Search Results (19,469)

Acinetobacter baumannii is a significant pathogen of hospital-acquired infections, and its multidrug resistance (MDR) and extended drug resistance (XDR) have become increasingly severe, posing a global public health challenge. This article provides a narrative review of the major resistance mechanisms of Acinetobacter baumannii, including β-lactamase production, efflux pump overexpression, target site modification, reduced membrane permeability, and biofilm formation. Additionally, it summarizes the current main drugs and their target sites for treating MDR Acinetobacter baumannii infections, with a focus on the mechanism of action, antibacterial activity, and clinical research progress of the novel fully synthetic fluorocycline antibiotic—eravacycline. Eravacycline inhibits protein synthesis by high-affinity binding to the bacterial ribosomal 30S subunit and demonstrates activity against multidrug-resistant Acinetobacter baumannii (excluding Pseudomonas aeruginosa), providing a potential novel therapeutic option for MDR/XDR Acinetobacter baumannii infections. Finally, the article outlines future research directions and treatment strategies. Due to the narrative nature of this review, no systematic methodology (e.g., PRISMA) was applied, and the available clinical evidence, particularly for CRAB infections, remains limited. Full article

Oral administration remains the most convenient and favored route for systemic delivery of small-molecule drugs, primarily due to patient compliance and the absence of invasive procedures. Yet, poor aqueous solubility, chemical/enzymatic instability, and limited permeability in the gastrointestinal (GI) tract often result in low bioavailability (BA) of many therapeutic agents. Polymeric micelles formed from the self-assembly of amphiphilic block copolymers have gained considerable attention as a nanotechnology-driven solution to overcome these challenges. Their hydrophobic core–hydrophilic shell structure enables efficient encapsulation of poorly soluble small molecule drugs, providing protection from acidic or enzymatic degradation while potentially enhancing drug transport across the intestinal epithelium. This review examines the design principles, formulation strategies, and in vivo performance of polymeric micelles for oral delivery of small molecule drugs. We discuss strategies to improve micelle stability in the GI environment, including optimization of core hydrophobicity, kinetic stabilization, and corona engineering, and compare polymeric micelles with established alternatives such as self-micro emulsifying drug delivery system (SMEDDS) and amorphous solid dispersions (ASDs) across critical performance parameters. Despite decades of preclinical progress, no oral polymeric micelle formulation has reached regulatory approval, underscoring the persistent challenge of maintaining micellar structural integrity under the dynamic conditions of the GI environment. This review therefore examines not only the promise but also the structural vulnerabilities of oral micelles, proposing a stability-centered framework for interpreting micelle function under GI conditions. Finally, we discuss current translational challenges and suggest directions for future research toward clinical application of oral polymeric micelle systems. Full article

Background/Objectives: The precise characterization of the key microstructural and physicochemical attributes in sustained-release microspheres remains a technical bottleneck, hindering the understanding of drug release mechanisms, and limiting insights into the “process–structure–performance” relationship. To address this, we developed novel methods to conduct in-depth research on the microscopic properties of microspheres. Methods: Scanning electron microscopy (SEM) combined with a deep learning-based image segmentation (DLIS) algorithm was established for quantitative analysis of the pore structure. Laser confocal Raman spectroscopy (LCRS) was employed for in situ, non-destructive, three-dimensional (3D) visualization and quantitative mapping of the active pharmaceutical ingredient (API) distribution within microspheres. Results: This study successfully developed and applied SEM-DLIS and LCRS as reliable tools for microstructural and physicochemical characterization. SEM-DLIS analysis revealed significant differences in surface and internal pore structure among microspheres from different manufacturers and between particles of different sizes from the same batch. LCRS imaging further identified distinct API distribution patterns: uniform dispersion, outer-layer enrichment, and heterogeneous distribution. The combined data elucidate that the initial burst release is governed by the synergistic effect of surface porosity and API surface enrichment, whereas the sustained release kinetics are jointly regulated by the internal pore structure, particle size, and API spatial distribution. Conclusions: The findings establish that microstructure dictates release behavior and that all observed structural variations are linked to critical process parameters (CPPs), validating the “process determines structure” hypothesis. The established methodology provides a critical technical framework for the reverse engineering and quality equivalence assessment of generic microspheres, as well as for the quality-by-design-based optimization of innovative drug products, thereby advancing both pharmaceutical development and regulatory science. Full article

Small-molecule drug development faces high attrition rates driven by complex pharmacokinetics and unforeseen toxicities. While deep learning offers high predictive accuracy, its opaque “black-box” nature hinders mechanistic transparency, clinical trust, and regulatory approval. This review synthesizes how Interpretable Machine Learning, synergized with systems pharmacology, advances this paradigm by enhancing mechanistic transparency in drug development. By providing insights into algorithmic decisions, Interpretable Machine Learning helps researchers identify molecular features that are statistically associated with absorption, distribution, metabolism, and excretion optimization and preemptively mitigate toxicophores, while noting that these associations require experimental validation to establish genuine causality. Furthermore, integrating multi-omics data via Interpretable Machine Learning guides rational polypharmacology, bridging in silico target identification with “dry-wet loop” validations. Crucially, Interpretable Machine Learning accelerates clinical translation by discovering causal biomarkers, refining patient stratification, and generating transparent “Model Cards” to satisfy U.S. Food and Drug Administration/ European Medicines Agency regulations. We also discuss future challenges: data heterogeneity, out-of-distribution generalizability, and the evolution toward Causal Artificial Intelligence. Ultimately, the integration of Interpretable Machine Learning provides a framework for more transparent and evidence-based drug design, realizing the promise of precision medicine. Full article

Background: Alcohol use disorder (AUD) is a grave mental health condition that can result in significant health and social consequences. The medications Naltrexone and Nalmefene are indicated for the treatment of AUD, with Naltrexone having received the most extensive research attention. Methods: The majority of papers assessing universal measures of alcohol consumption employed two primary metrics: total alcohol consumption (TAC) and the number of days per month where individuals engaged in heavy drinking (HDD). Indicators pertaining to the maintenance of complete abstinence were excluded due to the absence of sufficient data. The safety of both substances was also assessed, as were the frequency of side effects and independent patient dropout. The study also incorporated practical factors of the therapy, such as the route of administration, dosage regimen, and the drug’s patient convenience, which can have a significant impact on adherence to therapy. Results: Nalmefene, administered in an “as needed” regimen, demonstrated statistically significant activity in reducing HDD and total alcohol consumption (TAC) among patients with AUD, particularly those with elevated World Health Organization (WHO) DRL risk. Preliminary findings from the ESENSE1 (Efficacy of Nalmefene in Alcohol Dependence; the first phase III study), ESENSE 2 (Efficacy of Nalmefene in Alcohol Dependence, the second phase III study), and SENSE (the final phase III long term-safety and cost-effectiveness study) studies indicate a substantial decrease in HDD and TAC following the initial month of treatment. These effects persist throughout the subsequent follow-up period. Several Japanese studies have corroborated the effectiveness of Nalmefene, demonstrating its efficacy across both short-term and long-term applications. Furthermore, these studies have substantiated its safety profile, indicating that there is no inherent risk of addiction or the emergence of withdrawal symptoms. The mild nature of adverse events (most commonly nausea and dizziness) led to a relatively low discontinuation rate of Nalmefene treatment. A subsequent study, employing a recognized methodology, corroborated the efficacy of psychosocial support in enhancing treatment outcomes. Meta-analyses demonstrate that Naltrexone exhibits comparable efficacy in reducing the frequency and severity of alcohol consumption. In select populations, the injectable form (LAI) of this pharmaceutical agent facilitates less frequent dosing, which is advantageous for the treatment process. A comparison of Nalmefene and Naltrexone reveals that the latter does not demonstrate a significant impact on the likelihood of individuals returning to heavy alcohol consumption. Conclusions: In the treatment of AUD, both naltrexone and nalmefene have been shown to yield positive outcomes, particularly in terms of reducing the HDD and TAC. According to the World Health Organization (WHO) classification, Nalmefene is indicated for individuals with a high risk of developing serious conditions. It has been demonstrated to produce rapid and sustained results while exhibiting a favorable safety profile, characterized by the absence of significant adverse effects. Naltrexone is a medication that has proven to be effective. LAI may have a positive impact on the efficacy of treatment. Full article

A stable gut microbial community (SGMC) created by the culture of fecal samples in a chemostat-based gut model is a physiologically relevant, reproducible tool for ecological research on the gut microbiome. It is also a subject of continuous improvement for the model to better mimic the in vivo system. In this research, compositions of fecal homogenates and the derived SGMC were analyzed based on shotgun metagenomic sequencing. It was found that taxa in the fecal inocula could be divided into resilient or sensitive types according to their response to environmental factors; taxa were sorted into three subsets—shared, emerged, and lost—by how they were represented in the established communities. The first two subsets consisted of resilient species, constituting an SGMC, which was suitable for long-term, ecological research. In contrast, species of the lost subset were sensitive to the new environmental conditions and were missing from the SGMC. However, these lost species may carry host-dependent information that is useful or even critical for drug and functional foods development or nutrition research. The differentiation between the three subsets reveal the community shift and metabolic profile along with SGMC formation and could serve as a diagnosis for understanding the extent to which the SGMC mimics, or differs from, the actual ecosystem in vivo or the donor’s fecal samples, which may be useful in work to upgrade in vitro models. Full article

Effective hand washing takes time and hand sanitizers that contain alcohol have a number of drawbacks, and frequent use of alcohol may cause skin damage. The objective of this study is to formulate nanostructured lipid carrier systems containing chlorhexidine digluconate to be applied topically for hand hygiene, especially for people sensitive to alcohol. A cytotoxicity experiment was conducted to ascertain the safe dosage for each of the three nano-cream formulas (F1, F2 and F3). Following each treatment, the viral titer was assessed using tissue culture infectious dose₅₀ and standard plaque assays. The selected formulation was characterized rheologically. Furthermore, fifteen volunteers of various ages and genders participated in the vivo antimicrobial test of the selected formulation as a hand sanitizer. All of the formulas were found to be safe. Using the disc diffusion method, the three formulations exhibited in vitro antimicrobial effects against different microbes. F1 showed biphasic release, reasonable skin deposition and spherical droplets under a microscope. F1 exhibited a non-Newtonian shear thinning flow behavior. After 30 min, the reduction values for rotavirus and Phix-174 were 21 and 4%, respectively. Additionally, the impact of F1 was assessed on the infectivity of simian rotavirus sa-11 (ds RNA) and Phix-174 (ss DNA) bacteriophage. According to the findings of the in vivo study, the percentage of total bacterial counts that were removed varied from 91 to 100%. Moreover, the range of the removal percentage of total fungi was 95.38 to 100%. In summary, F1 can be used as an economic, safe, and effective hand antiseptic. It can also completely replace alcohol in the market. Full article

CD22 is a critical inhibitory coreceptor predominantly expressed on the surface of B cells, playing a pivotal role in modulating B cell receptor (BCR) signaling and maintaining immune homeostasis. Its high B cell lineage specificity, rapid internalization capacity, and signal attenuation mediated by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) render it an ideal therapeutic target for B cell-related pathologies. In recent years, CD22-targeted therapeutic strategies have demonstrated significant clinical breakthroughs in the treatment of hematological malignancies and autoimmune diseases. These strategies encompass immunotoxins, radioimmunoconjugates, antibody–drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy. Notably, while monotherapies have achieved high response rates, dual-targeting approaches (e.g., CD19/CD22 CAR-T) have further mitigated the risk of antigen escape and profoundly enhanced long-term durable efficacy. This review systematically summarizes the molecular mechanisms of CD22 and the latest clinical advancements in its targeted therapies. Furthermore, we highlight the promising translational potential of CD22-targeted strategies—particularly CAR-T cell therapy—from oncology to the management of autoimmune disorders, outlining future research priorities within this rapidly evolving field. Full article

Selenium has played a fundamental role in the evolution of aerobic life, thanks to its unique redox properties and its incorporation into antioxidant selenoproteins such as glutathione peroxidases (GPx). This evolutionary perspective has inspired decades of research aimed at developing small organoselenium compounds as GPx-like antioxidant drugs. However, despite extensive in vitro evidence and numerous publications, no organoselenium antioxidant has been commercialized, and even Ebselen, the most extensively studied selenium-based drug candidate, has repeatedly failed in multiple clinical trials. In this opinion article, we posit the hypothesis that a conceptual bias may underlie a significant proportion of the research conducted to date in this field. The antioxidant activity of GPx is contingent on a highly regulated enzymatic environment that is extremely difficult to reproduce with small synthetic molecules. Consequently, many compounds described as GPx mimetics may behave less like true antioxidants and more like redox-active electrophiles capable of disrupting complex thiol-dependent equilibria. It is recommended that future research should adopt a more holistic approach to the study of selenium pharmacology, moving beyond a reductionist interpretation of GPx-like activity. Instead, the focus should be on the complex network of cellular redox processes and selective redox targeting. It is only through a more profound mechanistic comprehension of selenium chemistry within biological systems that it will be feasible to ascertain whether organoselenium compounds can genuinely establish a presence within the domain of medicinal chemistry, extending beyond their persistent yet predominantly laboratory-restricted achievements. In a similar vein, undertaking a thorough examination of the mechanisms may facilitate a more profound comprehension of the fate of organoselenium compounds in their intricate interaction with biological targets. This, in turn, may enable the conception of novel molecules that function as effective and selective pro-oxidants against specific targets. Full article

Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) that occurs in most types of chronic liver diseases (CLDs) as a response to sustained liver injury. While the ECM comprises different proteins, collagen being the most abundant, the term matrisome refers to a plethora of ECM-related molecules, including collagen-associated proteins, growth factors, cytokines, enzymes and their endogenous inhibitors. The hepatic matrisome undergoes significant qualitative and quantitative changes during liver fibrosis. Despite intense research over recent years, our understanding of the matrisome in the liver—both in health and disease—and particularly of its function beyond its conventional structural role, remains poor. This review highlights how comprehending hepatic matrisome responses to liver injury can yield novel insights into disease progression and regression and could be exploited as a potential antifibrotic strategy. The antifibrotic potency of drugs that interfere with the matrisome at different levels has been demonstrated in preclinical studies, but translation to clinical trials remains still limited. So far, simtuzumab (LOXL2 inhibitor antibody), imatinib (small-molecule inhibitor against discoidin domain receptors—DDRs), bexotegrast (integrin inhibitor), GR-MD-02 (galectin 3 inhibitor), and BMS-986263 (siRNA-targeting HSP47) have been or are being evaluated in clinical trials related to CLD, and some of them have shown promising results. Full article

The rational design of mixed micellar systems has emerged as a cornerstone of modern nanomedicine, offering unprecedented control over the solubility and bioavailability of challenging therapeutic agents. This review provides a comprehensive analysis of the physicochemical principles governing the assembly of amphiphilic drugs and surfactants into synergistic nanostructures. By articulating the transition from traditional guest/host solubilization to “drug-as-component” models, we highlight the critical role of molecular interactions in achieving therapeutic precision. It further outlines the experimental methodologies used to investigate these systems and elucidates how they enhance the solubility, stability, and bioavailability of poorly water-soluble drugs. Special emphasis is placed on the practical applications of synergy in reducing systemic toxicity and optimizing drug release kinetics, providing a roadmap for the development of next-generation nano-pharmaceuticals. The functionality of these systems is significantly influenced by the molecular interactions among their constituents; thus, quantitative analysis of these interactions might enhance the formulation of more effective pharmaceuticals. This review outlines the key physicochemical principles of mixed micelle formation, including thermodynamics and synergistic interactions of amphiphiles, while emphasizing their relevance in current research and practical pharmaceutical applications. Various experimental methods, such as surface tension measurement, conductometric and calorimetric tests, and spectroscopic techniques, are compared in terms of their conditions of application and performance in understanding micelle formation and micelle structure. We clearly point out that the interpretation and evaluation of the properties of colloidal systems containing drug molecules solubilized by mixed micelles and an amphiphilic drug incorporated into micelles must be discussed and evaluated separately. Understanding the limitations and characteristics of the physical/chemical principles applied is essential for the rational design of mixed micelle carriers tailored to specific therapeutic needs. Full article

Background/Objectives: Artificial intelligence (AI) is increasingly used in clinical decision-support systems, yet its adoption in low- and middle-income countries, including Jordan, remains limited and underexplored. Understanding how healthcare professionals perceive AI-assisted clinical decision-making is essential for safe and contextually appropriate implementation. This study explored healthcare professionals’ perceptions of AI-assisted clinical decision-making in Jordan, with particular attention to trust, accuracy, accountability, professional judgement, digital literacy, and health-system readiness. Medication-related safety and prescribing concerns were examined as secondary cross-cutting issues where they emerged from participants’ accounts. Methods: A qualitative study was conducted using semi-structured, in-depth interviews with 22 purposively sampled healthcare professionals from public, private, and university-affiliated healthcare institutions in Amman, Irbid, and Zarqa. Participants included physicians, nurses, pharmacists, and allied health professionals with varied specialties and levels of seniority. Data were analysed using Braun and Clarke’s reflexive thematic analysis. Member checking, peer debriefing, reflexive memos, and audit trails were used to enhance trustworthiness, and reporting followed the Consolidated Criteria for Reporting Qualitative Research (COREQ). Results: Eight overarching themes were identified: conditional trust in AI-assisted clinical decision-making; concerns regarding accuracy and confident algorithmic errors; accountability and professional responsibility; AI as an adjunct rather than a substitute for clinical judgement; the influence of experience, specialty, and digital literacy on AI acceptance; Jordanian health-system readiness; privacy, confidentiality, and algorithmic bias; and training requirements for safe AI use. Medication-related safety emerged as a cross-cutting concern, particularly in relation to dosing, polypharmacy, drug–drug and drug–herb interactions, and the risk of over-reliance on AI-generated recommendations. Conclusions: Healthcare professionals in Jordan expressed cautious but constructive views toward AI-assisted clinical decision-making. AI was perceived as potentially useful when used to support, rather than replace, professional judgement. Participants’ accounts suggest that safe implementation depends on local validation, clear accountability frameworks, ethical data governance, interprofessional training, and careful consideration of medication-safety expertise where AI tools influence prescribing or therapeutic decisions. These findings highlight the importance of context-sensitive AI governance strategies that support trustworthy, accountable, and professionally supervised AI adoption in healthcare. Full article

Commercially available graphene quantum dots (GQDs) are promising nanomaterials for applications in research and preclinical diagnostics, drug delivery, and bioimaging. Their bioactivity is highly dependent on dose, route of exposure, duration, cell type, uptake mechanisms, tissue and cellular distribution, and physicochemical properties. This study aimed to evaluate genotoxic, cytotoxic, and cytostatic endpoints of blue- (B-GQDs) and green-emitting (G-GQDs) GQDs in human blood and salivary leukocytes. GQDs were tested at concentrations ranging from 2.5 to 100 µg/mL using distinct treatment periods. Fourier transform infrared spectroscopy (FTIR), trypan blue exclusion, comet, and cytokinesis-block micronucleus cytome (CBMN cyt) assays were performed. FTIR analysis revealed that G-GQDs, unlike B-GQDs, exhibit an absorption band typically associated with amine functional groups, which may contribute to their pronounced genotoxic effects. Peripheral blood mononuclear cells and salivary leukocytes showed higher sensitivity to G-GQDs compared to whole blood samples. Although no cytotoxic effects were observed, both GQDs induced significant DNA damage, with G-GQDs demonstrating greater genotoxic potential. These findings demonstrate that GQDs can induce DNA damage in the absence of detectable cytotoxic effects under the conditions tested, highlighting the importance of considering both physicochemical properties and cellular models in the safety assessment of nanomaterials. Full article

The global dissemination of carbapenem resistance is predominantly facilitated by plasmid-mediated carbapenemase genes, notably blaOXA-48-like genes. A comprehensive understanding of their evolutionary relationships and structural conservation is essential for monitoring their spread and informing therapeutic strategies. This study aimed to investigate the phylogenetic relationships and structural conservation of blaOXA-48-like carbapenemase genes in multiple Gram-negative bacterial species. We analysed blaOXA-48-like carbapenemase sequences obtained from a hospital in Pakistan and compared them with globally reported variants retrieved from GenBank. Carbapenemase gene sequences (blaOXA-48-like, blaNDM, and blaVIM) were analyzed using maximum-likelihood phylogenetics (MEGA11, Tamura–Nei model, 1000 bootstrap replicates). Comparative global sequences were retrieved from GenBank. Structural modeling of blaOXA-48-like genes was performed using SWISS-MODEL Workspace with the template PDB 3HBR, followed by validation using GMQE, QMEANDisCo, and Ramachandran plot analyses. Phylogenetic analysis revealed a tight clustering of blaOXA-48-like genes across A. baumannii, K. pneumoniae, and E. meningoseptica, showing high similarity to globally distributed plasmid-associated sequences. Structural modeling demonstrated strong conservation of the enzyme, with preserved catalytic residues (Ser70, Lys73, Ser118, Trp157, and Tyr211) and minimal structural deviation (RMSD < 0.3 Å). blaOXA-48-like carbapenemases exhibit strong phylogenetic conservation and structural stability across species and regions, consistent with the horizontal dissemination of blaOXA-48-like genes across bacterial hosts. These findings indicate that blaOXA-48-like carbapenemases have high evolutionary stability. Full article