Search Results (19,057)

Burkholderia pseudomallei, the causative agent of melioidosis, is endemic in Sarawak, Malaysian Borneo, where it is represented by a unique gentamicin-susceptible population. Despite trimethoprim-sulfamethoxazole (co-trimoxazole) being the cornerstone of eradication therapy, emerging reports of elevated minimum inhibitory concentrations (MICs) among Sarawak isolates have raised concerns over its clinical efficacy. We performed a retrospective and comprehensive antibiotic susceptibility assessment of clinical B. pseudomallei isolates from hospitals across Sarawak. Susceptibility to trimethoprim-sulfamethoxazole was determined using disk diffusion and the E-test, interpreted by both CLSI and EUCAST guidelines. Resistance to the individual components, trimethoprim and sulfamethoxazole, was characterized by broth microdilution. The results demonstrated a high prevalence of trimethoprim-sulfamethoxazole susceptibility, with 96.3% of isolates susceptible by CLSI criteria and 97.6% by EUCAST criteria. Interestingly, broth microdilution revealed that resistance to trimethoprim and sulfamethoxazole individually did not confer resistance to the synergistic combination. Our analysis validated CLSI guidelines as the most reliable standard for antimicrobial resistance surveillance in this region. This study provides evidence that trimethoprim-sulfamethoxazole remains effective for melioidosis treatment in Sarawak, offering crucial reassurance to clinicians. The paradoxical finding of susceptibility to the drug combination despite resistance to its individual components underscores the critical importance of the synergistic activity of trimethoprim-sulfamethoxazole and highlights the need for further investigation into the molecular basis of resistance in this distinct B. pseudomallei population. Full article

PARP inhibitors are a clinically validated class of anticancer therapeutics that exploit synthetic lethality to target homologous recombination-deficient tumors, such as those carrying BRCA1/2 mutations. Nevertheless, the rational design of mitochondria-targeted PARP inhibitors capable of selective mitochondrial accumulation and organelle-specific PARP modulation remains an unresolved objective. To enable organelle-specific modulation of PARP activity, we synthesized a series of trialkyl(aryl)phosphonium conjugates of olaparib and rucaparib designed to target mitochondria by cardiolipin binding. Their activity was evaluated by PARP1 inhibition, cardiolipin affinity, and cytotoxicity in BRCA1-deficient HCC1937 breast cancer cells and non-malignant H9C2 cardiomyocytes. All conjugates retained potent PARP1 inhibition (IC₅₀ = 3.4–17 nM), comparable to the parent drugs. Several derivatives, particularly compounds 2d and 6c, exhibited strong cardiolipin binding (EC₅₀ = 12.99 µM and 6.77 µM, respectively) and significantly enhanced cytotoxicity in HCC1937 cells (IC₅₀ = 0.93 and 2.01 µM), outperforming olaparib and rucaparib. Notably, cytotoxicity toward H9C2 cells was lower, indicating a favorable selectivity profile. Phosphonium conjugation preserves PARP1 inhibitory activity while conferring mitochondrial targeting and enhanced anticancer potency. These findings support the development of mitochondria-targeted PARP inhibitors as a next-generation therapeutic strategy with the potential to improve efficacy and overcome resistance in HR-deficient tumors. Full article

Whole-genome duplication, or tetraploidization, occurs in cells, tissues, or entire organisms. In human cancers, tetraploidization promotes aneuploidy and genomic instability, accelerating tumor progression, metastasis, and drug resistance. These adaptations demand metabolic rewiring, including mitochondrial plasticity. Here, we investigate the relationship between mitochondrial quantity/activity, including the mitochondrial transmembrane potential, the intracellular calcium, and the oxidative stress in diploid versus tetraploid cancer cells (colon, sarcoma, liver) and fungal and yeast models (C. albicans diploid/tetraploid strains; S. cerevisiae haploid/diploid/tetraploid strains). We demonstrate that tetraploid cells, whether from human carcinomas or yeast, exhibit consistently enlarged cell size, elevated mitochondrial content, and heightened metabolic activity compared to diploids. Our findings underscore mitochondrial adaptation as a hallmark of tetraploidization, offering novel therapeutic targets for chromosomally unstable tumors. Full article

(1) Background: Listeria monocytogenes (Lm) is recognized by the World Health Organization (WHO) as one of the four principal foodborne pathogens. This study aimed to investigate the molecular characteristics of Lm isolates from Jiaxing, China, using whole-genome sequencing (WGS) to enhance our understanding of their molecular epidemiology. (2) Methods: A total of 39 foodborne Lm isolates and 7 clinical Lm isolates were analyzed via WGS to identify resistance genes, virulence factors, lineage, sequence type (ST), and clonal complex (CC). Antibiotic susceptibility was assessed using Minimum Inhibitory Concentration (MIC) testing, and serotypes were confirmed via multiplex PCR. (3) Results: We found that 39 food isolates were mainly lineage II (66.67%), with 13 STs; ST8 was the dominant ST, and 2 new types, ST3210 and ST3405, were found. Among the seven clinical isolates, lineage I was dominant (57.14%), and ST87 was the dominant ST. Serotype 1/2a was dominant, accounting for 54.35%, followed by 1/2b, which accounted for 36.96%. The overall antimicrobial resistance rate was 13.04%, with a multidrug resistance rate of 2.17%. All strains harbored LIPI-1 and LIPI-2, and five strains carried LIPI-3 genes: one strain belonged to ST619 of lineage I, two strains belonged to ST224 of lineage I, and two strains belonged to ST11 of lineage II. (4) Conclusions: This study clarified the genotype and serotype characteristics of Listeria monocytogenes in Jiaxing, as well as their molecular characteristics relating to drug resistance and virulence, thus providing a technical basis for improving exposure risk assessment of Listeria monocytogenes. Continuous monitoring, prevention, and control are recommended to further improve regional public health and safety. Full article

Gastrointestinal nematode (GIN) infections are the most prevalent parasitic diseases in grazing sheep worldwide, causing significant productivity losses, high mortality and, as a result, economic losses and emerging animal welfare concerns. Conventional control strategies, primarily relying on anthelmintic treatments, face limitations due to rising drug resistance and environmental concerns, underscoring the need for sustainable alternatives. Selective breeding for host genetic resistance has emerged as a promising strategy, while recent advances in transcriptomics and integrative omics research are providing deeper insights into the immune pathways and molecular and genetic mechanisms that underpin host–parasite interactions. This review summarizes current evidence on transcriptomic signatures associated with resistance and susceptibility to H. contortus and T. circumcincta GIN infections, highlighting candidate genes, functional genetic markers, key immune pathways, and regulatory networks. Furthermore, we discuss how other omics approaches, including genomics, proteomics, metabolomics, microbiome, and multi-omics integrations, provide perspectives that enhance the understanding of the complexity of the GIN resistance trait. Transcriptomic studies, particularly using RNA-Sequencing technology, have revealed differential gene expression, functional genetic variants, such as SNPs and INDELs, in expressed regions and splice junctions, and regulatory long non-coding RNAs that distinguish resistance from susceptible sheep, highlighting pathways related to Th2 immunity, antigen presentation, tissue repair, and stress signaling. Genomic analyses have identified SNPs, QTL, and candidate genes linked to immune regulation and parasite resistance. Proteomic and metabolomic profiling further elucidates breed- and tissue-specific alterations in protein abundance and metabolic pathways, while microbiome studies demonstrate distinct microbial signatures in resistant sheep, suggesting a role in modulating host immunity. In conclusion, emerging multi-omics approaches and their integration strategies provide a comprehensive framework for understanding the complex host–parasite interactions that govern GIN resistance, offering potential candidate biomarkers for genomic selection and breeding programs aimed at developing sustainable, parasite-resistant sheep populations. Full article

Antimicrobial resistance (AMR) is a major global health concern, which complicates treatment of microbial infections and wounds. Conventional therapies are no longer effective against drug resistant microbes; hence, novel antimicrobial approaches are urgently required. Silver nanoparticles (AgNPs) offer stronger antimicrobial activity, and in situ synthesis improves stability, uniformity, cost efficiency, and bioactivity while minimising contamination. These features make AgNPs well-suited for incorporation into textiles and wound dressings. Red wine extract (RW-E), rich in antioxidant and anti-inflammatory compounds was used to hydrothermally synthesise RW-AgNPs and RW-AgNPs-loaded on cotton (RWALC) by optimising pH and RW-E concentration. Characterisation was performed using UV–Vis spectroscopy, dynamic light scattering (DLS), and High Resolution and Scanning electron microscopy (HR-TEM and SEM). Antibacterial activities were evaluated against human pathogens through agar disc diffusion assay for RWALC and microdilution assay for RW-AgNPs. RWALC showed higher potency against both Gram-negative and Gram-positive bacteria, with inhibition zones of 12.33 ± 1.15 to 23.5 ± 5.15 mm, that surpassed those of ciprofloxacin (10 ± 3 to 19.17 ± 1.39 mm at 10 μg/mL). RW-AgNPs exhibited low minimum inhibitory concentrations (MIC: 0.195–3.125 μg/mL) and minimum bactericidal concentrations (MBC: 0.78–6.25 μg/mL). Preincubation with β-mercaptoethanol (β-ME) inhibited the antibacterial activity of RWALC, suggesting that thiolated molecules are involved in AgNPs-mediated effects. This study demonstrated that green-synthesised RW-AgNPs, incorporated in situ into cotton, conferred strong antibacterial properties, warranting further investigation into their mechanisms of action. Full article

Host–virus relationships regulate every phase of viral infection and critically influence course of illness and the effectiveness of treatment. Viruses utilize host receptors, intracellular trafficking routes, metabolic programs, and immunological signaling networks to introduce infection, while host cells use innate and adaptive immune responses that both limit viral replication and, in certain situations, cause tissue damage. Given the fast viral evolution and drug resistance linked to virus-directed therapy, there is growing proof that these host-dependent mechanisms are appealing and underutilized targets for antiviral treatment. Recent developments in single-cell technology, proteomics, and functional genomics have made it possible to systematically identify host dependency and restriction factors shared by different viral families, exposing common molecular vulnerabilities that might be targeted therapeutically. This review integrates current knowledge of virus–host interplay via a translational lens, highlighting processes that directly guide the formation of host-directed antivirals and immune-regulating treatments. We emphasize host processes involved in viral entry, replication, and immune signaling that have shown therapeutic significance, while illustrating the difficulties of balancing antiviral effectiveness with immunopathology. By framing host–virus interactions through a therapeutic lens, this review attempts to offer a targeted and translationally relevant viewpoint for next-generation antiviral research. Full article

A novel lytic bacteriophage, XAN_XB1, was isolated from hospital wastewater through host bacterial enrichment and evaluated for its potential in controlling multidrug-resistant Stenotrophomonas maltophilia infections. Transmission electron microscopy revealed that XAN_XB1 has a long tail, possessing an icosahedral head of ~80 nm in diameter and a tail measuring ~150 nm in length. It produced clear plaques of 0.5–1 mm on host bacterial lawns. Host range analysis demonstrated its ability to infect multiple multidrug-resistant S. maltophilia isolates. Biological characterization showed that the phage is chloroform-insensitive, retains strong lytic activity across a wide temperature (4–60 °C) and pH (3.0–10.0) range, and achieves more rapid host suppression under higher multiplicity of infection (MOI). Whole-genome sequencing determined a ~47 kb double-stranded DNA genome encoding 64 predicted open reading frames, with no known virulence or antibiotic resistance genes. Phylogenetic analysis of MCP and terminase large subunit sequences placed XAN_XB1 in a unique Caudoviricetes, with ANI values below the 95% ICTV threshold verifying its status as a novel phage species. The XAN_XB1 therapy significantly alleviates S. maltophilia infection-induced severe pulmonary inflammatory lesions, high mortality, elevated serum inflammatory factors and massive pulmonary bacterial colonization in male BALB/c mice, confirming its favorable therapeutic effect on such infections. Collectively, these results reveal that is an efficacious candidate for therapeutic development against S. maltophilia infections. Full article

Background/Objectives: Mechanisms underlying treatment resistance in hematopoietic malignancies such as acute lymphoblastic leukemia (ALL) include (1) enhanced activity of anticancer drug efflux mechanisms (MRP1); (2) suppressed activity of anticancer drug influx mechanisms (ENT-1); (3) enhanced drug detoxification activity (AKR1B10, AKR1C3, CYP3A4); (4) influence of the tumor microenvironment (GRP94), etc. We conducted this study to comprehensively and clinically examine treatment resistance due primarily to a decrease in the tumor intracellular anticancer drug concentrations. Methods: The subjects were 19 ALL patients who underwent initial induction therapy with alternating Hyper CVAD/MA therapy. Antibodies against 23 types of treatment resistance-associated proteins were used for immunohistochemical analysis of tumor specimens obtained from the patients, and correlations between the results of immunohistochemistry and the overall survival (OS) were retrospectively analyzed using the Kaplan–Meier method. Results: Based on the patterns of expression of the enzymes involved in treatment resistance, we classified the patients (Urayasu classification for ALL, which we believe would be very useful for accurately stratifying patients with ALL according to the predicted prognosis), as follows: Good prognosis group, n = 1, 5%: AKR1B1(+)/AKR1B10(−), 5-year overall survival (OS), 100%; Intermediate prognosis-1 group, n = 9, 5%: AKR1B1(−)/AKR1B10(−) plus MRP1(−), 5-year OS, 68%; Intermediate-2 prognosis group, n = 6.3%: AKR1B1(−)/AKR1B10(−) plus MRP1(+), median survival, 17 months, 5-year OS, 20%; and Poor prognosis group, n = 3, 16%: AKR1B1(−)/AKR1B10(+), median survival, 18 months, 5-year OS, 0%. n = 2. Conclusions: The Urayasu classification for ALL is considered reliable for predicting the prognosis of patients with ALL after the initial Hyper CVAD/MA remission induction therapy. Full article

Background/Objectives: Malaria remains a major global health burden, increasingly complicated by resistance to artemisinin-based therapies. Because artemisinin activation depends on heme and porphyrin chemistry, we sought to exploit host red blood cell (RBC) heme metabolism as a therapeutic vulnerability. This study aims to develop and evaluate a host-directed “bait-and-kill” strategy that selectively sensitizes malaria-infected RBCs to artemisinin. Methods: We integrated quantitative proteomics, erythropoiesis transcriptomic analyses, flow cytometry, and in vitro malaria culture assays to characterize heme metabolism in mature RBCs and Plasmodium falciparum-infected RBCs (iRBCs). The heme precursor 5-aminolevulinic acid (ALA) was used to induce porphyrin accumulation, and dihydroartemisinin (DHA) was applied as the killing agent. Drug synergy, porphyrin accumulation, reactive oxygen species (ROS) induction, and parasite survival were assessed, including ring-stage survival assays using artemisinin-resistant clinical isolates. Results: Mature RBCs retain a truncated heme biosynthesis pathway capable of accumulating porphyrin intermediates, while uninfected RBCs are impermeable to ALA. In contrast, iRBCs exhibit increased membrane permeability, allowing selective ALA uptake and porphyrin accumulation. ALA alone did not induce cytotoxicity or ROS, whereas DHA induced ROS and parasite killing. The ALA + DHA combination resulted in synergistic parasite elimination, including complete clearance of artemisinin-resistant P. falciparum isolates from the Greater Mekong Subregion, with no recrudescence observed over three weeks of culture. Evidence supports a predominant role for host-derived heme metabolites in mediating this synergy. Conclusions: The bait-and-kill strategy selectively exploits host RBC heme metabolism to restore and enhance artemisinin efficacy while sparing uninfected cells. Using clinically safe compounds, this host-directed approach provides a promising, resistance-bypassing framework for malaria treatment and combination drug development. Full article

Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem cell persistence, hypoxia-induced metabolic and epigenetic plasticity, adaptive oncogenic signaling, and profound immunosuppression within the tumor microenvironment. Emerging evidence shows that dysfunction of the glymphatic system, mislocalization of aquaporin-4, and increased intracranial pressure compromise cerebrospinal fluid–interstitial fluid exchange and impair antigen drainage to meningeal lymphatics, thereby weakening immunosurveillance. GBM simultaneously remodels the blood–brain barrier into a heterogeneous and permeable blood–tumor barrier that restricts uniform drug penetration yet enables tumor progression. These alterations intersect with profound immunosuppression mediated by pericytes, tumor-associated macrophages, and hypoxic niches. Advances in imaging, including DCE-MRI, DTI-ALPS, CSF-tracing PET, and elastography, now allow in vivo characterization of glymphatic function and interstitial flow. Therapeutic strategies targeting the fluid-immune interface are rapidly expanding, including convection-enhanced delivery, intrathecal and intranasal approaches, focused ultrasound, nanoparticle systems, and lymphatic-modulating immunotherapies such as VEGF-C and STING agonists. Integrating barrier modulation with immunotherapy and nanomedicine holds promise for overcoming treatment resistance. Our review synthesizes the mechanistic, microenvironmental, and translational advances that position the glymphatic–immune axis as a new frontier in glioblastoma research. Full article

Silver nanoparticles (AgNPs) possess distinct physicochemical characteristics and demonstrate high antibacterial potential that highlights them as promising alternatives against a wide range of pathogens. The immense antibacterial potential of AgNPs is primarily attributed to the release of silver ions that lead to the disruption of bacterial cell membrane, generation of reactive oxygen species (ROS), inhibition of protein synthesis and interference with DNA replication. Variations in AgNPs’ shape, size, and surface characteristics are also considered key factors determining their effectivity as well as specificity. AgNPs are considered potent antibacterial agents, including against antibiotic- and drug-resistant strains. However, inappropriate dosages or unoptimized application of may result in potential toxicity, consisting one of the main drawbacks of the AgNPs’ safer administration. This article reviews the recent literature on the antibacterial potential of AgNPs, focusing on their broad mechanisms of action, applicability, especially in agriculture, biomedical and environmental fields, toxicity and future perspectives. Full article

The progression of neoplastic diseases is driven by a complex interplay of biological processes, including uncontrolled proliferation, enhanced invasion, metastasis, and profound metabolic reprogramming. Among the hallmarks of cancer, as revised by Hanahan and Weinberg, the reprogramming of energy metabolism has emerged as a critical feature that enables cancer cells to meet their heightened bioenergetic and biosynthetic demands. One significant aspect of this metabolic adaptation is the accumulation of lipid droplets (LDs) dynamic, cytoplasmic organelles primarily involved in lipid storage and metabolic regulation. LDs serve as reservoirs of neutral lipids and play a multifaceted role in cancer cell physiology. Their accumulation is increasingly recognized as a marker of tumor aggressiveness and poor prognosis. By storing lipids, LDs provide a readily accessible source of energy and essential building blocks for membrane synthesis, supporting rapid cell division and growth. Moreover, LDs contribute to cellular homeostasis by modulating oxidative stress, maintaining redox balance, and regulating autophagy, particularly under nutrient-deprived or hypoxic conditions commonly found in the tumor microenvironment. Importantly, LDs have been implicated in the development of resistance to cancer therapies. They protect cancer cells from the cytotoxic effects of chemotherapeutic agents by buffering endoplasmic reticulum (ER) stress, inhibiting apoptosis, and facilitating survival pathways. The presence of LDs has been shown to correlate with increased resistance to a variety of chemotherapeutic drugs, although the precise molecular mechanisms underlying this phenomenon remain incompletely understood. Emerging evidence suggests that chemotherapy itself can induce changes in LD accumulation, further complicating treatment outcomes. Given their central role in cancer metabolism and therapy resistance, LDs represent a promising target for therapeutic intervention. Strategies aimed at disrupting lipid metabolism or inhibiting LD biogenesis have shown potential in sensitizing cancer cells to chemotherapy and overcoming drug resistance. In this review, we comprehensively examine the current understanding of LD biology in cancer, highlight studies that elucidate the link between LDs and drug resistance, and discuss emerging approaches to target lipid metabolic pathways to enhance therapeutic efficacy across diverse cancer types. 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

Background: Libya, a conflict-affected North African country, has a fragile health system and poor surveillance, leaving it largely underrepresented in global estimates. Earlier Libyan reviews were descriptive, lacking breakpoint standardization, isolate-level pooling, or AMR-attributable mortality and DALY estimates. To our knowledge, this study represents the first comprehensive report that integrates phenotypic and genotypic data to estimate deaths and DALYs attributable to AMR-induced mortality and morbidity, describe spatiotemporal patterns, and model future trajectories. Methods: We performed a meta-analysis according to the PRISMA 2020 guideline of Libyan studies reporting phenotypic or genotypic resistance among clinical bacterial isolates (1970–2024), combined with microbiology records from hospitals and national surveillance systems (preregistered in PROSPERO ID: CRD420251066018). Susceptibility results were standardized to CLSI/EUCAST and deduplicated using WHO GLASS first-isolate rules. We used random-effects meta-regression to estimate pooled resistance, and the counterfactual approach of Global Burden of Disease (GBD) was applied to estimate AMR-attributable DALYs. Molecular data on resistance genes, sequence types, and tuberculosis mutations were systematically collected. Results: We included 62 eligible studies together with national and facility-level surveillance datasets, providing isolate-level susceptibility data for 31,439 clinical isolates from Libya. In 2024, we estimated 2183 deaths (95% UI 1752–2614) attributable to AMR, representing 9.7% (95% UI 7.8–11.6) of total deaths with a mortality rate of 15.2 per 100,000 (12.2–18.2). DALYs attributable to AMR increased from 14,628 (95% UI 11,702–17,554) in 1970 to 96,715 (95% UI 77,372–116,058). The highest pooled resistance involved carbapenem-resistant/MDR A. baumannii, third-generation cephalosporin- and fluoroquinolone-resistant Enterobacterales, and carbapenem-resistant P. aeruginosa. Molecular data showed widespread ESBLs, OXA-/NDM-type carbapenemases, plasmid-mediated colistin resistance, high-risk E. coli ST131 and K. pneumoniae ST147 lineages, and canonical drug-resistant M. tuberculosis mutations. Conclusions: Combined with global and regional evidence, our findings suggest a high and increasing burden of AMR in Libya. These findings emphasize the need for rapid expansion of data collection systems, GLASS-aligned surveillance, diagnostic capacities, and infection control measures. Full article