Search Results (3,460)

In this study, new improved inhibitors of the viral enzyme 3-chymotrypsin-like protease (3CL^pro) were designed using structure-based drug design techniques in an effort to discover more effective treatment of coronavirus disease 2019 (COVID-19). Three-dimensional models of 3CL^pro–inhibitor complexes were prepared by in situ modification of the crystal structure of the submicromolar covalent inhibitor IPCL6 for a set of 25 known inhibitors with published inhibitory potencies (${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$). The QSAR model was prepared with a reasonable correlation between the calculated free energies of formation of the 3CL^pro-IPCL complex (∆∆G_com) and the experimentally determined activities ${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$, which explained approximately 92% of the variation in the 3CL^pro inhibition data. A similar agreement was achieved for the QSAR pharmacophore model (PH4) built on the basis of the active conformations of the IPCL inhibitors bound at the active site of the 3CL^pro. The virtual combinatorial library of more than 567,000 IPCL analogues was screened in silico using the PH4 model and resulted in the identification of 39 promising analogues. The best inhibitors designed in this study show high predicted affinity for the 3CL^pro protease, as well as favourable predicted ADME properties. For the best new virtual inhibitor candidate IPCL 80-27-74-4, the inhibitory concentration ${IC}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ was predicted equal to 0.8 nM, which represents a significant improvement in the inhibitory potency of known IPCLs. Ultimately, molecular dynamics simulations of the 12 newly designed top-scoring IPCL inhibitors demonstrated that the 3CL^pro–inhibitor complexes exhibited good structural stability, confirming the potential for further development of the designed IPCL analogues. Full article

Acinetobacter baumannii is a leading intensive care unit (ICU) pathogen associated with high rates of carbapenem resistance and poor clinical outcomes. This narrative review synthesizes recent clinical, microbiological, and pharmacokinetic/pharmacodynamic (PK/PD) evidence regarding resistance mechanisms and therapeutic strategies. A literature review was performed in PubMed, Scopus, and Web of Science (January 2015–August 2025), focusing on multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, ICU-acquired infections, and pivotal trials involving cefiderocol and sulbactam–durlobactam. Resistance is driven by OXA-type carbapenemases (notably OXA-23/24/58), efflux systems (AdeABC/IJK/FGH), porin alterations (CarO, Omp33–36), and lipopolysaccharide (LPS) modifications conferring colistin resistance. Management options include polymyxins, optimized tigecycline dosing, β-lactam/β-lactamase inhibitors, and newer agents such as cefiderocol and sulbactam–durlobactam, though mortality and safety outcomes vary across trials. A comparative table is included, summarizing antimicrobial mechanism coverage, PK/PD parameters, and adverse effects to support regimen selection in ventilator-associated pneumonia (VAP) and bacteremia. Optimized, multimodal approaches integrating timely diagnostics, targeted combination therapies, infection prevention, and antimicrobial stewardship are essential to improve outcomes and limit the spread of MDR and XDR A. baumannii. Full article

The endophytic Streptomyces sp. PRh3 (PRh3), isolated from Dongxiang wild rice (DXWR), exhibited impaired biosynthetic capacity in the laboratory. To address this defect, rifampicin-based ribosome engineering was first applied to PRh3 to generate PRh3-r55, which acquired a characteristic H473Y rifampicin-resistant mutation in rpoB to activate the production of two β-carboline alkaloids JBIR-133 and JBIR-134. Then the biosynthetic gene cluster (BGC) ksl was introduced into PRh3-r55 for heterologous expression, generating PRh3-r55K. This combined approach achieved a synergistic effect, enabling the strain to produce not only the expected JBIR-133, JBIR-134, and kitasetaline, but also a novel sulfur-containing molecule, novkitasetaline. Structural elucidation identified novkitasetaline as a unique tryptamine-substituted kitasetaline derivative at the C-3 position of its pyridine ring. Notably, this structural modification conferred significant antimalarial activity to novkitasetaline, rendering it active against drug-sensitive Plasmodium falciparum 3D7 (IC₅₀ = 32.65 ± 2.93 μM) and three other drug-resistant P. falciparum strains: K13^C580Y, Dd2, and HB3 (IC₅₀ = 45.98 ± 4.17~59.67 ± 3.15 μM), primarily by disrupting late-stage parasite development. These efforts not only identified a promising antimalarial lead compound but also demonstrated that combining ribosome engineering with heterologous expression is an effective strategy for discovering bioactive natural products from Streptomyces. Full article

Chitosan, a naturally derived polysaccharide obtained by chitin deacetylation, has attracted considerable attention in dentistry as a multifunctional biomaterial owing to its excellent biocompatibility, biodegradability, and tunable physicochemical properties. This narrative review provides an up-to-date overview of the use of chitosan-based sponges in dental tissue engineering, bone regeneration, post-extraction wound management, and periodontal therapy. Chitosan sponges, characterized by high porosity, flexibility, and superior absorbency, serve as effective wound dressings, drug delivery carriers, and scaffolds that promote cell proliferation and tissue regeneration. Their intrinsic antibacterial, antifungal, hemostatic, and immunomodulatory properties further enhance their therapeutic value in managing complex oral conditions. In periodontal treatment, they enable localized drug delivery and support soft and hard tissue healing, while in post-extraction care, they aid hemostasis and reduce complications such as alveolar osteitis. Moreover, their osteoconductive and osteoinductive potential positions them as promising materials for alveolar bone repair and implantology. Chemical modification of chitosan and the incorporation of bioactive compounds allow customization of sponge formulations to meet specific clinical needs. Despite encouraging preclinical findings, challenges remain due to variability in chitosan sources, differences in the degree of deacetylation, and limited clinical validation. This review highlights the potential of chitosan sponges as innovative tools in regenerative dentistry and underscores the need for further standardization, mechanistic studies, and long-term clinical trials to ensure their safe and effective translation into dental practice. Moreover, the broad clinical applications of chitosan sponges beyond dentistry confirm their potential as a universal biomaterial platform in regenerative medicine. Full article

Mesenchymal stromal/stem cells (MSCs) appear in many studies, and their utilization is a developing area of study. Scientists are investigating the abilities of MSCs and the possibilities of using them in anticancer therapies, as well as combining such therapies with those currently used clinically. This article provides an overview of MSC-based therapeutic strategies, assessing their potential in the context of cancer treatment. These are engineering or biotechnological approaches that utilize the natural properties of MSCs in a targeted and therapeutically effective manner. The review focuses on innovative methods such as genetic modifications to express desired therapeutic molecules, highlighting their potential applications in clinical practice. Innovative strategies include modifications to express anticancer proteins, miRNA (microRNA), siRNA (small interfering RNA), lncRNA (long non-coding RNA), and circRNA (circular RNA) that induce specific effects, as well as the delivery of therapeutic genes and oncolytic viruses. However, further studies are required to address the existing impediments, which are also discussed in this review. A major challenge in the clinical application of MSCs is their bidirectional role, an issue that remains a central focus of current research and is examined in this article. Full article

Chondroitin sulfate (CS)-based nanoparticles have emerged as versatile and multifunctional platforms for cancer therapy, integrating effective drug delivery with diagnostic capabilities. Their ability to exploit the enhanced permeability and retention (EPR) effect enables selective accumulation within tumor tissues, while surface modification with CS enhances targeting efficiency through strong conformational and electrostatic affinity for CD44 receptors, which are overexpressed in many cancer cells. In addition, CS interacts with E-selectin, providing dual-targeting capabilities superior to those of other polysaccharides such as hyaluronic acid. A wide variety of CS-derived nanostructures—including micelles, nanogels, hybrid liposomes, and CS–drug conjugates—have shown great potential not only in drug delivery but also in advanced therapeutic modalities such as photodynamic, sonodynamic, and immunotherapy. This review discusses recent advances (2020–2025) in CS-based nanoplatforms for cancer therapy, with particular emphasis on the role of CS within nanostructures. It highlights how the functionalization of nanoparticles with CS represents a powerful strategy to improve colloidal stability, pharmacokinetics, and receptor-mediated uptake, thereby enabling controlled, site-specific drug release and reducing off-target toxicity. Ultimately, these advances open new opportunities for cancer treatment, with the potential for bench-to-clinic translation through the integration of AI-guided design, organelle-specific targeting, multi-pathway modulation, and immune system engagement. Full article

The coagulation cascade triggered by the contact between blood and the surface of implantable/interventional devices can lead to thrombosis, severely compromising the long-term safety and efficacy of medical devices. As an alternative to systemic anticoagulants, surface anticoagulant modification technology can achieve safer hemocompatibility on the device surface, holding significant potential for clinical application. This article systematically elaborates on the latest research progress in the surface anticoagulant modification of blood-contacting materials. It analyzes and discusses the main strategies and their evolution, spanning from physically inert carbon-based coatings and heparin-based drug-functionalized surfaces to hydrophilic/hydrophobic dynamic physical barriers, biologically signaling regulatory coatings, and bio-integrative/regenerative endothelium-mimicking surfaces. The advantages and limitations of the respective methods are outlined, and the potential for synergistic application of multiple strategies is explored. A special emphasis is placed on current research hotspots regarding novel anticoagulant surface technologies, such as hydrogel coatings, liquid-infused surfaces, and 3D-printed endothelialization, aiming to provide insights and references for developing long-term, safe, and hemocompatible cardiovascular implantable devices. Full article

The characterization and biomedical modification of bentonite clays from the Kalzhat deposit (Kzh), which is situated in Kazakhstan’s Zhetysu region, are the main objectives of this work. In order to improve the raw material’s structural qualities, the montmorillonite fraction was enriched, and coarse impurities were eliminated using the Salo method. The presence of meso- and micropores that guarantee high dispersity and specific surface area, as well as the prevalence of montmorillonite and kaolinite, was all confirmed by physicochemical analysis. Particle size measurements indicated finely dispersed structures with a propensity to aggregate, whereas thermal analysis demonstrated resilience under heating. After effective functionalization with silver nanoparticles, a porous hybrid system with improved surface reactivity was produced. These enhancements demonstrate the modified bentonite’s usefulness as a multifunctional carrier for the immobilization and controlled release of pharmaceuticals, with potential uses in drug delivery systems, antimicrobial coatings, and wound-healing materials. The material has potential use in sorption and environmental protection technologies in addition to its biomedical application. Overall, Kzh’s structural and functional performance is greatly improved by the combination of purification and functionalization with silver nanoparticles, highlighting its promise as a useful element in the development of next-generation polymer–composite systems. Full article

Poly (lactic-co-glycolic acid) (PLGA) is a widely used copolymer with applications across medical, pharmaceutical, and other industrial fields. Its biodegradability and biocompatibility make it one of the most versatile polymers for nanoscale drug delivery. The present review addresses current knowledge and recent advances in PLGA-based co-delivery nanoformulations with a special reference to design strategies, functional mechanisms, and translational potential. Conventional and advanced fabrication methods, the structural design of PLGA-based nanocarriers, approaches to scale-up and reproducibility, classification of co-delivery types, mechanisms governing drug release, surface modification and functionalization are all discussed. Special attention is given to PLGA-based co-delivery systems, encompassing drug–drug, drug–gene, gene–gene and multi-modal combinations, supported by recent studies demonstrating synergistic therapeutic outcomes. The review also examines clinical translation efforts and the regulatory landscape for PLGA-based nanocarriers. Unlike most existing reviews that typically focus either on PLGA fundamentals or on co-delivery approaches in isolation, this article bridges these domains by providing an integrated, comparative analysis of PLGA-based co-delivery systems and elucidating a critical gap in linking design strategies with translational requirements. In addition, by emphasising the relevance of PLGA-based co-delivery for combination therapies, particularly in cancer and other complex diseases, the review highlights the strong clinical and translational potential of these platforms. Key challenges, such as reproducibility, large-scale manufacturing, and complex regulatory pathways, are discussed alongside emerging trends and future perspectives. Taken together, this review positions PLGA-based co-delivery strategies as a critical driver for advancing precision therapeutics and shaping the future landscape of nanomedicine. Full article

Eosinophilic esophagitis (EoE) has emerged as a major cause of dysphagia and food impaction worldwide. This narrative review traces the evolving therapeutic pipeline for EoE, highlighting agents spanning from late-stage clinical development to final approval. We summarize mechanistic insights that have driven a shift from broad immunosuppression to precise inhibition of type-2 inflammatory pathways, including blockade of key interleukin pathways. Randomized trials have demonstrated histologic and symptomatic gains, yet regulatory approvals and optimal positioning within treatment algorithms are pending. Parallel innovations in drug delivery aim to maximize mucosal exposure while minimizing systemic burden. Key challenges include heterogeneity in disease phenotype, paucity of long-term safety data, and the need for non-invasive biomarkers to guide precision prescribing. Cost considerations and patient preferences will shape adoption. By integrating advances across immunology, formulation science and clinical trial design, the therapeutic pipeline for EoE holds promise to transform care from empirical suppression to mechanism-based disease modification. Full article

Mannans are structurally composed of β-(1 → 4)-linked mannose units, which are widely distributed in plant cell walls, yeast, and bacterial exopolysaccharides. Mannans have emerged as multipurpose biopolymers with significant industrial and biomedical potential. Celebrated mannans include guar gum, locust bean gum, konjac glucomannan, yeast mannans, and softwood glucomannans. This comprehensive review highlights the sources, structural diversity, extraction methods, physicochemical properties, safety, and functional characteristics. The major bioactivities of mannans, including immunomodulatory, antioxidative, and prebiotic effects, reflect their relevance in biopharmaceutical applications. Moreover, mannans serve as valuable raw materials for developing biodegradable films, hydrogels, and nanocomposites applied in sustainable materials and drug delivery systems. Despite promising applications, challenges related to their large-scale production, standardization, and functional optimization remain to be investigated. Future perspectives focus on integrating advanced biotechnological approaches and chemical modifications to enhance the functional versatility of mannans. Overall, mannans represent a sustainable, multifunctional biopolymer with expanding applications across food, pharmaceutical, and biomedical industries. Full article

Objective: The six-helix bundle (6-HB) is critical for HIV-1 membrane fusion. To disrupt this process, peptide inhibitors have been meticulously designed to target interactions within the 6-HB regions, thereby blocking membrane fusion and exerting inhibitory effects. Current peptide inhibitors like Enfuvirtide suffer from drug resistance and short in vivo half-life. This study aims to design novel anti-HIV-1 peptides by integrating heptad-repeat rules and membrane-anchor strategies. Methods: Artificial peptides were designed using HR rules from the HIV-1 gp41 6-HB motif and membrane-anchor modifications. Results: EK35S-Palm has emerged as a highly promising candidate for HIV-1 inhibition, exhibiting robust binding affinity to the target and effectively impeding the 6-HB spontaneous formation. Discussion: HR-based design avoids viral sequence homology, and membrane anchoring enhances local agent concentration, improving pharmacokinetics. The HR binding and membrane stabilization of EK35S-Palm provide synergistic inhibition. Conclusions: Integrating HR structural design with membrane-anchor strategies yields potent HIV-1 fusion inhibitors. EK35S-Palm demonstrates superior efficacy and stability over current therapies. These approaches hold great potential for overcoming the current therapy limitations and advancing the more effective and durable HIV-1 fusion inhibitors. Full article

Personalizing therapy using medical marijuana (MM) is based on understanding the pharmacogenomics (PGx) and drug–drug interactions (DDIs) involved, as well as identifying potential epigenetic risk markers. In this work, the evidence regarding the role of variants in phase I (CYP2C9, CYP2C19, CYP3A4/5) and II (UGT1A9/UGT2B7) genes, transporters (ABCB1), and selected neurobiological factors (AKT1/COMT) in differentiating responses to Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been reviewed. Data indicating enzyme inhibition by CBD and the possibility of phenoconversion were also considered, which highlights the importance of a dynamic interpretation of PGx in the context of current pharmacotherapy. Simultaneously, the results of epigenetic studies (DNA methylation, histone modifications, and ncRNA) in various tissues and developmental windows were summarized, including the reversibility of some signatures in sperm after a period of abstinence and the persistence of imprints in blood. Based on this, practical frameworks for personalization are proposed: the integration of PGx testing, DDI monitoring, and phenotype correction into clinical decision support systems (CDS), supplemented by cautious dose titration and safety monitoring. The culmination is a proposal of tables and diagrams that organize the most important PGx–DDI–epigenetics relationships and facilitate the elimination of content repetition in the text. The paper identifies areas of implementation maturity (e.g., CYP2C9/THC, CBD-CYP2C19/clobazam, AKT1, and acute psychotomimetic effects) and those requiring replication (e.g., multigenic analgesic signals), indicating directions for future research. Full article

Spectroscopic techniques offer significant potential for investigating ligand–protein interactions, particularly for assessing conformational modifications and binding affinity. In the present study, a complementary approach combining near-UV circular dichroism (CD) and second-derivative fluorescence spectroscopy was applied to evaluate how two representative nonsteroidal anti-inflammatory drugs—phenylbutazone (PHB, a marker of Sudlow’s site I) and ketoprofen (KP, a marker of Sudlow’s site II)—influence the tertiary structure of human serum albumin in its native form (HSA) and after glycation by glucose (gHSA_GLC), fructose (gHSA_FRC), and glucose–fructose syrup (gHSA_syrup). The results demonstrate that glycation substantially modifies the tertiary structure of HSA and decreases its drug-binding capacity at Sudlow’s sites I and II, with the most pronounced conformational changes observed for gHSA_FRC, confirming fructose as the most reactive glycation agent. PHB induced distinct conformational rearrangements, including a characteristic increase in ellipticity near ~290 nm, indicating perturbations in the chiral microenvironment surrounding Trp214 within Sudlow’s site I. By contrast, KP induced weaker, site-specific structural changes, primarily within Phe-rich hydrophobic domains of site II. Glycation consistently increased the polarity and solvent exposure of aromatic residue microenvironments—particularly within Tyr-rich regions—while the local environment of Trp214 remained comparatively stable. These findings suggest that PHB and KP modulate the conformational flexibility of glycated HSA predominantly by reorganizing Tyr-rich regions rather than directly perturbing Trp214. Overall, the study shows that glycation heterogeneity significantly influences protein–drug interactions, with important implications for altered pharmacokinetics in diabetes and metabolic disorders. The combined application of near-UV CD and second-derivative fluorescence spectroscopy offers a sensitive and complementary strategy for distinguishing structural differences between non-glycated and glycated HSA and for characterizing drug–albumin interactions at the tertiary structural level of the macromolecule. Full article

Antibiotic resistance (AR) has long been interpreted through the lens of genetic mutations and horizontal gene transfer. Yet, mounting evidence suggests that epigenetic regulation, including DNA and RNA methylation, histone-like proteins, and small non-coding RNAs, plays a similarly critical role in bacterial adaptability. These reversible modifications reshape gene expression without altering the DNA sequence, enabling transient resistance, phenotypic heterogeneity, and biofilm persistence under antimicrobial stress. Advances in single-molecule sequencing and methylome mapping have uncovered diverse DNA methyltransferase systems that coordinate virulence, efflux, and stress responses. Such epigenetic circuits allow pathogens to survive antibiotic exposure, then revert to susceptibility once pressure subsides, complicating clinical treatment. Parallel advances in CRISPR-based technologies now enable direct manipulation of these regulatory layers. CRISPR interference (CRISPRi) and catalytically inactive dCas9-fused methyltransferases can silence or reactivate genes in a programmable, non-mutational manner, offering a new route to reverse resistance or sensitize pathogens. Integrating methylomic data with transcriptomic and proteomic profiles further reveals how epigenetic plasticity sustains antimicrobial tolerance across environments. This review traces the continuum from natural bacterial methylomes to engineered CRISPR-mediated epigenetic editing, outlining how this emerging interface could redefine antibiotic stewardship. Understanding and targeting these reversible, heritable mechanisms opens the door to precision antimicrobial strategies that restore the effectiveness of existing drugs while curbing the evolution of resistance. Full article