Search Results (1,121)

Glioblastoma multiforme (GBM) is characterized by aggressive growth, extensive vascularization, high metabolic malleability, and a striking capacity for therapy resistance. Current treatments involve surgical resection and concomitant radiation therapy and chemotherapy, prolonging survival times marginally due to the therapy resistance that is built up by the tumor cells. A growing body of research has identified exosomes as critical enablers of therapy resistance. These nanoscale vesicles enable GBM cells to disseminate oncogenic proteins, nucleic acids, and lipids that collectively promote angiogenesis, maintain autophagy under metabolic pressure, and suppress apoptosis. As interest grows in targeting tumor communication networks, exosome-based therapeutic strategies have emerged as promising avenues for improving therapeutic outcomes in GBM. This review integrates current insights into two complementary therapeutic strategies: inhibiting exosome biogenesis and secretion, and engineering exosomes as precision vehicles for the delivery of anti-tumor molecular cargo. Key molecular regulators of exosome formation—including the endosomal sorting complex required for transport (ESCRT) machinery, tumor susceptibility gene 101 (TSG101) protein, ceramide-driven pathways, and Rab GTPases—govern the sorting and release of factors that enhance GBM survival. Targeting these pathways through pharmacological or genetic means has shown promise in suppressing angiogenic signaling, disrupting autophagic flux via modulation of autophagy-related gene (ATG) proteins, and sensitizing tumor cells to apoptosis by destabilizing mitochondria and associated survival networks. In parallel, advances in exosome engineering—encompassing siRNA loading, miRNA enrichment, and small-molecule drug packaging—offer new routes for delivering therapeutic agents across the blood–brain barrier with high cellular specificity. Engineered exosomes carrying anti-angiogenic, autophagy-inhibiting, or pro-apoptotic molecules can reprogram the tumor microenvironment and activate both the intrinsic mitochondrial and extrinsic ligand-mediated apoptotic pathways. Collectively, current evidence underscores the potential of strategically modulating endogenous exosome biogenesis and harnessing exogenous engineered therapeutic exosomes to interrupt the angiogenic and autophagic circuits that underpin therapy resistance, ultimately leading to the induction of apoptotic cell death in GBM. Full article

A growing body of work has linked the dysregulation of transmembrane (TMEM) proteins to the proliferation, metastasis, drug resistance, and tumor microenvironment remodeling of lung cancer, the leading global cause of cancer mortality. Renamed members such as STING1 (stimulator of interferon response cGAMP interactor 1, TMEM173), ANO1 (anoctamin-1, TMEM16A), ORAI1 (ORAI calcium release-activated calcium modulator 1, TMEM142A), ORAI3 (TMEM142C), and NDC1 (NDC1 transmembrane nucleoporin, TMEM48) are among the most extensively studied ones. Mechanisms of TMEM dysregulation in lung cancer span the modulation of Ca²⁺ influx, lysosomal exocytosis, ferroptosis, Wnt and β-catenin signaling, and immune cell infiltration and immune checkpoint rewiring, among others. Epigenetic silencing and targetable fusions (i.e., TMEM106B-ROS1 and TMEM87A-RASGRF1) create DNA-level vulnerabilities, while miRNA sponges offer RNA-level druggability. A subset of studies revealed context-specific expression (endothelial, B cell, and hypoxic EV) that can be exploited to remodel the tumor microenvironment. One study specifically focused on how isoform-specific expression and localization of TMEM88 determine its functional impact on tumor progression. Yet for most TMEMs, only pre-clinical or early-phase data exist, with many supported by a single study lacking independent validation. This review brings together scattered evidence on TMEM proteins in lung cancer, with the aim of guiding future work on their possible use as biomarkers or therapeutic targets. Full article

Drug resistance remains a significant challenge in cancer therapy, accounting for most relapses and contributing substantially to cancer-related mortality worldwide. Several molecular processes are linked to the development of resistance to anticancer drugs, with the most studied mechanisms including epigenetic changes, drug efflux, cell survival signalling pathways, and inactivation of anticancer drugs. Both intrinsic and acquired forms of resistance hinder tumour cell elimination, reducing treatment success. This translates to poorer patient outcomes and the need for more aggressive treatment regimens. Therefore, understanding these molecular processes is crucial for enhancing the efficacy of anticancer therapy. Medicinal plants offer potential to counter various resistance mechanisms through their diverse phytocompounds. These compounds may offer benefits including consistent availability, anticancer potency, few side effects, and minimal drug resistance. However, the bioavailability of these phytochemicals and the lack of extensive clinical trials remain key challenges. Therefore, this review provides in-depth information on the mechanisms that lead to drug resistance during cervical cancer therapy, the challenges related to phytochemical bioavailability, the current status, and future needs for clinical trials evaluating the application of medicinal plants to combat drug resistance in cancer cells. Full article

Bovine mastitis remains a major challenge in dairy production despite extensive antimicrobial use, with therapeutic failure increasingly attributed to factors beyond classical antimicrobial resistance (AMR). Growing evidence indicates that treatment inefficacy arises from the combined effects of pharmacokinetic/pharmacodynamic (PK/PD) constraints, biofilm-mediated tolerance, intracellular persistence, and the adaptive capacity of mastitis pathogens. Intramammary therapy is particularly limited by poor tissue penetration, episodic drug elimination via milk flow, and inactivation by milk components, frequently resulting in subtherapeutic exposure at the site of infection. These limitations are amplified in chronic and subclinical mastitis, where biofilms and intracellular reservoirs reduce antimicrobial susceptibility and promote relapse and resistance selection. This narrative review integrates current knowledge on pharmacokinetic and pharmacodynamic (PK/PD) barriers, microbial survival strategies, and antimicrobial resistance (AMR) mechanisms that underlie treatment failure in bovine mastitis. It critically evaluates conventional antimicrobial therapies alongside emerging approaches, including antimicrobial peptides, bacteriophages and endolysins, nanoparticle-based delivery systems, immunomodulators, CRISPR-guided antimicrobials, and drug repurposing strategies. Overall, available evidence highlights the potential of these approaches to enhance therapeutic durability, particularly in settings where biofilm formation, intracellular persistence, and resistance limit conventional treatment efficacy. By mapping research coverage across mastitis phenotypes and therapeutic outcomes, this review identifies key gaps in long-term efficacy and resistance mitigation and underscores the need for PK/PD-guided, biofilm-aware, and resistance-conscious strategies to support durable next-generation mastitis management. Full article

Background/Objectives: Infections due to multidrug-resistant (MDR) Acinetobacter baumannii represent a critical challenge in modern healthcare, with limited therapeutic options. Eravacycline, a novel fluorocycline antibiotic, demonstrates promising in vitro activity, but real-world clinical data for complex intra-abdominal infections (IAIs) are scarce. We present two cases of severe IAI caused by carbapenem-resistant A. baumannii (CRAB) successfully treated with eravacycline. Methods: We describe the clinical course, microbiological findings, and outcomes of two critically ill patients. Case 1 was a 75-year-old male with biliary peritonitis following an endoscopic procedure. Case 2 was a 64-year-old male with infected pancreatic walled-off necrosis. Both patients had cultures positive for CRAB and failed multiple prior antibiotic regimens. Results: In both cases, the initiation of intravenous eravacycline led to significant clinical improvement, including resolution of septic shock and defervescence. A marked reduction in inflammatory markers (C-reactive protein and procalcitonin) was observed, alongside microbiological clearance of CRAB. Eravacycline was well tolerated, with no significant adverse events. Conclusions: These case reports suggest that eravacycline can be an effective and safe salvage therapy for complex IAIs caused by CRAB, even in scenarios of partial source control. It represents a valuable addition to the antimicrobial armamentarium for managing infections caused by these extensively drug-resistant organisms. Full article

Antimicrobial resistance in urinary tract infections (UTIs) poses a critical public health challenge, yet comparative data between outpatient and inpatient settings remain limited, particularly in Latin America. This study characterized the epidemiology, microbiology, and resistance patterns of UTIs in northwestern Mexico. A retrospective analysis of 1041 patients with UTI (May–November 2024) was conducted. Microorganism identification and antimicrobial susceptibility were determined using the MicroScan WalkAway system in accordance with CLSI guidelines. Results: Outpatients accounted for 80.5% of cases and inpatients for 19.4%, with a 3.1% mortality rate. Escherichia coli predominated (62.9%), with a significant association with outpatients (p = 0.02), whereas Enterobacter cloacae, Acinetobacter spp., Candida tropicalis, and C. albicans were associated with inpatients (p < 0.05). Pediatric patients exhibited distinctive microbiological profiles: Pseudomonas aeruginosa (9.7% vs. 2.1%, p = 0.032), Enterococcus faecalis (33.3% vs. 16.2%, p = 0.001), and Staphylococcus epidermidis (26.6% vs. 6.5%, p = 0.027) were significantly more prevalent than in adults. Multidrug resistance (MDR) was detected in 27.1% of isolates, and extensive drug resistance (XDR) in 3.2%. XDR was associated with Gram-positive bacteria (12.2% vs. 1.4%, p < 0.001). Carbapenem-resistant Enterobacteriaceae (CRE) were identified in 0.9% (7/772) of cases, with 42.9% occurring in outpatients. Hospitalization (OR: 2.01; 95% CI: 1.43–2.83), surgical services (OR: 1.41; 95% CI: 1.02–1.97), and recent surgery (OR: 2.37; 95% CI: 1.04–5.39) were independent predictors of MDR/XDR infections. Conclusions: These findings demonstrate the emergence of CRE within the community and distinctive pediatric resistance patterns, underscoring the need for tailored antimicrobial stewardship strategies in this region. Full article

National Tuberculosis Reference Laboratories (NTRLs) are central to tuberculosis (TB) control programs. Between 2018 and 2024, the Republic of Congo, a country of 6 million inhabitants, achieved a transformative strengthening of its TB diagnostic system, coordinated by the NTRL. Strategic investments, supported mainly by international partners, enabled a substantial decentralization of services, expanding the diagnostic network from 38 to 113 diagnostic and testing centers and increasing GeneXpert sites from 3 to 31. The expansion of the diagnostic network and specimen referral system was associated with a reduced structural gap in diagnostic coverage by extending access to GeneXpert testing to a larger number of peripheral and previously underserved centers. Critically, the establishment of a BSL-3 laboratory and the deployment of advanced assays like Xpert MTB/XDR ended the reliance on overseas testing by introducing in-country capacity for multidrug-resistant and pre-extensively drug-resistant TB detection. These systemic improvements were associated with significant positive outcomes, including an annual molecular testing surging from 11,609 in 2022 to over 27,000 in 2024 and bacteriological confirmation rates rising from 34 to 73%. This comprehensive laboratory systems strengthening, which also facilitated cross-programmatic initiatives like HIV and Mpox testing integration, underscores how sustained investment in infrastructure, logistics, and quality management is fundamental to improving case detection, surveillance, and progress toward the WHO End TB Strategy milestones. Full article

The precision drive industry has seen rapid growth, leading to an increased demand for actuators that are both highly accurate and responsive. Among these, non-resonant piezoelectric motors are particularly noteworthy. These motors are extensively employed in applications such as high-precision manufacturing, precision drug delivery, and cellular puncture, owing to their adaptable drive control and resistance to external disturbances. Given the specific requirements of these applications, it is crucial to quickly determine the relationship between the motor input parameters and output characteristics—a challenging endeavor. In this research, we examine a typical non-resonant piezoelectric motor using multiple sets of experimental data. A machine learning algorithm is employed to swiftly establish the correlation between electromechanical input parameters and output trajectory characteristics. Data are analyzed using a random forest model to understand the underlying influence mechanisms. Based on this analysis, predictions and recommendations are made to achieve optimal operating conditions for the motor. This study demonstrates that machine learning serves as an effective tool for predicting piezoelectric motor performance, facilitating rapid assessment of motor output capabilities. Full article

Phosphatidylinositol-3-kinases (PI3Ks) constitute an important validated therapeutic class involved in crucial cellular processes, and their dysregulation is associated with cancer initiation and progression. Nonetheless, intrinsic and acquired resistance mechanisms associated with PI3K pathway modulation have underscored the need for alternative therapeutic strategies. In this context, recent studies have shown that simultaneous inhibition of PI3K and histone deacetylases (HDAC) promotes synergistic antitumor effects in different cancer cell lines. HDACs are validated epigenetic targets that are extensively explored in clinical practice and have a pharmacophore with versatility for structural modifications, which facilitates the design of multitarget inhibitors. This review examines the rational design and synthetic evolution of dual PI3K/HDAC inhibitors, an area catalyzed by the development of fimepinostat, the first clinically evaluated agent exhibiting potent and balanced inhibition of both targets. We provide a critical overview of PI3K/HDAC multitarget inhibitors reported in recent years that have progressed to preclinical or clinical investigation, discussing the structural frameworks employed, medicinal chemistry strategies adopted, and structure–activity relationships established. Particular attention is given to advantageous molecular features as well as challenges related to toxicity, pharmacokinetic behavior, and pharmacodynamic modulation. From this comprehensive analysis, we outline key considerations and emerging design principles that may inform the next generation of PI3K/HDAC multitarget drug candidates. Insights derived from the diversity of chemical scaffolds, activity profiles, and selectivity patterns described herein may support the development of innovative therapeutic agents capable of overcoming current limitations in anticancer treatment. Full article

Acinetobacter baumannii has been characterized by CDC, WHO and most National Healthcare Systems worldwide as a critical nosocomial pathogen, and classified as an ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) pathogen. Mortality of invasive infections due to A. baumannii exceeds 40%. To highlight its impact on public health, ECDC has organized a special project on national lab co-ordination to accurately detect and report carbapenem-resistant strains, to identify epidemiological factors for infection (or colonization) with carbapenem-resistant A. baumanii at clonal and sub-genomic level. This review aims to describe the history, epidemiology, and evolution of resistance of A. baumannii, and stress the caveats associated with the management of systemic infections. Available active antimicrobials and drugs in the pipeline are listed, and available clinical evidence on their pharmacokinetics and efficacy in various types of infections are described. Clinician’s choice of treatment (drug, and monotherapy vs. combination treatment) depends on the patients’ profile, site of infection and antimicrobial resistance profile. Emphasis is laid on specific patient subpopulations, whose management is discussed. Full article

Background and Clinical Significance: Cutaneous aspergillosis caused by Aspergillus flavus is rare and coinfection with Klebsiella pneumoniae was reported only in pulmonary disease. Case Presentation: We describe a 57-year-old woman with no prior comorbidities who developed septic shock requiring intensive care, broad-spectrum antibiotics, corticosteroids, and renal replacement therapy. Six days after discharge, she was readmitted with fever, leukopenia, thrombocytopenia, cavitary lung lesions, and multiple erythematous nodules on the limbs and mammary regions. Bronchial aspirate cultures detected K. pneumoniae, while progressive cutaneous lesions required surgical debridement. Histopathology revealed angioinvasive septate hyphae, and MALDI-TOF identified A. flavus. The K. pneumoniae strain was extensively drug resistant; A. flavus was susceptible only to azoles. Despite targeted therapy, lesions progressed requiring bilateral mastectomy. Conclusions: This case illustrates a previously unreported scenario in which secondary immunosuppression after severe sepsis led to concurrent cutaneous A. flavus infection and extensively drug-resistant (XDR) K. pneumoniae. Early recognition of mixed fungal–bacterial infections is essential for appropriate management. Full article

The indiscriminate and excessive use of antimicrobial agents in livestock production is a major driver of antimicrobial resistance (AMR), thereby posing a grave threat to global public health. Although several surveillance studies have documented antimicrobial resistance patterns of swine-derived E. coli in different regions of China, comprehensive investigations integrating multilocus sequence typing (MLST), resistance determinants, and virulence gene profiles have remained scarce for central China, particularly Hubei province, since 2018. This study investigated the prevalence of antibiotic resistance, and molecular epidemiology of E. coli isolated from swine farms in Hubei province, China, while simultaneously analyzing their clonal and genetic diversity. A total of 148 E. coli isolates were collected from porcine sources in central China, revealing distinct regional variations in genetic diversity. Multilocus sequence typing (MLST) analysis identified 38 sequence types (STs) distributed across 7 clonal complexes (CCs) and several unassigned clones. ST46 emerged as the predominant sequence type (19.6% prevalence), followed by ST23 and ST10. Antimicrobial susceptibility testing demonstrated 100% resistance to lincosamides and sulfonamides, with all isolates exhibiting multidrug resistance (MDR) to antimicrobial classes. Genetic characterization detected 16 resistance determinants, with individual isolates carrying 5–7 resistance genes on average. The resistance profile included seven β-lactamase genes: blaTEM (61.5%), blaCTX-M-1G (57.4%), blaDHA (46.6%), blaSHV (39.2%), blaCTX-M-9G (24.3%), blaOXA (13.5%), and blaCMY-2 (1.4%); and eight aminoglycoside-modifying enzyme genes, including polymyxin resistance gene mcr-1 (7.4%). Virulence factor screening through PCR detected nine associated genes, with EAST1, fyuA, STa, K88, STb, Irp2, and LT-1 present in 95.3% of isolates, while K99 and 987P were absent in all specimens. This investigation documents alarmingly high antimicrobial resistance rates in swine-derived E. coli populations while elucidating their genetic diversity. The findings suggest that intensive antibiotic use in porcine production systems has driven the evolution of extensively drug-resistant bacterial isolates. These results emphasize the urgent need to implement antimicrobial stewardship programs in livestock management to mitigate AMR proliferation. Full article

Extensively drug-resistant (XDR) bacteria pose a serious global public health threat due to their high levels of resistance to multiple classes of antibiotics. This study aimed to characterize bacterial isolates obtained from clinical samples, evaluate their antibiotic resistance patterns, and investigate the antimicrobial and anticancer potential of essential oils (EOs) and their nanoemulsions (NEs). A total of 175 bacterial isolates were collected from various clinical sources, identified, and subjected to antibiotic susceptibility testing using both conventional methods and the VITEK^® 2 system. Among these, nine isolates were identified as extensively drug-resistant. Among the tested EOs, carvacrol exhibited the strongest antibacterial activity, with minimum inhibitory concentrations (MICs) ranging from 14 to 35 µg/mL, compared to 8 to 19 µg/mL for meropenem. To enhance its stability and efficacy, carvacrol nanoemulsions (CANE) were prepared via ultrasonication and characterized using zeta potential measurements, which indicated a positive surface charge of +14.2 mV, while dynamic light scattering (DLS) analysis revealed a narrow size distribution with a mean hydrodynamic diameter of 411.3 nm. High-resolution transmission electron microscopy (HR-TEM) showed spherical droplets ranging from 18 to 144 nm in size, with an average diameter of 69 ± 28 nm. The nanoemulsion formulation significantly enhanced antibacterial activity, with MICs reduced to 11 ± 0.0–23 ± 0.21 µg/mL, compared to 14 ± 0.13–35 ± 0.11 µg/mL for pure carvacrol oil. Gas chromatography–mass spectrometry (GC–MS) analysis identified major active constituents, including thymol, methoxyphenyl, estragole, and D-limonene, which are likely contributors to the observed antimicrobial and anticancer effects. In addition, carvacrol nanoemulsions demonstrated potent cytotoxicity against multiple human cancer cell lines (HepG2, MCF-7, PC-3, and Caco-2) while showing minimal toxicity toward normal cells. Confocal microscopy further confirmed apoptosis induction in treated cancer cells, suggesting a mitochondria-mediated apoptotic pathway. In conclusion, this study highlights the strong therapeutic potential of essential oils—particularly carvacrol and its nanoemulsion formulation—as dual-action agents exhibiting broad-spectrum antibacterial activity against XDR pathogens and selective cytotoxicity against cancer cells. Full article

Tuberculosis (TB) remains a leading infectious killer, increasingly complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease; current regimens, although effective, are prolonged, toxic, and often fail to reach intracellular bacilli in heterogeneous lung lesions. This narrative review synthesizes how next-generation antimycobacterial strategies can be translated “from molecule to patient” by coupling potent therapeutics with delivery platforms tailored to the lesion microenvironment. We survey emerging small-molecule classes, including decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1) inhibitors, mycobacterial membrane protein large 3 (MmpL3) inhibitors, and respiratory chain blockers, alongside optimized uses of established agents and host-directed therapies (HDTs). These are mapped to inhalable and nanocarrier systems that improve intralesional exposure, macrophage uptake, and targeted release while reducing systemic toxicity. Particular emphasis is placed on pulmonary dry powder inhalers (DPIs) and aerosols for direct lung targeting, stimuli-responsive carriers that trigger release through pH, redox, or enzymatic cues, and long-acting depots or implants that shift daily dosing to monthly or quarterly schedules to enhance adherence, safety, and access. We also outline translational enablers, including model-informed pharmacokinetic/pharmacodynamic (PK/PD) integration, device formulation co-design, manufacturability, regulatory quality frameworks, and patient-centered implementation. Overall, aligning stronger drugs with smart delivery platforms offers a practical pathway to shorter, safer, and more easily completed TB therapy, improving both individual outcomes and public health impact. Full article

Background: The global incidence of multidrug-resistant and extensively drug-resistant tuberculosis continues to rise. The ribosome serves as a target for multiple antimicrobials, making functional research on it hold great significance. Methods: Using homologous recombination combined with a multiple serine integrase-mediated site-specific recombination system, we replaced the two endogenous rRNA operons in Mycobacterium smegmatis MC² 155 with a single copy of the single rRNA operon from Mycobacterium tuberculosis H37Rv, constructing the M. smegmatis BRkoA strain. We assessed growth kinetics at 37 °C, cold sensitivity at lower temperatures, transcriptional levels by RT-qPCR, 70S ribosome integrity through cryo-EM, and antimicrobial susceptibility by microdilution assays. Results: The BRkoA strain was successfully constructed. It exhibited markedly slower growth compared to the wild-type strain. Cold-sensitivity assays indicated potential ribosome assembly defects, while transcriptional analysis suggested altered rRNA processing and modification. Cryo-EM analysis further demonstrated the absence of specific ribosomal proteins in the BRkoA 70S ribosome. Moreover, BRkoA displayed reduced susceptibility tendency to several ribosome-targeting antibiotics, including kanamycin, amikacin, paromomycin, gentamicin, and linezolid. Conclusions: Replacement of the two endogenous rrn operons in M. smegmatis with a single copy of the single M. tuberculosis rrn operon using a serine integrase-mediated recombination system caused growth impairment and decreased sensitivity tendency to several ribosome-targeting antimicrobials. These findings suggest that ribosome structural variation contributes to intrinsic drug resistance mechanisms. Full article