Search Results (4,563)

Background/Objectives: Dry powder inhalation (DPI) is a promising strategy for the treatment of respiratory diseases such as cystic fibrosis (CF), where thick and viscous mucus limits drug penetration and contributes to persistent infection and inflammation. Although inhalation allows rapid drug action with reduced systemic exposure, its efficacy depends on the ability of inhaled drugs to achieve and maintain therapeutic concentrations in the lungs and to overcome airway barriers. This study aimed to develop and characterize effervescent dry powder formulations designed to enhance mucus permeabilization through mechanical disruption while delivering an antibiotic. Methods: Effervescent microparticles containing sodium bicarbonate, an organic acid (citric or tartaric acid), and levofloxacin were produced by spray drying using a triple-fluid nozzle to control component distribution and prevent premature effervescence. The influence of functional excipients, including L-leucine and mannitol, on particle formation, aerosol performance, and process yield was evaluated. Microparticles were characterized in terms of morphology, fine particle fraction (FPF), and effervescence-related properties. Results: Formulations containing L-leucine and citric acid reduced particle agglomeration and achieved a fine particle fraction of up to approximately 18%, although with a lower process yield. In contrast, formulations based on tartaric acid and mannitol improved both production yield and aerosol performance, with FPF values increasing up to 27.3% and more efficient CO₂ release. The resulting microparticles exhibited spherical, hollow, and partially fragmented morphology, consistent with premature CO₂ generation during spray drying. Conclusions: The effervescent approach, combined with controlled spray drying parameters, represents a promising formulation strategy to modulate particle behavior and drug release in mucus-relevant environments. These findings support further investigation of effervescent DPI systems for improved pulmonary drug delivery in CF. Full article

The introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) has significantly enhanced the prognosis for patients with rheumatoid arthritis (RA). Nevertheless, improving quality of life remains a major clinical challenge requiring the implementation of multidirectional therapeutic measures. Pain reduction plays a particularly important role in this context, representing one of the primary treatment goals for many patients. Scientific evidence indicates that effective pain management is a crucial predictive factor for the improvement of mental and physical health in patients with RA. The aim of this literature review was to summarise the mechanisms of action of Janus kinase inhibitors (JAKi), with particular emphasis on their modulation of pain generation and transmission. Furthermore, the study aimed to compare the results of clinical studies and assess the actual effectiveness of these drugs in reducing pain in clinical practice. JAKi exhibit peripheral analgesic effects by directly reducing the production of pro-nociceptive cytokines and modulating macrophage polarisation. Moreover, they influence central pain processing mechanisms by modulating the IL-6/JAK/STAT3 pathway and by reducing microglial and astrocyte proliferation in the dorsal horn of the spinal cord. The results of randomised clinical trials confirm that JAKi provide rapid, clinically significant pain reduction. Some studies also point to the persistence of this effect over a longer period, and to their greater efficacy compared with conventional disease-modifying antirheumatic drugs (cDMARDs) and bDMARDs. The efficacy of this group of drugs has also been noted in patients with an inadequate response to prior therapy with biological drugs. A key focus of future research remains determining the optimal timing for introducing JAKi in the treatment of RA and identifying predictive factors to enable the selection of patients most likely to benefit from this class of drugs. Full article

Microphysiological Systems (MPS) have emerged as a transformative platform in biomedical research, enabling the investigation of disease mechanisms, drug screening, and toxicity prediction by closely simulating human physiological functions. However, the rapid advancement of MPS technology has raised a series of complex ethical challenges. These include the sourcing and application of human-derived stem cells, the protection of donors’ personal and genetic data, the potential for brain organoids to develop consciousness-like characteristics, and the challenges to species boundaries posed by human–animal chimera research. Meanwhile, although regulatory authorities encourage innovation, specialized certification standards and ethical review guidelines for MPS are yet to be fully established. The lack of technical standardization and a coherent ethical governance framework remain a major bottleneck hindering the broader application and industrialization of MPS. This review systematically outlines the key ethical issues facing MPS, compares the evolution and differences in international ethical regulatory frameworks, and discusses strategies for addressing these challenges—including the establishment of dynamic ethical governance mechanisms, harmonization of international standards, and the promotion of benefit-sharing and public engagement. Finally, we highlight the need to develop a scientific, unified, and actionable ethical governance system that balances technological innovation with responsible translation, supporting the sustainable development of MPS technology. Full article

Background: Chagas disease, caused by the parasite Trypanosoma cruzi, remains a major neglected tropical disease, with millions of people living with the infection worldwide. Current treatments are effective in the acute stage of the disease, but are poorly tolerated and show reduced efficacy in chronic infections, highlighting an urgent need for novel therapeutic strategies. A key bottleneck in early-stage drug discovery is target identification, which is traditionally dependent on costly and low-throughput experimental methods. Computational approaches offer a cost-effective and fast alternative to traditional methods. Methods: In this study, we present an integrated in silico pipeline that combines ligand-based and structure-based computational approaches to prioritize potential molecular targets for bioactive compounds against T. cruzi. The ligand-based component performed similarity searches across curated bioactivity databases containing known ligand–protein associations, and the most similar candidates were then further evaluated using a structure-based approach through pairwise structural alignment against the T. cruzi proteome from AlphaFold. Results: The pipeline was validated using eight compounds with known targets, successfully recovering the correct target in six cases. Additionally, two compounds with anti-T. cruzi activity but unknown mechanisms of action were analyzed to hypothesize their potential targets. Conclusions: Overall, the pipeline demonstrated moderate success, with limitations arising from challenges in handling novel chemotypes and poorly annotated targets. Nevertheless, its modular nature allows for an easy adaptation to other neglected tropical diseases, providing a flexible and cost-effective framework for early-stage target prioritization. Full article

Introduction: Pain is one of the most common reasons why patients seek medical care, and chronic pain is now recognized as a major health problem worldwide. Better understanding of pain mechanisms has shown the importance of distinguishing nociceptive, neuropathic, and nociplastic pain in order to choose the most effective treatment. In recent years, topical analgesics have gained increasing attention because they can provide pain relief directly at the site of application while reducing systemic exposure and the risk of adverse effects. This is especially important in older adults, patients with multiple diseases, and those exposed to polypharmacy. Methods: This narrative review presents the current knowledge on the pharmacology, efficacy, and safety of topical drugs used in pain treatment. Particular attention is given to topical non-steroidal anti-inflammatory drugs (NSAIDs), lidocaine, capsaicin, menthol, and camphor. The review also discusses newer and less established therapies used mainly in neuropathic pain, including topical ketamine, amitriptyline, phenytoin, gabapentin, and clonidine. A structured, non-systematic literature search was conducted using the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases to identify studies evaluating the efficacy and safety of topical analgesic therapies. Results: Current evidence supports topical NSAIDs as first-line therapy for localized musculoskeletal pain and osteoarthritis, while lidocaine and high-concentration capsaicin patches are effective options in focal neuropathic pain. Although several newer topical therapies show promising results, more high-quality clinical studies are still needed. Overall, topical analgesia is an important part of multimodal pain management because it combines analgesic efficacy with a better safety profile compared with many systemic therapies. Conclusions: Taking the aspects discussed in this paper into account, it seems justified to search for new drug combinations that would contribute to effective pain therapy with topical agents. It is recognized that a multimodal approach to pain management, which utilizes drugs with different mechanisms of action, can increase efficacy and reduce the systemic adverse events of the drugs used. The effective and safe treatment of patients with pain, especially neuropathic pain, despite emerging new clinical trials, remains a challenge for clinicians. Full article

Foods rich in polyphenols are known to promote oral health by modifying the enamel pellicle. In doing so, they reduce bacterial adhesion, biofilm maturation, and erosion. The goal of this study was to screen local herbal drugs available in Central Europe for their potential suitability as part of a diet promoting oral health by targeting the initial stages of biofilm formation. To achieve this, an in situ study was conducted to evaluate the effects of the four polyphenol-rich herbal extracts of blackcurrant leaves, oak bark, horse chestnut leaves, and sweet chestnut leaves on early bacterial adhesion and biofilm formation on tooth enamel over an 8 h period. This research aimed to identify natural remedies that could support oral hygiene by targeting the initial stages of biofilm formation. Study Design and Experimental Procedures: Aqueous extracts were prepared by ultrasonic extraction. Eight human subjects wore bovine enamel slabs intraorally for 8 h. After 1 min of pellicle formation, the subjects rinsed with 8 mL of the extracts for 10 min, followed by intraoral exposure without food. An 8 h-exposure without rinse served as the negative control; 0.2% chlorhexidine gluconate (CHX) served as the positive control. After 8 h, bacterial adhesion and biofilm matrix formation on the enamel slabs were quantified ex vivo using DAPI/Concanavalin A staining and fluorescence microscopy. The LIVE/DEAD™ BacLight™ assay was used to assess bacterial viability. Statistical analysis was performed by the Mann–Whitney U test and Kruskal–Wallis test (p < 0.05), as well as the Bonferroni–Holm correction (p < 0.01). Results and Conclusions: The screened herbal drugs did not demonstrate a statistically significant impact on the number of adherent bacteria, suggesting that their mode of action may not directly interfere with bacterial adhesion mechanisms. However, all four extracts exhibited consistent trends toward reduced glucan formation and decreased bacterial viability. The observed inhibition of glucan formation indicates that these drugs may potentially target the enzymatic pathways responsible for polysaccharide synthesis. By disrupting glucan production, the structural integrity of the biofilm matrix might be compromised, which indirectly affects bacterial survival within the biofilm environment. Full article

Breast cancer (BC) is a major global public health problem. Classical therapies have limited success on the treatment of BC; therefore, new therapeutic options are needed. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that represent a revolutionary class of new drug candidates because they induce the degradation of harmful, undruggable proteins by activating the ubiquitination machinery of cells. Their unique mechanism of action offers several advantages over conventional drugs, but also disadvantages, as most of them are large molecules with unfavorable pharmacokinetic properties, which limits their bioavailability. Vepdegestrant (Veppanu^TM) is an orally administered, estrogen receptor (ER) targeting chimera that was approved by the FDA on 1 May 2026, for the treatment of adults with ESR1-mutated advanced or metastatic breast cancer. Thus, vepdegestrant became the first-ever approved PROTAC drug. In this article, we briefly summarize the structure, mechanism of action, and key available pharmacokinetic and pharmacological data of vepdegestrant. Full article

Background/Objectives: Shashen Maidong Decoction (SMD) has a long history of use within the traditional Chinese medicine (TCM) system and is currently employed in modern clinical practice for the treatment of various diseases. The characterization of the chemical constituents of TCM drugs is a prerequisite and foundation for research into bioactive compounds and quality control. However, no study has yet undertaken a comprehensive identification of its chemical constituents. Therefore, it is necessary to establish suitable analytical methods to comprehensively and systematically characterize the chemical constituents of SMD. Methods: Ultra-performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry (UHPLC-Q Exactive orbitrap HRMS) and the Global Natural Products Social Molecular Networking (GNPS) technology were employed. The chemical constituents in SMD were systematically identified by comparing mass spectrometry data with reference standards, databases and relevant literature, and by analyzing mass spectrometry fragmentation patterns. Results: A total of 86 compounds were identified in SMD, including 27 flavonoids, 2 homoisoflavonoids, 34 organic acids, 2 alkaloids, 4 amino acids, 5 saccharides, 3 triterpenes and 9 other constituents. Conclusions: This study represents the first relatively comprehensive and systematic characterization of the chemical constituents in SMD, enriching modern understanding of SMD and laying the foundation for the identification of bioactive compounds, the elucidation of mechanisms of action, and further development and utilization. Full article

Mitochondria-targeting metal complexes (MTMCs) are a mechanistically distinct class of metallopharmaceuticals. Unlike first-generation platinum drugs that form nuclear DNA adducts, MTMCs exploit organelle-specific vulnerabilities such as hyperpolarised mitochondrial membrane potential (ΔΨm), elevated reactive oxygen species (ROS), limited mitochondrial DNA (mtDNA) repair capacity, and redox-dependent enzymes such as thioredoxin reductase (TrxR). We systematically searched PubMed, Web of Science, Scopus, and Google Scholar databases for studies published between 2016 and 2026, applying predefined inclusion criteria that included subcellular localization evidence and functional bioenergetic endpoints. The search identified 147 studies covering Pt(II/IV), Ru(II/III), Au(I/III), Ir(III), Os(II), Re(I), and V(IV/V) complexes and metal–organic framework nanoplatforms. Mechanistic evidence converges on four intramitochondrial target categories: inhibition of ETC (Electron Transport Chain) Complexes I/III with consequent ATP depletion; ROS overproduction, coupled with glutathione and TrxR depletion; outer mitochondrial membrane permeabilization and intrinsic apoptotic cascade activation; and mtDNA damage within a compartment limited to base excision repair. Multi-modal cell death—the co-occurrence of apoptosis, ferroptosis, necroptosis, and autophagic cell death—was a recurrent finding across the reviewed studies. This review thoroughly surveys the latest trends in MTMC drug design (metals, ligand structures, and mechanisms of action) and summarises analytical techniques for speciation, pharmacokinetics, safe monitoring, and resistance, while critically analysing translational barriers and clinical failures. To address the field’s inconsistent terminology, we introduce an explicit localization evidence hierarchy that distinguishes mitochondria-targeting complexes (through quantitative ICP-MS fractionation or co-localization with defined Pearson/Manders coefficients) from simply mitochondria-localising or mitochondria-perturbing agents, and we apply it throughout. We also point out that the idea of selectivity being purely driven by membrane voltage (ΔΨm) and thermodynamics is constrained by membrane and protein binding, as well as the transmembrane pH gradient, kinetic limitations, and demonstrated heterogeneity of cancer-cell membrane potential, and, as such, the functional mitochondrial effects must not be equated with mitochondrial accumulation. Since elemental quantification cannot distinguish intact complex from protein adducts and decomposition products, speciation-aware pharmacokinetics emerges as a prerequisite for a credible exposure–response interpretation. The translational progress will depend less on new chemotypes than on this analytical and pharmacokinetic rigour, together with organelle-level safety monitoring and biomarker-guided patient selection. Full article

Objectives: The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the current treatment limitations—particularly the emergence of drug resistance and the reduced efficacy of some existing drugs against new variants—highlight the need for novel antiviral strategies with novel action mechanisms. Fusion inhibitors that disrupt six-helix bundle (6-HB) formation during viral entry represent a promising approach. Posaconazole, an antifungal agent, has been identified as a weak fusion inhibitor, but suffers from poor membrane permeability and modest activity. This study aimed to enhance its antiviral potency by conjugating it with cell-penetrating polyarginine peptides and to investigate the mechanism of action. Methods: A series of posaconazole-polyarginine conjugates were synthesized via click chemistry. Antiviral activity was evaluated using pseudotyped SARS-CoV-2 Omicron XDV in HEK293T cells. Mechanisms were investigated by circular dichroism, native PAGE, size-exclusion HPLC, molecular docking, and isothermal titration calorimetry. Metabolic stability was assessed using hepatic microsomes. Results: Posa-R8 exhibited potent antiviral activity comparable to the clinical candidate EK1, with minimal cytotoxicity. Mechanistic studies confirmed that Posa-R8 binds the HR2 region of the spike protein, disrupts 6-HB formation, and inhibits membrane fusion. It also showed strong lipid bilayer affinity and improved phase I metabolic stability over EK1. Conclusions: Polyarginine conjugation enhances the membrane-binding affinity and antiviral efficacy of posaconazole. Posa-R8 represents a promising lead for developing next-generation SARS-CoV-2 fusion inhibitors. Full article

Drug repurposing represents a rational and resource-efficient strategy to expand the oncological armamentarium by leveraging the established pharmacology, clinical experience, and safety-monitoring frameworks of approved non-oncological agents. Clozapine (CZP), an atypical antipsychotic characterized by broad receptor pharmacology, complex biotransformation, and clinically relevant toxicological liabilities, has emerged as a candidate of interest following preclinical evidence of context-dependent anticancer activity across multiple tumor types. As such, CZP provides an informative case study at the interface between therapeutic drug action and xenobiotic behavior. This review provides a critical and integrated synthesis of the current evidence supporting the repurposing of CZP in oncology, with particular emphasis on the relationship between its molecular mechanisms, dose–exposure requirements, pharmacological complexity, and potential toxicity. Analysis of in vitro and in vivo studies across glioblastoma, non-small cell lung cancer, breast cancer, and melanoma brain metastasis models indicates that CZP can impair tumor cell proliferation and survival through a form of mechanistic plasticity. Rather than acting through a single conserved pathway, CZP appears to disrupt shared upstream processes related to pro-survival signaling, cellular stress tolerance, and metabolic homeostasis, while engaging tumor-specific downstream responses, including autophagic cell death, mitochondria-dependent apoptosis, oxidative stress, and coordinated modulation of survival and angiogenic pathways. Despite this mechanistic rationale, translation remains substantially constrained, most notably by the order of magnitude gap between anticancer-effective concentrations in vitro and clinically achievable plasma exposures, requiring careful distinction between potentially useful anticancer pharmacology and nonspecific xenobiotic-induced cellular stress and clinically unacceptable toxicity. Key limitations include the discrepancy between anticancer-effective concentrations observed in vitro and exposures achievable during standard psychiatric dosing, the limited understanding of how CZP metabolism and metabolite formation may influence efficacy and toxicity, the absence of integrated pharmacokinetic–pharmacodynamic and toxicokinetic modeling, and the lack of dedicated clinical trial evidence. To address these challenges, this review examines complementary translational strategies, including patient-derived organoids, co-culture systems, microphysiological platforms, pharmacokinetic and toxicological modeling, and computational digital twin frameworks. Together, these approaches may support a biologically informed and risk-aware evaluation of CZP, helping to identify responsive tumor contexts, anticipate exposure-related liabilities, and prioritize rational combination strategies. By integrating therapeutic potential with xenobiotic pharmacology and toxicology, this review positions CZP within the evolving landscape of precision oncology and evidence-driven drug repurposing. Full article

Plant extracts and plant-derived bioactive compounds are considered important natural agents in cancer research due to their antiproliferative, pro-apoptotic, antioxidant, anti-inflammatory, and anti-angiogenic effects. However, the low solubility, limited bioavailability, instability, and challenges in their standardization directly limit their therapeutic use. Therefore, the development of new delivery systems has become necessary. In this context, hydrogels are among the biomaterial platforms gaining attention in cancer treatment. This review provides a comprehensive assessment of the potential of hydrogel systems containing plant extracts and plant-derived bioactive compounds in cancer treatment. The article discusses cancer types, the limitations of current treatments, mechanisms of action of plant-derived bioactive compounds against cancer, stimulus-responsive hydrogel systems, and the design criteria for extract-loaded hydrogels. In addition, hydrogel systems containing plant-derived components and combination approaches that use these components alongside anticancer drugs have been investigated. According to the literature, these compounds may increase anticancer activity through local, prolonged release, reduce the toxicity of chemotherapeutic agents in some cases, and exhibit complementary or synergistic antitumor effects with chemotherapeutic drugs. They also point out the potential of treatment strategies targeting the tumor microenvironment. However, researchers need to conduct more comprehensive studies on extraction standardization, biosafety, release kinetics, in vivo efficacy, and clinical scalability. In conclusion, hydrogel systems containing plant extracts and plant-derived bioactive compounds should be considered not as direct alternatives to cancer treatments but as rational biomaterial platforms that enable controlled release, local application, and combination therapies. Full article

One of the most pressing challenges facing healthcare today is the rise of biofilm infections and antibiotic-resistant bacteria, which demand entirely new therapeutic strategies beyond conventional antibiotic reliance. A biofilm is a structured community of microorganisms encased in a self-produced extracellular polymeric substance (EPS) matrix, which confers resistance to host immune defenses and antimicrobial agents. Accumulating evidence demonstrates that plant-derived secondary metabolites—including flavonoids, phenolic acids, tannins, terpenoids, and alkaloids—exert potent antibacterial and antibiofilm activities through diverse mechanisms of action. These natural compounds inhibit biofilm formation by disrupting bacterial adhesion, suppressing quorum sensing, degrading the EPS matrix, and impairing bacterial motility. Beyond independent bioactivity, phytochemicals demonstrate significant synergistic potential when combined with conventional antibiotics, revitalizing antimicrobial efficacy against drug-resistant pathogens. Nanoformulation and biogenic carrier technologies further enhance the bioavailability and therapeutic potency of these compounds. Despite these advances, critical challenges persist, including poor bioavailability, physicochemical instability, dose-dependent toxicity, and the risk of resistance development. This review presents a critical and integrative analysis of the pharmacological mechanisms of plant secondary metabolites, with particular emphasis on their role in combating biofilm-associated infections and antibiotic resistance, and discusses translational opportunities including structure–activity relationship (SAR)-guided optimization, high-throughput screening platforms, and advanced drug delivery systems. Collectively, plant secondary metabolites represent a scientifically compelling and clinically relevant pipeline for the development of next-generation antimicrobial and antibiofilm therapeutics. Full article

Xanthotoxin (8-methoxypsoralen) belongs to the group of naturally occurring furanocoumarin (furocoumarin) compounds and is a product of plant secondary metabolism. Analysis of the available literature indicates that xanthotoxin exhibits a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, immunomodulatory, and antibacterial effects. Xanthotoxin has been shown to stimulate autophagy via inhibition of the AKT/mTOR pathway, as well as to block cell migration by modulating RIG-1 and NF-κB signaling. Moreover, its effects on JNK/MAPK, PI3K/AKT, Calcium–CaMYK/PYK2, and other signaling cascades have been confirmed. Among its most promising properties is the ability to inhibit ABC transporters, thereby preventing the reduction of chemotherapeutic agent concentrations within tumor cells and enhancing their intracellular accumulation. Thus, the aim of this study was to evaluate xanthotoxin as a potential anticancer agent. The literature review was based on publications indexed in Google Scholar, Scopus, Web of Science, and PubMed and published between 2010 and 2026. Studies describing the biological properties of xanthotoxin, its toxicity, anticancer mechanisms of action, and modulation of ABC transporters were included. This literature review summarizes the pharmacological profile of xanthotoxin, and its biological activities and therapeutic potential, as well as its antitumor effects in various cancer cell lines. The available evidence may provide a foundation for the future development of xanthotoxin as a lead compound for anticancer drug discovery. Full article

Squamous cell lung cancer (SqCLC) accounts for 20–30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10–15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1–3% and HER2 amplifications observed roughly in 2–4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC. Full article