Search Results (363)

The development of functionality in wound dressings has progressed since the discovery by Winter that moist wounds heal more rapidly. Approaches to incorporate functionality on several fronts of wound healing have been targeted. Here, we consider three functional features that have received increased attention for their role in promoting healing in hard-to-heal wounds: control of protease levels, hydrogen peroxide generation, and antibacterial efficacy against multidrug resistance bacteria, the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. We review some clinically employed dressings used to treat chronic and burn wounds that have been characterized by their functional protease-modulating activity and contrast one well-studied analog with a cotton-based technology. Similarly, hydrogen peroxide generation profiles were obtained for dressings in different moist wound healing categories and contrasted with a modified form of a known hemostatic cotton-based technology. We examined ascorbic acid-modified forms of a cotton-based technology used for bleeding control in an ESKAPE antibacterial assessment using the AATCC 100 TM. The results for the cotton-based technology were significant protease uptake, hydrogen peroxide generation capacities at proliferative and antimicrobial levels, and >99.99% efficacy against ESKAPE pathogens. These results reflect the importance of considering new forms of cotton fiber technology for incorporation in advanced wound dressing approaches. Full article

Topical antibiotics have long been used for the prevention and treatment of superficial skin and soft tissue infections; however, increasing evidence indicates that their clinical value is undermined by rising antimicrobial resistance, high rates of allergic sensitization, inadequate activity against biofilms, and a lack of wound-healing properties. Agents such as bacitracin, neomycin, polymyxin B, mupirocin, and fusidic acid act through narrow, target-specific mechanisms that facilitate resistance selection and provide limited benefit in chronic or polymicrobial wound environments. Contemporary antimicrobial stewardship frameworks therefore discourage routine use of topical antibiotics and increasingly favor non-antibiotic antiseptics with broad-spectrum activity and low resistance risk, including silver, iodine, polyhexamethylene biguanide, octenidine, and medical-grade honey. These modalities, however, primarily serve to reduce microbial burden and do not directly address the underlying biological impairments that prevent healing. Nitric oxide-releasing gels (NORGs) represent a novel class of topical antimicrobials that combine multi-target bactericidal activity with physiologic pro-healing effects. Nitric oxide exerts potent antimicrobial and antibiofilm effects via oxidative and nitrosative stress, disruption of metabolic pathways, inhibition of DNA replication, and interference with quorum sensing. Simultaneously, nitric oxide enhances angiogenesis, modulates inflammation, improves microvascular perfusion, and promotes fibroblast and keratinocyte function. Preclinical models and early-phase clinical studies demonstrate broad-spectrum efficacy—including activity against multidrug-resistant organisms—with favorable tolerability and minimal risk of resistance development. Although the current evidence base remains preliminary, NORGs offer a promising antimicrobial platform with the potential to reduce reliance on topical antibiotics while simultaneously addressing key barriers to wound healing. Larger randomized controlled trials, direct comparisons with established advanced dressings, and robust pharmacoeconomic evaluations are needed to define their optimal role within stewardship-aligned wound-care practice. Full article

Drug-resistant Klebsiella pneumoniae and related Enterobacterales represent an escalating global public health threat, increasingly limiting therapeutic options in both healthcare- and community-associated infections. This review summarizes how resistance in K. pneumoniae emerges from the synergy of intrinsic barriers and acquired determinants. Key molecular mechanisms include reduced permeability via porin remodeling (notably OmpK35/OmpK36), multidrug efflux (e.g., AcrAB-TolC and OqxAB), and enzymatic drug inactivation driven by extended-spectrum beta-lactamases and carbapenemases (e.g., KPC, OXA-48-like enzymes, and metallo-beta-lactamases). We also highlight clinically meaningful pathways underlying polymyxin/colistin resistance, including mgrB inactivation and PhoPQ/PmrAB-mediated lipid A modification. In addition to stable genetic resistance, adaptive programs can shape transient tolerance and persistence, including stress responses that modulate gene expression under antibiotic and host-imposed pressures. The ability of these organisms to form biofilms, particularly on medical devices, further complicates treatment and eradication. Finally, we discuss therapeutic implications and current options and limitations—including novel beta-lactam/beta-lactamase inhibitor combinations and siderophore cephalosporins—and emphasize the importance of aligning therapy and surveillance with the underlying resistance mechanisms and circulating high-risk lineages. Full article

Nanomaterials are widely used in biomedical research as drug and antibody carriers, and some nanomaterials have been shown to exhibit antimicrobial activity. Previously, silver nanoclusters (AgNCs) were predicted to interact with the bacterial TolC protein, which is involved in the development of multidrug resistance in pathogens. In this study, glutathione-coated AgNCs were synthesized and characterized. Their toxicological properties were studied in a microplate assay against five bacterial strains, both as single components and in mixtures with heavy metal salts and antibiotics. The resulting AgNCs had a diameter of 2.2 ± 0.5 nm, with excitation and emission maxima of λ = 490 nm and λ = 638 nm, respectively. No significant growth inhibition was observed at the concentrations used in resistance modulation assays (≤2.5 µg/mL Ag), except for transient effects at very high concentrations. A decrease in bacterial resistance to copper (II) and cadmium (II) cations and the antibiotics erythromycin and levofloxacin was observed upon the addition of AgNCs containing 2.5 μg/mL silver to the nutrient medium. A dose-dependent effect of AgNCs on bacterial resistance to toxicants was established. Thus, nanoclusters can be considered as inhibitors of bacterial resistance to heavy metals and antibiotics, which may be useful in studying bacterial adaptation mechanisms and developing technologies for overcoming multidrug resistance in bacteria. Full article

Cancer therapy resistance emerges from highly integrated molecular systems that enable tumor cells to evade cell death and survive cytotoxic therapeutic stress. High Mobility Group Box 1 (HMGB1) is increasingly gaining recognition as a central coordinator of these resistance programs. This review delineates how HMGB1 functions as a molecular switch that dynamically redistributes between cellular compartments in response to stress, with each localization enabling a distinct layer of resistance. In the nucleus, HMGB1 enhances chromatin accessibility and facilitates the recruitment of DNA repair machinery, strengthening resistance to radio- and chemotherapeutic damage. Cytosolic HMGB1 drives pro-survival autophagy, maintains redox stability, and modulates multiple regulated cell death pathways, including apoptosis, ferroptosis, and necroptosis, thereby predominantly shifting cell-fate decisions toward survival under therapeutic pressure. Once released into the extracellular space, HMGB1 acts as a damage-associated molecular pattern (DAMP) that activates key pro-survival and inflammatory signaling pathways, establishing microenvironmental circuits that reinforce malignant progression and therapy escape. HMGB1 further intensifies resistance through upregulation of multidrug resistance transporters, amplifying drug efflux. Together, these compartmentalized functions position HMGB1 as a central node in the networks of cancer therapy resistance. Emerging HMGB1-targeted agents, ranging from peptides and small molecules to receptor antagonists and nanoformulations, show promise in reversing resistance, but clinical translation will require precise, context- and redox-informed HMGB1 targeting to overcome multifactorial resistance program in refractory cancers. Full article

The substantial interest in plant-based drugs or plant-derived phytocompounds drives researchers to conduct comprehensive investigations on their therapeutic properties. Mollugin, one of the major active constituents of Rubia cardifolia, has been well-studied for its pharmacological properties, demonstrating potent anti-inflammatory properties by suppressing the TAK-1-mediated activation of NF-κB/MAPK and enhancing the Nrf2/HO-1-mediated antioxidant response. It exhibits strong anticancer effects through ferroptosis via IGF2BP3/GPX4 pathways, induces mitochondrial apoptosis, and targets NF-κB, ERK, and PI3K/Akt/mTOR to suppress tumor progression. Mollugin also inhibits JAK2/STAT and PARP1 pathways, suppressing IL-1β expression via the modulation of ZFP91. Moreover, it regulates the MAPK/p38 pathway, promotes neuroprotection, and improves cognitive performance through GLP-1 receptor activation. Mollugin promotes osteogenesis by activating the BMP-2/Smad1/5/8 signaling pathway and downregulates MAPK, Akt, and GSK3β expression, leading to the inhibition of osteoclastogenesis. It overcomes multidrug resistance by downregulating MDR1/P-gp, CREB, NF-κB, and COX-2 through AMPK activation. Its antibacterial effect is mediated by strong binding to FUR, UDP, and IpxB proteins in Enterobacter xiangfangensis. Mollugin mitigates Klebsiella pneumoniae infection, suppresses adipogenesis without causing cytotoxicity, and protects endothelial cells via the BDNF/TrkB-Akt signaling pathway. Synthetic derivatives of mollugin, such as oxomollugin and azamollugin, have shown enhanced anticancer and anti-inflammatory effects by regulating EGFR, PKM2, TLR4/MyD88/IRAK/TRAF6, and NF-κB/IRF3 pathways with improved solubility and stability. Collectively, these findings emphasize the broad-spectrum activity of mollugin. This review provides a critical interpretation of the mechanistic pathways regulated by mollugin and its derivatives, emphasizing their pharmacological significance and exploring their potential for future translation as multitarget drug candidates. Full article

Multidrug resistance (MDR) presents a significant challenge in the treatment of glioblastoma. We evaluated six novel adamantane–sclareol hybrids that integrate a natural labdane diterpene scaffold with an adamantane moiety to address this issue. Compounds 2, 5, and 6 demonstrated the ability to bypass P-glycoprotein (P-gp)-mediated resistance in resistant U87-TxR cells and induced collateral sensitivity, with compound 2 exhibiting the highest selectivity for glioblastoma compared to normal glial cells. Mechanistic studies revealed that compounds 2 and 5 selectively triggered early apoptosis in MDR cells, significantly elevated levels of H₂O₂ and peroxynitrite, and disrupted mitochondrial membrane potential. Additionally, these compounds altered the expression of key genes involved in glutathione (GSH) and thioredoxin (Trx) antioxidant defense systems and increased ASK1 protein levels, indicating the activation of ROS-driven apoptotic signaling. Both compounds inhibited P-gp function, leading to enhanced intracellular accumulation of rhodamine 123 (Rho 123) and synergistically sensitized U87-TxR cells to paclitaxel (PTX). A preliminary Rag1 xenograft study demonstrated that compound 5 effectively suppressed tumor growth without causing significant weight loss. Collectively, these findings position adamantane–sclareol hybrids, particularly compounds 2 and 5, as promising strategies that exploit an MDR-associated reactive oxygen species (ROS) vulnerability, combining selective cytotoxicity, redox disruption, and P-gp modulation to eliminate resistant glioblastoma cells and enhance the efficacy of chemotherapeutics. Full article

The rapid rise of antimicrobial resistance (AMR) has emerged as a critical global health crisis, driven by the widespread emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens. This growing threat, coupled with the stagnation in the development of novel antibiotics, necessitates the investigation of alternative antimicrobial strategies. Plant-derived essential oils (EOs) have emerged as promising candidates due to their broad-spectrum antibacterial activity, multi-targeted mechanisms, and capacity to enhance the efficacy of existing antibiotics. Recent studies have underscored the potential of EOs in disrupting biofilms, inhibiting quorum sensing, modulating efflux pumps, and reversing resistance in a variety of bacterial pathogens, including those listed as priorities by the World Health Organization. Notably, many of these effects have been demonstrated against resistant strains isolated directly from clinical samples, thereby enhancing the translational significance of EOs. In addition to their antimicrobial properties, advances in analytical, omics-based, and microfluidic technologies have further elucidated the mechanisms of EOs and may accelerate their therapeutic development. Nevertheless, challenges such as variability in composition, lack of standardized testing protocols, and limited in vivo data continue to impede clinical application. Therefore, the aim of this scoping review is to critically examine the advances over the past decade in the antibacterial activity of plant EOs against clinical isolates, with a particular focus on their efficacy against resistant bacterial pathogens and their potential role in combating AMR. Full article

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs) and a major contributor to the global antimicrobial resistance crisis. The increasing prevalence of multidrug-resistant (MDR) strains, including expanded-spectrum β-lactamases (ESBL) and carbapenemase-producing isolates, severely limits treatment options. This review provides an overview on the key molecular mechanisms of UPEC antibiotic resistance, such as enzymatic inactivation, target-site mutations, efflux pump activity, and biofilm formation. Beyond conventional antibiotics, special emphasis is placed on phytochemical strategies as promising alternatives. Flavonoids, alkaloids, terpenoids, and essential oils exhibit antibacterial, anti-adhesive, and antibiofilm properties. These natural bioactive compounds modulate motility, suppress fimbrial expression, inhibit quorum sensing, and enhance antibiotic efficacy, acting both as standalone agents and as adjuvants. Current in vitro and in vivo studies highlight the potential of plant-derived compounds and biologically based therapies to combat UPEC. However, challenges related to standardization, bioavailability, and clinical validation remain unresolved. Integrating molecular mechanistic insights with advanced phytochemical research may offers a sustainable and effective strategy for mitigating UPEC antibiotic resistance. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a leading cause of death from a single infectious agent worldwide. Conventional antibiotic therapies face significant limitations, including multidrug resistance, poor treatment adherence, limited penetration into granulomas, and systemic toxicity. Recent advances in nanomedicine have paved the way for nanotheranostic approaches that integrate therapeutic, diagnostic, and preventive functions into a single platform. Nanotheranostic systems enable targeted drug delivery to infected macrophages and granulomatous lesions, real-time imaging for disease monitoring, and controlled, stimuli-responsive release of antitubercular agents. These platforms can be engineered to modulate host immune responses through host-directed therapies (HDTs), including the induction of autophagy, regulation of apoptosis, and macrophage polarization toward the bactericidal M1 phenotype. Additionally, nanocarriers can co-deliver antibiotics, immunomodulators, or photosensitizers to enhance intracellular bacterial clearance while minimizing off-target toxicity. The review also discusses the potential of nanotechnology to improve TB prevention by enhancing vaccine efficacy, stability, and targeted delivery of immunogens such as BCG and novel subunit vaccines. Key nanoplatforms, including polymeric, lipid-based, metallic, and hybrid nanoparticles, are highlighted, along with design principles for optimizing biocompatibility, multifunctionality, and clinical translatability. Collectively, nanotheranostic strategies represent a transformative approach to TB management, bridging diagnosis, therapy, and prevention in a single, adaptable platform to address the unmet needs of this global health challenge. Full article

Introduction: Bacterial infections, especially those caused by multidrug-resistant strains, remain a major health concern. This study investigates 4-chlorobenzyl p-coumarate, assessing its antibacterial mechanism, pharmacokinetic profile, and potential to modulate antimicrobial resistance. Methods: In silico studies were conducted, including molecular docking, molecular dynamics simulations, and pharmacokinetic predictions, alongside in vitro assays assessing efflux pump inhibition, antibiotic modulation, and bacterial DNA analysis. Results: The compound showed higher binding affinity and complex stability with the enzyme phosphatidylglycerol phosphate synthase, while also exhibiting reduced residue fluctuations and better flexibility with the NAD⁺-dependent DNA ligase. Molecular interactions with the efflux proteins MepA and NorA were also observed. Pharmacokinetic predictions indicated a favorable profile, including suitability for oral administration. Experimentally, the compound inhibited the MepA and NorA efflux pumps, modulated the activity of the antibiotics ciprofloxacin and norfloxacin, and reduced DNA concentration in treated cells. Conclusions: The findings suggest that the compound acts through dual mechanisms, with a prediction of activity by disrupting phosphatidylglycerol synthesis and DNA replication while inhibiting and modulating MepA and NorA efflux pumps. Full article

The lysosome is no longer viewed as a simple degradative “trash can” of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical “microreactor” that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5–5), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective “safe house,” yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome’s broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody–drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine–thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies. Full article

Objectives: Pseudomonas aeruginosa is an opportunistic pathogen of high clinical relevance due to its ability to form biofilms, its inherent virulence regulated by quorum-sensing systems, and its multidrug resistance. In the present study, we evaluated the inhibitory potential of nine extracts from Inula species (chloroform and methanolic fractions, including a sesquiterpene lactone-enriched fraction) against biofilm formation and virulence-associated traits of P. aeruginosa PAO1 and three multidrug-resistant clinical isolates, as well as their cytotoxicity, biocompatibility, and ability to affect cytokine and nitric oxide production in infected skin explants. Methods: The following methods were applied: fractionation and extraction of plant extracts; cytotoxicity assessment on HFF cells; crystal violet assay for determining antibiofilm activity; fluorescence microscopy for evaluating biofilm viability; electron microscopy for assessing the 3D structure of biofilms and morphological alterations; inhibition assays of pyocyanin pigment, protease activity, bacterial motility, interleukin-17, and nitric oxide production; histological analysis of mouse skin explants. Results: Quantitative analyses of antibiofilm activity revealed that five of the tested extracts inhibited biofilm formation by more than 50%. Structural and functional analyses using confocal laser scanning microscopy and scanning electron microscopy demonstrated a substantial reduction in biofilm thickness, exfoliation of biofilm biomass, the presence of isolated bacterial clusters, metabolically inactive cell populations, and morphological abnormalities associated with cell elongation, invaginations, and polar deformations as a consequence of treatment. In addition, the plant extracts strongly affected virulence factors regulated by quorum sensing. The methanolic fractions from I. britannica and I. bifrons significantly suppressed pyocyanin synthesis. In contrast, the chloroform fractions from I. helenium and I. spiraeifolia produced the largest inhibition zones in assays for extracellular protease activity. Furthermore, all chloroform extracts suppressed bacterial motility, with the lowest swarming diameter observed for the chloroform and lactone-enriched fractions from I. britannica. The chloroform extracts of I. helenium and I. bifrons, methanolic extracts of I. britannica, and chloroform and methanolic extracts of I. spiraeifolia showed relatively low toxicity to normal diploid human fibroblasts. Methanolic and chloroform fractions from I. britannica disrupted biofilm integrity and reduced IL-17A and nitric oxide production in infected skin explants. Conclusions: All these findings indicate a possible synergistic action of the chemical constituents within the fractions on quorum-sensing regulation, biofilm formation, cellular viability, and modulation of host inflammatory responses. Full article

Candida and other pathogenic yeast species, able to transition from non-invasive commensal organisms to invasive pathogens, are characterized by a high ability to adapt to stress conditions encountered in the human host, such as pH and temperature shifts, CO₂ and oxygen level variations, and nutritional limitations. Although Candida albicans remains the main cause of Candida-related infections, non-albicans Candida (NAC) species, including C. tropicalis, C. parapsilosis, C. krusei, and non-Candida species such as Yarrowia lipolytica, Candidozyma auris, and Nakaseomyces glabratus, are gaining clinical importance. These species exhibit diverse mechanisms of pathogenicity, including morphological transition, modulation of gene expression pathways (cAMP-PKA/MAPK, Hsp, calcineurin, GlcNAc-mediated signaling), cell wall remodeling, post-translational reprogramming, biofilm formation, antifungal resistance, and enzyme secretion. C. albicans exhibits high morphological and metabolic plasticity for survival across body niches. N. glabratus and C. tropicalis show strong azole resistance and biofilm formation, while C. parapsilosis and C. krusei pose risks through surface adhesion and treatment resistance. C. auris stands out for heat tolerance, multidrug resistance, and outbreak potential. Y. lipolytica, though rare, forms persistent filamentous biofilms in critical care settings. Cryptococcus neoformans remains a life-threatening pathogen capable of immune evasion and crossing the blood–brain barrier. This review compares molecular mechanisms of pathogenicity across these fungi, emphasizing environmental adaptation, conserved and species-specific responses, and potentially highlighting targets for therapeutic management. Full article

Cancer poses a considerable challenge to global public health and stands as the second leading cause of mortality worldwide. Chemotherapy provides limited benefits for advanced-stage cancer, mainly due to high systemic toxicity and drug resistance. Optimal cancer treatment requires a sophisticated, multidisciplinary collaboration aimed at extending survival, enhancing quality of life, and reducing toxicity. Natural products present advantages, including a wide array of structural diversity, reduced toxicity, improved immune modulation, and the ability to act on multiple targets. Nanomedicine design shows promise in tumor treatment and diagnosis by improving efficacy and minimizing side effects. Due to the heterogeneity of tumors in genetics, metabolism, and microenvironment, natural product-based carrier-free drug delivery platforms have been actively investigated and demonstrated considerable potential for enhanced tumor treatment. “Triadic” strategies can simultaneously perform various functions on a carrier-free intelligent nanoplatform. These include combinational chemotherapy, photodynamic therapy (PDT) with bioimaging and chemotherapy, PDT combined with photothermal therapy (PTT) and chemotherapy, chemo-radio-theranostics, as well as gene therapy (GT) in conjunction with PTT and chemotherapy. This multifaceted approach enhances therapeutic efficacy, reduces multidrug resistance, and minimizes systemic toxicity. This review encompasses recent advancements in cancer therapy using carrier-free “triadic” nanomedicines based on natural products (between 2024 and 2025) and evaluates this evolving field, emphasizing the pivotal role of natural products—berberine, camptothecin, hypericin, erianin, curcumin, lactose, paclitaxel, gambogic acid, and glycyrrhizic acid—in drug delivery platforms. Furthermore, it addresses the challenges and bottlenecks encountered by carrier-free drug delivery platforms, offering valuable insights into their development trajectories. Full article