. This enables the restoration of redox homeostasis and the suppression of inflammatory responses, thereby improving vascular function and delaying both microvascular and macrovascular disease progression. However, the clinical translation of natural products still faces multiple challenges and requires comprehensive mechanistic studies and rigorous validation to fully realize their therapeutic potential. Full article

Motor vehicle crashes are a persistent cause of unintentional deaths in the United States. Scholarship on how manmade interventions and natural phenomena interact to effectuate such calamitous outcomes is longstanding. One manmade intervention of interest in the literature is daylight saving time (DST). Unfortunately, results on how the natural phenomena attributable to DST interact with driver behavior are inconsistent. To advance knowledge on DST-safety interactions, this study adopts a multilevel model approach to fatal motor vehicle crash outcomes in the contiguous United States. Results from a national analysis contextualize results from zonal analyses to unmask within- and between-time zone differences in DST-safety interactions. In the national analysis, motor vehicle crash fatalities decrease somewhat during DST (−0.10%). In the zonal analyses, motor vehicle crash fatalities decrease more so in the Central and Eastern time zones (−2.00% and −2.00%, respectively), but increase somewhat in the Pacific and Mountain time zones (+0.30%) during DST. The spatiotemporal context of the national analysis highlights specific policy implications from the zonal analyses to decrease the lethality of motor vehicle crashes. Specifically, interdictions to target alcohol and/or drug involvement in the northern latitudes of the Pacific and Mountain time zones during DST, the Central time zone at dawn or dusk before or after DST, and the northern latitudes in the Eastern time zone before or after DST are important. Generally, national DST-safety benefits mask zonal DST-safety costs in the Pacific and Mountain time zones. Full article