Search Results (4,595)

Background: Kinkeliba (Combretum micranthum G. Don), commonly used in West African traditional pharmacopeia for its anti-inflammatory and gastrointestinal properties, remains poorly studied regarding its potential role in the prevention or treatment of ulcerative colitis. Objective: This study evaluated the therapeutic potential of the ethanolic extract of Combretum micranthum (EECM) in a murine model of chronic DSS-induced colitis. Methods: Male C57BL/6 mice were subjected to three cycles of 1.5% DSS administration over nine weeks to induce chronic colitis. EECM was administered orally at 50, 100, or 200 mg/kg during the final week. Disease severity was evaluated using the Disease Activity Index (DAI), colon length, biochemical and hematological markers, along with histopathological and immunohistochemical assessment of colonic tissue. Results: EECM treatment significantly improved clinical parameters and prevented colon shortening in chronic DSS-induced colitis. These improvements were associated with the restoration of serum biochemical and hematological profiles, along with reduced histopathological damage and preservation of colonic tissue architecture. Immunohistochemical analysis further demonstrated decreased CD3-positive T-lymphocyte infiltration in colonic tissue, suggesting modulation of local immune cell responses. Conclusions: These findings highlight the therapeutic potential EECM in ulcerative colitis and support further investigations to elucidate its mechanisms of action and evaluate its efficacy in future translational studies. Full article

Carbapenem-resistant Acinetobacter baumannii (CRAB) is classified as a critical priority pathogen by the World Health Organization, and new therapeutic alternatives are urgently needed. In this study, we performed genomic mining of 27,531 A. baumannii genomes and identified 5144 prophage-derived endolysin candidates. Four highly prevalent candidates (E1–E4) were recombinantly expressed and functionally evaluated against A. baumannii. Among them, E1 exhibited the strongest bactericidal activity against reference strains ATCC 19606 and CMCC 25001, with a minimum inhibitory concentration in the micromolar range. E1 effectively disrupted preformed biofilms (>60% reduction) and remained stable under a broad range of temperatures (4–60 °C), pH values (6–8), and NaCl concentrations (up to 500 mM). Structural analysis indicated that E1 adopts a canonical lysozyme-like fold with key residues for peptidoglycan binding, and its lytic activity in vitro relied on 1 mM EDTA-mediated outer membrane permeabilization. In a murine peritoneal infection model, combination therapy with E1 and meropenem (each at 1 × MIC) significantly increased the survival rate to 66.7% and reduced bacterial loads in blood and multiple organs. This study demonstrates that prophage-derived endolysin E1 acts synergistically with meropenem against A. baumannii, supporting E1 as a promising candidate for developing combination therapies against CRAB. Full article

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon characterized by dysregulated mucosal immunity and progressive epithelial injury. Upadacitinib (UPA), a selective Janus kinase 1 (JAK1) inhibitor, has demonstrated clinical efficacy in UC, but its therapeutic application is often constrained by adverse effects arising from systemic drug exposure. This underscores the need for advanced, site-specific delivery systems that enhance local efficacy while minimizing systemic toxicity. Here, we developed a colon-targeted natural lipid nanoparticle formulation of UPA (UPA-nLNP) to improve therapeutic performance and safety. UPA-nLNP was prepared by thin-film hydration using digalactosyldiacylglycerol (DGDG), monogalactosyldiacylglycerol (MGDG), and phosphatidic acid (PA), mimicking the lipid composition of ginger-derived exosomal particles, and was characterized for particle size, surface charge, and encapsulation efficiency. The formulation exhibited excellent mucus-penetrating capability and was evaluated in a dextran sulfate sodium (DSS)-induced acute colitis model in C57BL/6 mice following oral administration (5 mg/kg). Pharmacokinetic analysis demonstrated increased colonic accumulation with reduced systemic exposure compared to free UPA. Treatment with UPA-nLNP improved body weight recovery, reduced disease biomarkers, and suppressed key proinflammatory cytokines in the colon, with no evidence of systemic toxicity. This innovative strategy holds strong potential to enhance the clinical utility of JAK1 inhibitors by providing a safer and more effective therapeutic approach for ulcerative colitis. Full article

Background: Crocodilians rarely develop cancer despite long lifespans and continuous exposure to environmental carcinogens, suggesting robust natural anti-tumor defense mechanisms. Methods: We investigated the anti-cancer activity of sera derived from phylogenetically related species—alligators, crocodiles, and chickens—and studied their underlying immune mechanisms. The anti-tumor activity of alligator serum was tested in murine models of melanoma and lymphoma. Results: Alligator serum (AS) and its (NH₄)₂SO₄-precipitated fraction (ASa) showed rapid and potent cytotoxicity toward multiple murine and human cancer cell lines while sparing non-malignant human cells. Importantly, ASa attenuated melanoma and lymphoma tumor growth in mice. Electrophysiological analyses in PN71 cancer cells treated with ASa revealed rapid membrane depolarization and formation of high-conductance pores consistent with Complement-mediated membrane attack complex (MAC) activity. Proteomic analyses identified the Complement component C5 as a major protein enriched in active fractions, implicating the Complement system in cancer cell killing. Based on phylogenetic similarity of C5, crocodile and chicken sera exhibit alligator-like comparable anti-cancer activity. Mechanistic studies in chicken serum showed that the anti-cancer activity depends on Ca²⁺ and Mg²⁺ ions, terminal Complement components (C5–C8), and IgM antibodies that initiate Complement activation. Immunodepletion of IgM significantly reduced cytotoxicity, whereas purified chicken IgM activated human Complement to induce cancer cell death. Conclusions: These findings identify a conserved IgM–Complement immune mechanism capable of selectively targeting malignant cells. The evolutionary conservation and cross-species functionality of this pathway highlight its potential as a bio-inspired strategy for developing novel Complement-based cancer immunotherapies. Full article

Pulmonary bioengineering holds significant promise for the development of functional lungs suitable for transplantation in patients with terminal lung diseases; however, it encounters considerable challenges. The inherent structural complexity, diverse cellular composition, and the intricate process of re-endothelialization the pulmonary vasculature complicate efforts to reconstruct viable lungs for transplantation. This study aimed to establish an innovative re-endothelialization technique utilizing decellularized scaffolds, integrating canine yolk sac-derived endothelial precursor cells with mechanical respiratory stimuli within a bioreactor framework. Wistar rat lungs were subjected to a decellularization protocol employing SDS + Triton X-100 0.5% and subsequently assessed for cytocompatibility with murine fibroblasts (3T3) and yolk sac (YS) cells in fragments. Following this, the recellularization of the whole-lung scaffold was evaluated under constant mechanical respiratory stimulation with YS cells. Each stage of the process was rigorously analyzed using histological staining, DAPI, scanning electron microscopy (SEM), and genomic DNA quantification. The findings reveal that the implemented alternating decellularization protocol resulted in a structured scaffold conducive to the culture of various cell types in fragments. When subjected to the complete scaffold recellularization model, the results indicated that YS cells are advantageous for the re-endothelialization process. Moreover, when employed in conjunction with the bioreactor model incorporating respiratory stimulation, these cells demonstrated enhanced cellular diffusion capacity and facilitated more homogeneous recellularization of the entire organ. These results signify a notable advancement in the reconstruction of new tissues for pulmonary transplantation. Full article

Invasive pulmonary aspergillosis (IPA) poses a serious threat to immunocompromised hosts, with limited therapeutic options highlighting the need for novel strategies. Coptis chinensis Franch. (CCF), a traditional Chinese herb containing antimicrobial alkaloids like berberine, was investigated for its therapeutic efficacy and immunological effects in a murine IPA model. Immunosuppressed female KM mice infected with Aspergillus fumigatus AF293 were treated with CCF or amphotericin B (AmB). CCF significantly improved survival, reduced fungal burden, and alleviated lung pathology, without inducing hepatotoxicity or nephrotoxicity. Transcriptomic profiling revealed a time-dependent immune response. Complement-related pathways were enriched at 2 days post-infection, whereas neutrophil recruitment and NET-related pathways became more prominent by day 4. Hub gene analysis identified Syk, Rac2, Ncf1, and Cybb as key nodes associated with the NADPH oxidase complex. Western blot and inhibitor experiments further supported the involvement of this pathway in CCF-mediated protection. Additionally, 16S rDNA sequencing indicated enrichment of Clostridium species in the gut microbiota of CCF-treated mice, which was positively correlated with the expression of NADPH oxidase-related genes, suggesting a potential gut–lung association. In conclusion, these findings support the antifungal efficacy of CCF in IPA and suggest that its protective effects may involve coordinated changes in complement-related responses, NADPH oxidase-associated neutrophil activity, and gut microbiota composition. Full article

Acute kidney injury (AKI) continues to pose a significant clinical challenge due to its high morbidity rates and limited therapeutic options. Recent evidence suggests that natural compounds may provide renoprotective benefits by modulating oxidative stress and inflammation. This study examines the protective effects of a novel polysaccharide peptide extracted from Ganoderma lucidum (GL-PPQ1) against renal ischemia–reperfusion (I/R) injury, with particular emphasis on the integrin β3/Fibronectin 1 (Fn1) signaling axis. A murine model of renal I/R injury was established, and GL-PPQ1 was administered orally for seven days before surgery. The assessment included renal function, histopathology, oxidative stress markers, and inflammatory cytokines. Additionally, transcriptomic profiling and protein expression analyses were conducted to elucidate the underlying mechanisms. The results revealed that GL-PPQ1 pretreatment significantly reduced renal tubular damage, lowered serum creatinine and blood urea nitrogen levels, and diminished oxidative stress and inflammatory responses. RNA sequencing revealed that GL-PPQ1 affected gene sets associated with extracellular matrix remodeling and cell adhesion. Western blot and immunohistochemistry further confirmed that GL-PPQ1 decreased the expression of integrin β3 and Fn1, suggesting a regulatory effect on their interaction during I/R injury. These findings demonstrate that GL-PPQ1 offers substantial kidney protection by mitigating oxidative stress, inflammation, and dysregulation of the integrin β3/Fn1 signaling pathway. Thus, this study supports that polysaccharide peptides derived from Ganoderma lucidum could have the potential to serve as both a dietary supplement and a therapeutic agent in the treatment of AKI. Full article

Background: Electrochemotherapy enhances the intracellular delivery of anticancer agents through electroporation but is traditionally limited to cytotoxic drugs associated with significant side effects. Vitamin C (ascorbic acid) exhibits selective anticancer activity when accumulated at high intracellular concentrations; however, its therapeutic application is restricted by poor membrane permeability and rapid systemic clearance. Methods: In this study, we investigated whether reversible electroporation, applied using a custom-designed variable plate electrode system designed to deliver a uniform electric field, could potentiate the antitumor efficacy of low-dose vitamin C. Numerical simulations were performed to optimize electrode spacing and stimulation voltage, suggesting homogeneous electric field coverage throughout the tumor volume. The proposed approach was evaluated in vitro using MDA-MB-231 and 4T1 breast cancer cell lines and in vivo in a 4T1 murine breast cancer model. Results: Low-dose vitamin C alone produced minimal cytotoxic effects, whereas its combination with electroporation significantly reduced cell viability and increased apoptotic and necrotic cell death in vitro. In vivo, vitamin C–assisted electrochemotherapy resulted in pronounced tumor growth suppression, with tumor volumes reduced to approximately 0.34-fold of baseline by day 15, accompanied by decreased proliferation and marked tissue disruption. Conclusions: These findings demonstrate that uniform-field reversible electroporation markedly enhances the intracellular delivery and antitumor activity of low-dose vitamin C, supporting this technology-driven strategy as a promising, low-toxicity alternative to conventional chemotherapeutic agents in electrochemotherapy for solid tumors. Full article

Background and aims: Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the progressive dilation of the aorta, culminating in rupture. At present, there are no pharmacological treatments to prevent AAA development or reduce rupture rate. A recent study showed that patients prescribed Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have significantly lower risks of mortality, AAA repair, and acute abdominal aortic syndrome. Semaglutide is a GLP-1RA with increased agonist capacity and longer half-life, compared to earlier generations of GLP-1RAs. In this study, we aimed to investigate the role and mechanisms of semaglutide in the prevention of AAA development and rupture in a murine model. Methods: AAA was induced in apolipoprotein-E-deficient mice, by continuous subcutaneous infusion of angiotensin II. Treatment with semaglutide (12 µg/kg) began seven days after disease induction (rescue trial) or simultaneously with disease induction (prophylactic trial). At experimental endpoint, aortic diameter was measured by high-frequency ultrasound and the aortic tissue was collected for histological analysis. Results: Prophylactic treatment with semaglutide drastically reduced mortality by dissection and rupture during the first seven days of disease development, but did not affect AAA formation at 28 days. Histological evaluation of the aorta at day seven showed a normal vessel wall thickness with a trend for a higher content of collagen in the aortic wall in mice treated with semaglutide, compared to controls. Conclusions: Semaglutide prevents aortic rupture and dissection in the early phases of AAA development in the angiotensin II mouse model, likely by promoting the maintenance of an adequate proportion of collagen in the vessel wall. Full article

Neonatal meningitis-associated Escherichia coli (NMEC) is a formidable pathogen in veterinary medicine. The emergence of atypical, multidrug-resistant (MDR) variants complicates disease control. An Escherichia coli (E. coli) strain was isolated from the brain tissue of a deceased calf with acute meningitis. Comprehensive characterizations were performed, including whole-genome sequencing (WGS), multi-locus sequence typing (MLST), antimicrobial susceptibility testing (AST), murine pathogenicity assays, and RT-qPCR evaluation of neuroinflammatory cytokines. Results: The isolate (O18ab:H14) was identified as a capsule-deficient NMEC strain belonging to phylogroup A and sequence type ST1434. WGS showed that the genome size of this strain is 5.1 Mb, containing 73 strictly defined antimicrobial resistance genes and 202 virulence factors. These may be involved in the compensatory mechanism for capsule deficiency, and further functional verification is required. Phenotypically, it exhibited a robust MDR profile. In the murine model, the strain demonstrated high lethality, and induced severe multi-organ lesions characteristic of both meningitis and systemic sepsis. While intraperitoneal injection bypasses natural colonization routes, the brain-specific bacterial persistence and neuronal pathology imply neurotropic potential. Furthermore, RT-qPCR confirmed a severe neuroinflammatory response, marked by the significant upregulation of IL-1β, IL-6, and TNF-α in the infected brains. This study characterizes a novel, highly virulent, and MDR capsule-deficient NMEC/SEPEC hybrid strain. The findings emphasize the urgent need for continuous genomic surveillance of atypical E. coli pathotypes in livestock. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by immune dysregulation that leads to widespread inflammation and damage across multiple organs. B lymphocytes play a vital role in SLE, with abnormal development and activation leading to autoreactive antibody production and immune complex formation, which damages tissues. Methods: The PPARα agonist WY14643 has anti-inflammatory effects in various inflammatory conditions, including CNS diseases. We investigated whether WY14643 decreases inflammatory mediator production in CD45R⁺ cells in the MRL/lpr mouse model of SLE. Flow cytometry was used to evaluate WY14643’s impact on the expression of IFN-γ, IL-6, iNOS, MCP-1, IL-1α, IL-2, Notch-1, Notch-3, GITR, and NF-κB p65 in splenic CD45R⁺ B cells. Additionally, we assessed the effect of WY14643 on the mRNA levels of these markers in the kidney using RT-PCR. Results: WY14643 decreased inflammatory markers such as CD45R⁺IFN-γ⁺, CD45R⁺IL-6⁺, CD45R⁺iNOS⁺, CD45R⁺MCP-1⁺, CD45R⁺IL-1α⁺, CD45R⁺IL-2⁺, CD45R⁺Notch1⁺, CD45R⁺Notch3⁺, CD45R⁺GITR⁺, and CD45R⁺NF-κB p65⁺ in splenic cells from MRL/lpr mice. Furthermore, WY14643 also lowered mRNA expression of IFN-γ, IL-6, iNOS, MCP-1, IL-2, IL-1α, Notch-1, Notch-3, GITR, and NF-κB p65 in the kidney. Conclusions: This study shows that WY14643 inhibits the production of inflammatory mediators and significantly reduces autoimmune features, including kidney inflammation, in MRL/lpr mice. Our results indicate that WY14643, a PPAR-α agonist, could be a potential therapy for lupus nephritis. Full article

Background: We aimed to investigate the potential synergistic effect of ivacaftor combined with colistin against Pseudomonas aeruginosa and Klebsiella pneumoniae, and to elucidate the underlying molecular mechanisms through metabolomic analysis and its reproducibility in a murine model. Methods: Six colistin-susceptible and 2 colistin-resistant cystic fibrosis P. aeruginosa isolates, along with two colistin-resistant K. pneumoniae clinical isolates, were studied. Antimicrobial susceptibility was assessed by broth microdilution, and synergy by checkerboard assay. Metabolomic profiling was conducted via LC-HRMS with statistical analysis. A murine pneumonia model, induced by intranasal administration of colistin-resistant strains, was used to validate in vivo ivacaftor and colistin synergy after 24 h. Results: No previously described colistin resistance mutations were identified in P. aeruginosa strains, whereas K. pneumoniae carried mgrB variations. Ivacaftor restored colistin susceptibility at 16 mg/L concentration, and at 1–2 mg/L led to at least a twofold reduction in colistin MIC. Metabolomic analysis of colistin-resistant P. aeruginosa strains revealed that ivacaftor induced modifications in phosphoethanolamine groups of lipid A. However, no synergistic effects were observed in the short-term in vivo pneumonia model, regardless of the administration route. Conclusions: Ivacaftor exhibited no direct antimicrobial activity against P. aeruginosa and K. pneumoniae isolates in vitro but restored colistin susceptibility through synergistic interactions. The lack of synergy in the murine pneumonia model may reflect treatment time and challenges in standardizing in vivo conditions. These findings highlight the potential of ivacaftor as an adjunct to colistin therapy, warranting further investigation into its clinical applicability. Full article

Despite the identification of several mediators of arteriogenesis, the growth of natural bypass, the role of lymphocytes, particularly T cells, in this process remains poorly defined. Among these, γδ T cells, which express alternative T cell receptors, have emerged as a key immune component. This study examined the roles of αβ and γδ T cells in arteriogenesis using a murine hindlimb model. While the absence of αβ T cells did not affect arteriogenesis, γδ T cell depletion markedly reduced vascular cell proliferation and perfusion recovery. Early phase analyses revealed impaired mast cell activation, whereas platelet–neutrophil aggregates and neutrophil extravasation were unaffected. In the later proliferative phase, γδ T cell depletion hindered perivascular M2-like (MRC1⁺) macrophage accumulation. Flow cytometric analysis of whole blood in wildtype mice revealed a temporal shift in γδ T cell populations from a CD27⁺/CD39⁻ phenotype, commonly associated with pro-inflammatory functions and IFNγ production, to CD39⁺ phenotypes, which have been linked to anti-inflammatory properties and IL-10 production. In rescue experiments, administration of IFNγ to γδ T cell-depleted mice restored mast cell activation, whereas IL-10 treatment reestablished M2-like (MRC1⁺) macrophage accumulation. These findings collectively identify γδ T cells as critical regulators of both early and late phases of arteriogenesis through coordinated inflammatory and regenerative mechanisms. Full article

Background/Objectives: Magnetic nanoparticles have emerged as powerful tools for biomedical imaging, targeted drug delivery, and hyperthermia therapy. Magnetic particle imaging (MPI) is among the most promising technologies built around its properties: a radiation-free, quantitative tomographic modality that detects superparamagnetic iron oxide nanoparticles (SPIONs) directly against a biologically silent background. This review synthesizes MPI’s physical principles, nanoparticle design strategies, and preclinical applications within the broader landscape of magnetic material engineering for biomedical use. Methods: A systematic review was conducted covering MPI signal generation and image reconstruction, nanoparticle core synthesis and surface coating approaches, and preclinical applications, spanning cell tracking, oncological imaging, vascular perfusion, neuroimaging, and MPI-guided theranostics. Studies were selected to provide quantitative benchmarks and direct comparisons with competing modalities where available. Results: MPI delivers signal-to-background ratios above 1000:1, iron-mass linearity at R² ≥ 0.99, regardless of tissue depth, and acquisition rates up to 46 volumes per second. Tracer architecture—encompassing single-core particles, multicore nanoflowers, and stimuli-responsive cluster designs—is the primary determinant of sensitivity, environmental robustness, and theranostic capability. Preclinical results include detection of cell populations in the low thousands, earlier ischaemia identification than diffusion-weighted MRI, real-time drug release quantification, and spatially confined tumour hyperthermia. Three translational bottlenecks are identified: the absence of a clinically approved tracer with optimal relaxation dynamics, hardware performance losses when scaling to human-bore systems, and overestimation of passive tumour accumulation in murine models. Conclusions: MPI illustrates how progress in magnetic material design directly expands clinical imaging and theranostic possibilities. Successful translation will require indication-driven, interdisciplinary development that integrates materials science, scanner engineering, and regulatory strategy in parallel. Full article

Background/Objectives: Glioblastoma remains the most lethal primary brain tumor in adults, and progress in oncolytic virotherapy is limited by the lack of immunocompetent models permissive to human-tropic viruses. Methods: Here, murine CT-2A and GL261 glioma and B16 melanoma cell lines were engineered to express human Coxsackievirus and Adenovirus Receptor (CXADR) fused to tagBFP, generating “humanized” tumors that preserve parental growth characteristics while acquiring high susceptibility to group B Coxsackieviruses (CVBs) and adenovirus serotype 5. Results: CXADR expression in CT-2A, GL261, and B16 cells markedly enhanced binding, internalization, and replication of CVBs in vitro, with the strongest effect observed for LEV14 (attenuated CVB5), which reached up to 10⁵-fold higher viral titers in humanized cells compared with parental cells. Unchanged sensitivity to vesicular stomatitis virus indicated receptor-specific effects. Humanized CT-2A-CXADR-BFP and GL261-CXADR-BFP cells initiated aggressive subcutaneous and intracranial tumors in syngeneic C57BL/6 mice without signs of immune rejection, and histology and MRI confirmed invasive high-grade glioma phenotypes. In intracranial CT-2A-CXADR-BFP tumors, repeated intratumoral LEV14 administration induced extensive tumor necrosis and prolonged survival despite the rapid development of neutralizing antibodies. Systemic intravenous LEV14 dosing produced strong oncolytic activity against subcutaneous CT-2A-CXADR-BFP tumors, as demonstrated by pronounced tumor growth inhibition, long-lasting regression in a subset of animals with gliomas, and improved overall survival. Conclusions: Collectively, these data establish CXADR-humanized models as versatile, immunocompetent platforms for evaluation of CXADR-dependent oncolytic enteroviruses. Full article