Search Results (20,489)

Background: The increasing prevalence of antifungal resistance among Candida albicans isolates necessitates the exploration of alternative antifungal strategies and novel molecular targets. Plant-derived bioactive compounds represent a promising source of antifungal agents; however, their chemical composition and mechanisms of action remain insufficiently characterized. Methods: Ethanolic extracts of Azadirachta indica leaves and Ficus benghalensis aerial roots were subjected to qualitative phytochemical screening, gas chromatography–mass spectrometry (GC–MS), and Fourier transform infrared (FTIR) analysis to characterize their bioactive constituents. Molecular docking studies were performed to evaluate the interaction of selected phytochemicals with C. albicans N-myristoyltransferase (PDB ID: 1IYK), a validated antifungal drug target. Results: Phytochemical screening revealed the presence of alkaloids, carbohydrates, and phenolic compounds in both extracts, while saponins were detected only in A. indica. GC–MS analysis demonstrated greater chemical diversity in A. indica, including fatty acids and phenolic derivatives, compared with F. benghalensis, which was dominated by terpenoids and long-chain hydrocarbons. FTIR analysis confirmed functional groups relevant to protein–ligand interactions. Molecular docking showed favorable binding interactions between several A. indica–derived compounds and N-myristoyltransferase, whereas compounds from F. benghalensis did not exhibit detectable binding under the conditions tested. Conclusions: The integrated phytochemical and in silico analyses provide insight into the antifungal potential of A. indica, suggesting possible interactions between identified phytochemicals and the selected drug target protein. This study highlights the value of combining chemical characterization with target-based computational screening in the rational exploration of plant-derived antifungal agents. Full article

Colistin (polymyxin E), a last-resort antibiotic for the treatment of multidrug-resistant Gram-negative bacterial infections, is becoming increasingly compromised by the rapid emergence and dissemination of resistance. The extensive use of colistin in agriculture and veterinary medicine has accelerated the spread of plasmid-mediated mobile colistin resistance (mcr) genes, facilitating transmission across human, animal, and environmental reservoirs. This review provides a comprehensive overview of the epidemiology, molecular mechanisms, and geographical distribution of colistin resistance in the Middle East and North Africa (MENA) region. Analysis of the available literature indicates that Tunisia reports the highest prevalence of colistin-resistant Gram-negative bacteria in North Africa (58.09%), followed by Egypt (24.76%), Algeria (14.29%), and Libya (2.86%). Across the region, mcr-1 is the predominant plasmid-mediated resistance determinant, whereas chromosomal alterations involving the mgrB, pmrA/pmrB, and phoP/phoQ regulatory systems are the principal non-plasmid-mediated mechanisms. Resistance has been documented in major clinical pathogens, including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, as well as in livestock, poultry, aquaculture, wildlife, food products, and environmental samples, highlighting the interconnected nature of resistance transmission under a One Health framework. The evidence demonstrates substantial geographical variability and significant gaps in surveillance across several MENA countries, limiting accurate regional burden estimates. Strengthening antimicrobial stewardship, harmonized surveillance programs, molecular monitoring of resistance determinants, and the implementation of One Health strategies are essential to limit the continued emergence and dissemination of colistin resistance throughout the region. Full article

The increased occurrence of tetracycline resistance (conferred by the tet(X3)/tet(X4) resistance genes) poses a major challenge to the clinical treatment of infections using tetracyclines, including tigecycline, which is the “last-resort” therapeutic agent. Thus, there is an urgent need to develop inhibitors targeting Tet(X3)/Tet(X4) to address the crisis of tetracycline resistance. This study revealed that quercetin is an inhibitor of Tet(X3)/Tet(X4), which, when combined with different tetracyclines, can exert synergistic growth-inhibitory effects against Tet(X3)/Tet(X4)-positive bacteria (fractional inhibitory concentration < 0.5). Quercetin + tigecycline significantly decreased the biofilm-forming ability of bacteria. Mechanistic investigations revealed that quercetin inhibits the catalytic activity of Tet(X4) against tetracycline antibiotics by binding to the catalytic active site. In the Galleria mellonella larval infection model of Tet(X4)-positive E. coli J53p47EC or Tet(X4)-negative E. coli J53, tigecycline + quercetin enhanced the survival rate, decreased melanization, and suppressed bacterial load. Thus, the findings of this study will enable the development of novel Tet(X3)/Tet(X4)-targeted therapeutic strategies for clinical infections caused by drug-resistant Enterobacteriaceae and Acinetobacter baumannii, especially Tet(X3)/Tet(X4)-positive pathogens. Full article

Monitoring poultry microbiota and antimicrobial resistance genes is important, as they can reflect flock health, farm conditions, and the level of antimicrobial resistance. Although shotgun metagenomics has been widely applied worldwide to investigate poultry microbiota and antimicrobial resistance, comparable baseline datasets describing the cloacal microbiota and resistome of poultry in Kazakhstan are scarce. In this study, taxonomic and resistome profiles were characterized in pooled metagenomes of the cloacal microbiota of chickens sampled from household and industrial poultry farms in Kazakhstan. Cloacal swabs were collected from laying hens, pooled at the house level, and analyzed using high-throughput metagenomic sequencing. Taxonomic profiles were generated at the genus level, and antimicrobial resistance gene signals were summarized by drug class. Compositional patterns were assessed using CLR/Aitchison ordination, the Mantel test, and Procrustes analysis. The pooled samples exhibited heterogeneous microbiota profiles at the genus level and included taxa of veterinary interest, such as Chlamydia, Avibacterium, and Gallibacterium spp. Resistome profiling revealed a broad but uneven distribution of antimicrobial resistance signals, including those associated with tetracyclines, fluoroquinolones, aminoglycosides, and beta-lactams. Taxonomic and resistome profiles showed preliminary alignment at the matrix level, indicating that resistome variations are partially linked to microbial community structure. Full article

Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA–WSB1–PSMA axis as a therapeutic vulnerability in refractory prostate cancer. Full article

Antimicrobial resistance in mycobacteria arises from a complex interplay of intrinsic and acquired mechanisms that collectively limit the efficacy of current therapeutic options. Intrinsic resistance is largely driven by the low permeability of the mycobacterial cell envelope, the activity of efflux pumps, and the presence of drug-modifying enzymes, which together restrict intracellular drug accumulation and contribute to broad baseline tolerance. This review integrates resistance mechanisms of both M. tuberculosis and M. abscessus, two clinically relevant mycobacteria that share core molecular pathways while exhibiting species-specific determinants that complicate treatment. Additional intrinsic factors, including biofilm formation and stress-induced adaptive responses, further enhance persistence and reduce susceptibility to multiple drug classes. Acquired resistance predominantly results from chromosomal mutations affecting drug targets or prodrug activation pathways, such as katG, inhA, rpoB, gyrA, and pncA in Mycobacterium tuberculosis, leading to high rates of multidrug-resistant and extensively drug-resistant disease. In nontuberculous mycobacteria, species-specific determinants—including inducible macrolide resistance mediated by erm(41) in M. abscessus, plasmid-mediated erm (55) variants, rrl and rrs mutations, diverse enzymatic inactivation systems, and regulatory alterations in the MarR family that result in inducible resistance to drugs such as ethionamide —generate highly variable resistance profiles that complicate treatment. Recent advances in molecular diagnostics, including PCR-based assays, whole-genome sequencing, CRISPR-based diagnostic platforms, AI-assisted diagnostics, and emerging multi-omics approaches, have improved the detection of resistance-associated mutations and enhanced understanding of mycobacterial pathophysiology. In parallel, new therapeutic agents and optimized regimens offer promising avenues to overcome resistance, although emerging resistance to novel drugs underscores the need for continued surveillance. This review synthesizes current knowledge on the molecular basis of resistance in M. tuberculosis and NTM, highlighting implications for diagnosis, treatment, and future research. Full article

Antifungal resistance in filamentous fungi has emerged as a major threat to global public health, posing a serious challenge particularly to immunocompromised populations. This review provides a systematic overview of the molecular mechanisms, diagnostic approaches, and clinical therapeutic strategies for antifungal resistance in filamentous fungi, with a focus on Aspergillus fumigatus, Fusarium spp., Mucorales, and Scedosporium spp./Lomentospora prolificans. Resistance mechanisms can be broadly categorized as intrinsic resistance and acquired resistance. Intrinsic resistance arises from species-specific genetic traits, such as structural differences in target sites, constitutive overexpression of efflux pumps, and metabolic pathway redundancy. Acquired resistance develops under drug pressure through target gene mutations (e.g., hotspot mutations and promoter tandem repeats in CYP51A), efflux pump overexpression, biofilm formation, and epigenetic regulation. For diagnosis, conventional culture and antifungal susceptibility testing remain the gold standard; however, molecular techniques—including MALDI-TOF MS, targeted resistance gene PCR, and metagenomics—are substantially improving detection efficiency. Therapeutic strategies should be stratified based on antifungal susceptibility testing results and species identification. Precision dosing guided by therapeutic drug monitoring, combination therapy, and the introduction of novel agents (including isavuconazole, rezafungin, fosmanogepix, and olorofim) are progressively improving clinical outcomes. Looking ahead, global surveillance and multisectoral collaboration are essential to deepen our understanding of resistance evolution, accelerate the clinical translation of novel diagnostic and therapeutic tools, and curb the global spread of resistance. Full article

Anemia management in chronic kidney disease patients is a significant challenge for modern healthcare professionals. Anemia in chronic kidney disease patients has multiple causes, which include erythropoietin deficiency, abnormal iron metabolism, resistance to erythropoietin signaling, bone marrow suppression, blood loss, inflammation, nutrition deficiencies, and oxidative stress. Vadadustat, a stabilizer of hypoxia-inducible factor (HIF), is indicated for the treatment of symptomatic anemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis. Evidence-based pharmaceutical care services are of great importance for chronic kidney disease patients because they provide safe and cost-effective care for patients. In the present article, we outline the most important pharmaceutical aspects that may affect the efficacy and safety of drug therapy with vadadustat and other HIF stabilizers. We conclude that evidence-based pharmaceutical care is one of the criteria that promotes management of vadadustat therapeutic efficacy and safety. Such an approach will contribute to improving patient adherence to treatment and, consequently, quality of life. Special attention is paid to structure-derived side effects of widely used HIF stabilizers, including their advantages and disadvantages. Based on all available safety and efficacy data for vadadustat, the overall risk–benefit profile remains positive for the approved indications for use. Full article

The continuous increase in vulvovaginal candidiasis cases worldwide is a global health concern that requires being addressed using innovative approaches. The current incidence of recurrent cases of the disease is particularly alarming, and this is not predicted to decrease in the coming years. Virulence factors of Candida spp. are still not entirely understood and the relevance of resistance to antifungal treatment, as well as differences between Candida species, must be considered when designing therapies. In this review, the key concepts of vulvovaginal candidiasis are introduced, and the potential of nanotechnology-based approaches being developed for mitigating the infection is highlighted. Several nanosystems proposed in recent years (including drug-loaded nanoparticles and intrinsically antifungal nanomaterials) are presented and their efficacy, as tested in animal models, is discussed in detail. Limitations of in vivo models are also specified and considerations for future work are addressed. Full article

Reactive oxygen species (ROS) are central regulators of cancer biology and represent a double-edged target in oncology. At physiological levels, ROS support signal transduction, proliferation, differentiation, and immune responses, whereas sustained ROS imbalance promotes DNA damage, genomic instability, metabolic reprogramming, and remodeling of the tumor microenvironment, thereby contributing to tumor initiation, progression, metastasis, and therapy resistance. Conversely, because many cancer cells operate close to the limit of tolerable oxidative stress, further ROS elevation can trigger apoptosis, ferroptosis, immunogenic cell death, and other cytotoxic programs. This review summarizes the major intracellular and microenvironmental sources of ROS, the mechanisms by which redox signaling shapes malignant transformation and tumor adaptation, and the antioxidant systems that buffer oxidative stress in cancer cells. We further discuss current therapeutic approaches based on both ROS suppression and ROS amplification, including redox-modulating small molecules, radiotherapy, photodynamic and sonodynamic therapy, catalytic nanomaterials, and ROS-responsive prodrugs and drug delivery systems. Particular attention is given to the context-dependent effects of ROS, the antioxidant paradox, tumor heterogeneity, hypoxia, off-target toxicity, and the need for robust redox biomarkers. A deeper understanding of tumor-specific redox vulnerabilities will be essential for developing precise and clinically effective ROS-oriented cancer therapies. Full article

Antiretroviral therapy (ART) has proven effective in suppressing HIV-1 replication, but further development of HIV-1 inhibitors is continually driven by the challenge of drug resistance and viral adaptation. The HIV-1 capsid is a promising target for treatment due to its high sequence conservation as well as its crucial role in the viral life cycle. Recently, we have developed a novel capsid-targeting biologic that prevents HIV-1 replication by efficient degradation of newly synthesized capsid. Here, we have investigated the sensitivity to viral escape as well as the breadth of this biologic against HIV-1 subtypes. The capsid-targeting biologic efficiently blocked replication of different primary HIV-1 isolates, and continuous exposure of these viruses to the biologic resulted in viral breakthrough of two out of ten primary HIV-1 isolates tested. Notably, the breakthrough variants did not have amino acid changes in the nanobody epitope but primarily in the matrix region. The breakthrough variants remained sensitive to the biologic albeit to a lesser extent. In the absence of the biologic, breakthrough variants showed increased replication kinetics when compared to their parental virus, suggesting that adaption to the biologic is likely due to the increased viral production and that the target area of the biologic is too conserved for actual escape. This is further underscored by the broad specificity of the biologic as importantly the biologic blocked infection of different HIV-1 subtypes that occur worldwide (A, B, C, D, CRF01_AE, CRF02_AG). These results demonstrate the broad neutralization potential of anti-capsid biologics with a high barrier to resistance, making capsid-targeting inhibitors important for novel antiretroviral drug strategies worldwide. Full article

Despite the development of new drugs, chemoresistance constitutes a major obstacle in cancer treatment. To investigate mechanisms of resistance and potential therapeutic targets, we developed doxorubicin-resistant models of HER2− (D2F2/Dox) and HER2+ (D2F2E2/Dox) breast cancer cells. Compared with parental cells, the D2F2/Dox and D2F2E2/Dox differed in morphology, increased migratory potential, elevated levels of the transcription factor signal transducer and activator of transcription 3 (Stat3), and a lower proliferation rate in D2F2E2/Dox. Moreover, D2F2/Dox and D2F2E2/Dox differed in the expression profiles of genes related to cell stemness, apoptosis, and drug efflux. Stat3 gene silencing in both doxorubicin-resistant cell types reversed the expression profiles of some genes (different in each resistant cell line), and decreased migratory potential was observed only in D2F2 cells. These data indicate that the acquired doxorubicin resistance was associated with Stat3 status; however, HER2− and HER2+ breast cancer cells did not indicate the same mechanism of chemoresistance acquisition. Importantly, Stat3 silencing did not substantially restore doxorubicin sensitivity, suggesting that effective therapy may require simultaneous targeting of multiple pathways. Furthermore, we demonstrated that siStat3 therapeutics could be selectively delivered to HER2+ cancer cells using H2.1MS1:MS2KN silk spheres, indicating their potential for targeted drug delivery in vivo. Full article

Breast cancer is a highly heterogeneous disease characterized by distinct molecular subtypes, dynamic tumor–microenvironment interactions, and variable therapeutic responses. Despite the availability of multiple preclinical platforms, a major challenge remains the lack of a coherent multiscale framework capable of integrating biological complexity across experimental systems. This limitation reduces the predictive power of individual models and highlights the need for complementary strategies that reproduce disease progression across multiple biological scales. In this context, advanced imaging technologies have emerged as essential tools for linking preclinical platforms and enhancing their translational relevance. This review examines how multimodal imaging supports the integration of in vitro, ex vivo, and in vivo breast cancer models. We discuss how optical imaging, high-frequency ultrasound, magnetic resonance imaging, positron emission tomography/computed tomography, and intravital microscopy provide complementary molecular, functional, anatomical, and cellular information for the longitudinal assessment of tumor growth, metastatic dissemination, microenvironment remodeling, and therapeutic response. Particular attention is given to emerging translational workflows that combine patient-derived models with advanced imaging to investigate drug sensitivity, treatment resistance, and tumor progression within a precision oncology perspective. We also highlight the role of multimodal imaging in biomarker validation across platforms and in the development of clinically relevant preclinical pipelines. Overall, advanced imaging represents a critical translational bridge across breast cancer model systems, improving the predictive value of preclinical studies and supporting imaging-guided precision oncology from bench to bedside. Full article

The rapid emergence and dissemination of antimicrobial resistance (AMR) among bacterial pathogens, particularly the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), represents one of the most pressing global public health challenges, contributing to increased morbidity, mortality, and healthcare costs. The limited development of new antibiotic classes over the past two decades has intensified the search for structurally novel antimicrobial agents and adjuvants capable of overcoming multidrug resistance. Natural products continue to serve as an invaluable source of anti-infective drug leads owing to their remarkable structural diversity and broad spectrum of biological activities. Mangrove ecosystems, located at the interface of terrestrial and marine environments, harbor highly diverse microbial communities, including fungi that have evolved under extreme environmental conditions and produce a wide range of unique secondary metabolites. Beyond their ecological significance, mangrove-associated fungi have emerged as prolific producers of bioactive compounds with promising antibacterial activity against multidrug-resistant pathogens. This review comprehensively summarizes recent advances (2018–2026) in the discovery of antibacterial metabolites from mangrove-associated fungi active against ESKAPE pathogens, which discusses their structural diversity, reported antimicrobial activities, and emerging strategies for accelerating natural product discovery, including genome mining, metabolomics, OSMAC, adaptive laboratory evolution, and artificial intelligence-assisted approaches. A total of 139 chemically distinct metabolites (Compounds 1–139) isolated from mangrove-associated fungi are critically reviewed, highlighting their potential as promising leads for the development of next-generation antimicrobial agents against ESKAPE pathogens. Full article

Castration-resistant prostate cancer (CRPC) is characterised by persistent androgen receptor (AR)-axis activity, therapy-driven resistance, and limited durability of available systemic treatments. Tumour-tropic mesenchymal stem/stromal cells (MSCs), including adipose-derived MSCs (ADSCs), have emerged as promising vehicles for targeted gene therapeutics. This review synthesises our three experimental studies examining stem cell-delivered gene-directed enzyme prodrug therapy (GDEPT) using cytosine deaminase (CD)/5-fluorocytosine (5-FC) and secreted TRAIL in CRPC xenograft models. We performed a comparative analysis of three studies in which hTERT-immortalised human ADSCs were engineered via lentiviral vectors to deliver CD alone, secreted TRAIL alone, or CD+TRAIL in combination, and were administered by intracardiac injection into male nude mice bearing PC3 xenografts. In vitro conversion efficiency, cell viability, apoptosis markers, and in vivo tumour volume endpoints were compared across studies. All three therapeutic platforms demonstrated measurable tumour growth inhibition relative to controls. The CD+TRAIL combination achieved the greatest in vivo efficacy (tumours approximately 26% of control at day 14), compared with CD alone (approximately 71%) or TRAIL paired with irinotecan. Enzymatic conversion of 5-FC to 5-FU exceeded 93% in conditioned medium. Primary translational risks include thrombotic events associated with systemic MSC dosing, tumourigenicity and genotoxicity of hTERT-immortalised, integrating-vector–engineered cells, immunogenicity of xenogeneic CD enzyme, and systemic 5-fluorouracil leakage from flucytosine metabolism. Stem cell-delivered CD/5-FC and TRAIL constitutes a biologically rational, modular strategy for local cytotoxicity and resistance circumvention in CRPC. Successful clinical translation will require resolution of delivery-route feasibility, thrombosis risk mitigation, and a rigorous investigational new drug (IND)-enabling safety package. Full article