Search Results (3,220)

Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial cell wall biosynthesis. Objectives: The objective was to design and characterize a novel small-molecule inhibitor targeting PBP2a as a strategy to combat MRSA. Methods: We synthesized a new indole triazole conjugate (ITC) using eco-friendly and click chemistry approaches. In vitro antibacterial tests were performed against a panel of strains to evaluate the ITC antibacterial potential. Further, a series of in silico evaluations like molecular docking, MD simulations, free energy landscape (FEL), and principal component analysis (PCA) using the crystal structure of PBP2a (PDB ID: 4CJN), in order to predict the mechanism of action, binding mode, structural stability, and energetic profile of the 4CJN-ITC complex. Results: The compound ITC exhibited noteworthy antibacterial activity, which effectively inhibited the selected strains. Binding score and energy calculations demonstrated high affinity of ITC for the allosteric site of PBP2a and significant interactions responsible for complex stability during MD simulations. Further, FEL and PCA provided insights into the conformational behavior of ITC. These results gave the structural clues for the inhibitory action of ITC on the PBP2a. Conclusions: The integrated in vitro and in silico studies corroborate the potential of ITC as a promising developmental lead targeting PBP2a in MRSA. This study demonstrates the potential usage of rational drug design approaches in addressing therapeutic needs related to ABR. Full article

Invasive fungal infections (IFIs) represent a growing global health threat, particularly for immunocompromised populations, with mortality exceeding 1.5 million deaths annually. Despite their clinical and economic burden—costing billions in healthcare expenditures—fungal infections remain underprioritized in public health agendas. This review examines the current landscape of antifungal therapy, focusing on advances, challenges, and future directions. Key drug classes (polyenes, azoles, echinocandins, and novel agents) are analyzed for their mechanisms of action, pharmacokinetics, and clinical applications, alongside emerging resistance patterns in pathogens like Candida auris and azole-resistant Aspergillus fumigatus. The rise of resistance, driven by agricultural fungicide use and nosocomial transmission, underscores the need for innovative antifungals, rapid diagnostics, and stewardship programs. Promising developments include next-generation echinocandins (e.g., rezafungin), triterpenoids (ibrexafungerp), and orotomides (olorofim), which target resistant strains and offer improved safety profiles. The review also highlights the critical role of “One Health” strategies to mitigate environmental and clinical resistance. Future success hinges on multidisciplinary collaboration, enhanced surveillance, and accelerated drug development to address unmet needs in antifungal therapy. Full article

Background/Objectives. This manuscript presents an overview of advances in oncological radiotherapy as an effective treatment method for cancerous tumors, focusing on mechanisms of action within metabolite–antimetabolite systems. The urgency of this topic is underscored by the fact that cancer remains one of the leading causes of death worldwide: as of 2022, approximately 20 million new cases were diagnosed globally, accounting for about 0.25% of the total population. Given prognostic models predicting a steady increase in cancer incidence to 35 million cases by 2050, there is an urgent need for the latest developments in physics, chemistry, molecular biology, pharmacy, and strict adherence to oncological vigilance. The purpose of this work is to demonstrate the relationship between the nature and mechanisms of past diagnostic and therapeutic oncology approaches, their current improvements, and future prospects. Particular emphasis is placed on isotope technologies in the production of therapeutic nuclides, focusing on the mechanisms of formation of simple and complex theranostic compounds and their classification according to target specificity. Methods. The methodology involved searching, selecting, and analyzing information from PubMed, Scopus, and Web of Science databases, as well as from available official online sources over the past 20 years. The search was structured around the structure–mechanism–effect relationship of active pharmaceutical ingredients (APIs). The manuscript, including graphic materials, was prepared using a narrative synthesis method. Results. The results present a sequential analysis of materials related to isotope technology, particularly nucleus stability and instability. An explanation of theranostic principles enabled a detailed description of the action mechanisms of radiopharmaceuticals on various receptors within the metabolite–antimetabolite system using specific drug models. Attention is also given to radioactive nanotheranostics, exemplified by the mechanisms of action of radioactive nanoparticles such as Tc-99m, AuNPs, wwAgNPs, FeNPs, and others. Conclusions. Radiotheranostics, which combines the diagnostic properties of unstable nuclei with therapeutic effects, serves as an effective adjunctive and/or independent method for treating cancer patients. Despite the emergence of resistance to both chemotherapy and radiotherapy, existing nuclide resources provide protection against subsequent tumor metastasis. However, given the unfavorable cancer incidence prognosis over the next 25 years, the development of “preventive” drugs is recommended. Progress in this area will be facilitated by modern medical knowledge and a deeper understanding of ligand–receptor interactions to trigger apoptosis in rapidly proliferating cells. Full article

Efflux is one of the key mechanisms used by Gram-negative bacteria to reduce internal antibiotic concentrations. These active transport systems recognize and expel a wide range of toxic molecules, including antibiotics, thereby contributing to reduced antibiotic susceptibility and allowing the bacteria to acquire additional resistance mechanisms. To date, unlike other resistance mechanisms such as enzymatic modification or target mutations/masking, efflux is challenging to detect and counteract in clinical settings, and no standardized methods are currently available to diagnose or inhibit this mechanism effectively. This review first outlines the structural and functional features of major efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. It then explores various strategies used to curb their activity, with a particular focus on efflux pump inhibitors under development, detailing their structural classes, modes of action, and pharmacological potential. We discuss the main obstacles to their development, including the structural complexity and substrate promiscuity of efflux mechanisms, the limitations of current screening methods, pharmacokinetic and tissue distribution issues, and the risk of off-target toxicity. Overcoming these multifactorial barriers is essential to the rational development of less efflux-prone antibiotics or of efflux pump inhibitors. Full article

The majority of studies of fungal utilization of chitosan are associated with the production of a specific enzyme, chitosanase, which catalyzes the hydrolytic cleavage of the macrochain. In our opinion, the development of approaches to obtaining materials with new functional properties based on non-destructive chitosan transformation by living organisms and their enzyme systems is promising. This study was conducted using a wide range of classical and modern methods of microbiology, biochemistry, and physical chemistry. The ability of the ascomycete Fusarium oxysporum Schltdl. to modify films of chitosan with average-viscosity molecular weights of 200, 450, and 530 kDa was discovered. F. oxysporum was shown to use chitosan as the sole source of carbon/energy and actively overgrew films without deformations and signs of integrity loss. Scanning electron microscopy (SEM) recorded an increase in the porosity of film substrates. An analysis of the FTIR spectra revealed the occurrence of oxidation processes and crosslinking of macrochains without breaking β-(1,4)-glycosidic bonds. After F. oxysporum growth, the resistance of the films to mechanical dispersion and the degree of ordering of the polymer structure increased, while their solubility in the acetate buffer with pH 4.4 and sorption capacity for Fe²⁺ and Cu²⁺ decreased. Elemental analysis revealed a decrease in the nitrogen content in chitosan, which may indicate its inclusion into the fungal metabolism. The film transformation was accompanied by the production of extracellular hydrolase (different from chitosanase) and peroxidase, as well as biosurfactants. The results obtained indicate a specific mechanism of aminopolysaccharide transformation by F. oxysporum. Although the biochemical mechanisms of action remain to be analyzed in detail, the results obtained create new ways of using fungi and show the potential for the use of Fusarium and/or its extracellular enzymes for the formation of chitosan-containing materials with the required range of functional properties and qualities for biotechnological applications. Full article

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Risk factors for EC include metabolic alterations (obesity, metabolic syndrome, insulin resistance), hormonal imbalance, age at menopause, reproductive factors, and inherited conditions, such as Lynch syndrome. For the inherited forms, several genes had been implicated in EC occurrence and development, such as POLE, MLH1, TP53, PTEN, PIK3CA, PIK3R1, CTNNB1, ARID1A, PPP2R1A, and FBXW7, all mutated at high frequency in EC patients. However, gene function impairment is not necessarily caused by mutations in the coding sequence of these and other genes. Gene function alteration may also occur through post-transcriptional control of messenger RNA translation, frequently caused by microRNA action, but transcriptional impairment also has a profound impact. Here, we review how chromatin modifications change the expression of genes whose impaired function is directly related to EC etiopathogenesis. Chromatin modification plays a central role in EC. The modification of chromatin structure alters the accessibility of genes to transcription factors and other regulatory proteins, thus altering the intracellular protein amount. Thus, DNA structural alterations may impair gene function as profoundly as mutations in the coding sequences. Hence, its central importance is in the diagnostic and prognostic evaluation of EC patients, with the caveat that chromatin alteration is often difficult to identify and needs investigations that are specific and not broadly used in common clinical practice. The different phases of the healthy endometrium menstrual cycle are characterized by differential gene expression, which, in turn, is also regulated through epigenetic mechanisms involving DNA methylation, histone post-translational modifications, and non-coding RNA action. From a medicolegal and policy-making perspective, the implications of using epigenetics in cancer care are briefly explored as well. Epigenetics in endometrial cancer is not only a topic of biomedical interest but also a crossroads between science, ethics, law, and public health, requiring integrated approaches and careful regulation. Full article

The shear tests are conducted on six precast segmental concrete beams (PSCBs) in this paper. A new specimen design scheme is presented to compare the effects of segmental joints on the shear performance of PSCBs. The failure modes, shear strength, structural deflection, stirrup strain, and tendon stress are recorded. The factors of shear span ratio, the position of segmental joints, and hybrid tendon ratio are focused on, and their effects on the shear behaviors are compared. Based on the measured responses, the shear contribution proportions of concrete segments, prestressed tendons, and stirrups are decomposed and quantified. With the observed failure modes, the truss–arch model is employed to clarify the shear mechanism of PSCBs, and simplified equations are further developed for predicting the shear strength. Using the collected test results of 30 specimens, the validity of the proposed equations is verified with a mean ratio of calculated-to-test values of 0.96 and a standard deviation of 0.11. Furthermore, the influence mechanism of shear span ratio, segmental joints, prestressing force, and hybrid tendon ratio on the shear strength is clarified. The increasing shear span ratio decreases the inclined angle of the arch ribs, thereby reducing the shear resistance contribution of the arch action. The open joints reduce the number of stirrups passing through the diagonal cracks, lowering the shear contribution of the truss action. The prestressing force can reduce the inclination of diagonal cracks, improving the contribution of truss action. The external unbonded tendon will decrease the height of the arch rib due to the second-order effects, causing lower shear strength than PSCBs with internal tendons. Full article

The increasing threat of antimicrobial resistance (AMR), along with the limited availability of new lead compounds in the drug development pipeline, highlights the urgent need to discover antimicrobial agents with innovative mechanisms of action. In this regard, metal complexes offer a unique opportunity to access mechanisms distinct from those of conventional antibiotics. Although iron (Fe) is an essential element for all forms of life, including pathogenic bacteria, it also poses a serious risk of cytotoxicity due to its redox activity, which can trigger the production of reactive oxygen species (ROS) via the Fenton reaction. This review highlights recent advances in the development of iron-based antimicrobial agents that harness the toxicity resulting from dysregulated iron uptake, thereby inducing bacterial cell death through oxidative stress. These findings may guide the development of effective treatments for pathogenic infections and offer new perspectives on leveraging redox chemistry of iron to combat the growing threat of global bacterial resistance. Full article

The global antimicrobial resistance crisis demands innovative strategies to combat bacterial infections, including those caused by drug-sensitive pathogens that evade treatment through biofilm formation or metabolic adaptations. Here, we demonstrate that Squama Manitis extract (SME)—a traditional Chinese medicine component—exhibits broad-spectrum bactericidal activity against clinically significant pathogens, including both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) species (MIC = 31.25 mg/mL), achieving significant reduction in bacterial viability within 24 h. Through integrated multi-omics analysis combining scanning electron microscopy and RNA sequencing, we reveal SME’s unprecedented tripartite mechanism of action: (1) direct membrane disruption causing cell envelope collapse, (2) metabolic paralysis through coordinated suppression of TCA cycle and fatty acid degradation pathways, and (3) inhibition of DNA repair systems (SOS response and recombination downregulation). Despite its potent activity, SME shows low cytotoxicity toward mammalian cells (>90% viability) and can penetrate Gram-negative outer membranes. These features highlight SME’s potential to address drug-resistant infections through synthetic lethality across stress response, energy metabolism, and DNA integrity pathways. While advocating for synthetic alternatives to endangered animal products, this study establishes SME as a polypharmacological template for resistance-resilient antimicrobial design, demonstrating how traditional knowledge and modern systems biology can converge to guide sustainable anti-infective development. Full article

This article explores how the European Union (EU) promotes gender equality beyond its borders, situating the analysis within broader debates on external Europeanization and normative power. While most studies have examined the domestic impact of EU policies, this paper focuses on how gender equality norms are projected internationally and conceptually investigates the mechanisms involved in their diffusion. Drawing on existing theoretical literature, the article analyzes how EU-level normative strategies may interact with domestic political, institutional, and societal dynamics in third countries, often in complex and contested ways. Rather than providing empirical testing, the study identifies core mechanisms—such as strategic communication, partnerships, and funding tools—and reflects on their limitations and the role of local agency in interpreting or resisting EU-promoted norms. The findings highlight the difficulty of isolating EU influence from other international and transnational drivers of norm diffusion, and the need for caution in attributing policy shifts solely to EU action. The article concludes that a better understanding of these processes requires more attention to domestic contexts, as well as future empirical research to complement conceptual analyses of Europeanization in sensitive policy domains such as gender equality. Full article

Antimicrobial resistance (AMR) has emerged as one of the most pressing global health challenges of our time. Alarming projections of increasing mortality from resistant infections highlight the urgent need for innovative solutions. While many candidates have shown promise in preliminary studies, they often encounter challenges in terms of efficacy and safety during clinical translation. This review examines cutting-edge approaches to combat AMR, with a focus on engineered antimicrobial peptides, functionalized nanoparticles, and advanced genomic therapies, including Clustered Regularly Interspaced Short Palindromic Repeats-associated proteins (CRISPR-Cas systems) and phage therapy. Recent advancements in these fields are critically analyzed, with a focus on their mechanisms of action, therapeutic potential, and current limitations. Emphasis is given to strategies targeting biofilm disruption and quorum sensing interference, which address key mechanisms of resistance. By synthesizing current knowledge, this work provides researchers with a comprehensive framework for developing next-generation antimicrobials, highlighting the most promising approaches for overcoming AMR through rational drug design and targeted therapies. Ultimately, this review aims to bridge the gap between experimental innovation and clinical application, providing valuable insights for developing effective and resistance-proof antimicrobial agents. Full article

In the face of escalating cyber threats to critical infrastructures, achieving robust cyber resilience has become paramount. This paper proposes an endogenous security-oriented framework for cyber resilience assessment, specifically tailored for critical infrastructures. Drawing on the principles of endogenous security, our framework integrates dynamic heterogeneous redundancy (DHR) and adaptive defense mechanisms to address both known and unknown threats. We model resilience across four key dimensions—Prevention, Destruction Resistance, Adaptive Recovery, and Evolutionary Learning—using a novel mathematical formulation that captures nonlinear interactions and temporal dynamics. The framework incorporates environmental threat entropy to dynamically adjust resilience scores, ensuring relevance in evolving attack landscapes. Through empirical validation on simulated critical infrastructure scenarios, we demonstrate the framework’s ability to quantify resilience trajectories and trigger timely defensive adaptations. Empiricalvalidation on a real-world critical infrastructure system yielded an overall resilience score of 82.75, revealing a critical imbalance between strong preventive capabilities (90/100) and weak Adaptive Recovery (66/100). Our approach offers a significant advancement over static risk assessment models by providing actionable metrics for strategic resilience investments. This work contributes to the field by bridging endogenous security theory with practical resilience engineering, paving the way for more robust protection of critical systems against sophisticated cyber threats. Full article

In this study, alkali-activated coal gangue-slag material (AACGS) was prepared using coal gangue and slag as precursors, and its feasibility as conductive mortar substrate material was preliminarily investigated. Firstly, this study employed Response Surface Methodology (RSM) to develop statistical models correlating the alkali equivalent, water-to-binder ratio, and slag content with the compressive strength, flexural strength, and resistivity of AACGS, aiming to identify the optimal mix proportions. Secondly, based on the optimal ratio identified above and using carbon fibers (CF) as the conductive phase, an alkali-activated conductive mortar (CF-AACGS) was prepared, and its compressive strength, flexural strength, and resistivity were tested. Lastly, XRD and SEM-EDS were conducted to characterize the mineral composition and microstructure of CF-AACGS. The results indicate that when the alkali equivalent, water-to-binder ratio, and slag content are 13.34%, 0.54, and 57.52%, respectively, the AACGS achieves compressive strength, flexural strength, and resistivity of 72.5 MPa, 7.0 MPa, and 62.41 Ω·m at 28 days. Under the action of the alkali activator, coal gangue and slag undergo hydration reactions, forming a denser N, C-(A)-S-H gel. This effectively improves the interface transition zone between the CF and AACGS, endowing the CF-AACGS with superior mechanical properties. Furthermore, the AACGS matrix enhances the conductive contact point density by optimizing CF dispersion, which significantly reduces the resistivity of the CF-AACGS. Full article

Background/Objectives: All current FDA-approved antibody–drug conjugates (ADCs) are single-target and single-payload molecules that have limited efficacy in patients due to drug resistance. Therefore, our goal was to generate a novel ADC that was less susceptible to single points of resistance to reduce the likelihood of patient relapse. Methods: We developed a dual-targeting, dual-payload ADC by conjugating a bispecific EGFR x cMET antibody to two payloads (MMAF and SN38) that had separate mechanisms of action using a novel tri-functional linker. This dual-payload ADC was tested for potency and efficacy in dividing and nondividing in vitro cell models using multiple tumor cell types. Efficacy of the dual-payload ADC was confirmed using in vivo models. Results: Our ADC with dual MMAF and SN38 payloads was more efficacious in inhibiting cell proliferation than single-payload ADCs across multiple cancer cell lines. In addition, the dual-payload molecule inhibited nondividing cells, which were more resistant to traditional ADC payloads. The dual-payload ADC also exhibited more potent tumor growth inhibition in vivo compared to that of single-payload ADCs. Conclusions: Overall, the bispecific antibody conjugated with both the MMAF and SN38 payloads inhibited tumor growth more strongly than ADCs conjugated with MMAF or SN38 alone. Developing dual-payload ADCs could limit the impact of acquired resistance in patients as well as lower the effective dose of each payload. Full article

Urinary tract infections (UTIs) are among the most prevalent bacterial infections in women, with high recurrence rates and growing concerns over antimicrobial resistance. The need for alternative or adjunctive therapies has spurred interest in plant-based treatments, which offer antimicrobial, anti-inflammatory, antioxidant, and immune-modulatory benefits. This review summarizes the mechanisms of action, clinical efficacy, and therapeutic potential of various medicinal plants and natural compounds for preventing and treating UTIs in women. Notable candidates include cranberry, bearberry, pomegranate, green tea, and other phytochemicals with proven anti-adhesive and biofilm-disrupting properties. Evidence from clinical trials and meta-analyses supports the role of cranberry natural products and traditional herbal medicines (THMs) in reducing UTI recurrence, especially when combined with antibiotics. Notably, A-type proanthocyanidins in cranberry and arbutin in bearberry are key bioactive compounds that exhibit potent anti-adhesive and biofilm-disrupting properties, offering promising adjunctive strategies for preventing recurrent urinary tract infections. Additionally, emerging therapies, such as platelet-rich plasma (PRP), show promise in restoring bladder function and reducing infection in women with lower urinary tract dysfunction. Overall, plant-based strategies represent a valuable and well-tolerated complement to conventional therapies and warrant further investigation through high-quality clinical trials to validate their efficacy, safety, and role in personalized UTI management. Full article