Search Results (6,762)

Chronic liver disease (CLD) encompasses a spectrum of progressive disorders, including metabolic dysfunction steatotic-associated liver disease (MASLD) and primary biliary cholangitis (PBC), which together represent a significant global health burden with few effective therapeutic options. The fibrogenic process, common to most forms of CLD, is driven by a complex interplay of cellular stress, inflammation, and wound-healing responses. Nicotinamide adenine dinucleotide phosphate oxidase isoforms 1 and 4 (NOX1 and NOX4) have emerged as key enzymatic sources of reactive oxygen species (ROS), serving as central mediators of hepatic oxidative stress, fibrogenesis, and inflammation. Setanaxib is a first-in-class, orally bioavailable, selective dual inhibitor of NOX1 and NOX4 that has progressed to clinical evaluation. This review synthesizes current knowledge on the molecular pharmacology of the NOX1/4 axis, preclinical evidence from translational models, and clinical trial outcomes to critically assess the therapeutic potential of targeted NOX inhibition in hepatic fibrosis. By attenuating hepatic stellate cell activation, modulating TGF-β signaling, reducing extracellular matrix (ECM) deposition, and regulating hepatic macrophage polarization, setanaxib exhibits pleiotropic antifibrotic effects. The compound also demonstrates favorable pharmacokinetic properties and a good safety profile in patients with PBC, with emerging evidence suggesting meaningful improvements in fatigue and quality of life. Finally, we examine the complex, and sometimes paradoxical, roles of NOX4 in liver pathophysiology, compare the evolving therapeutic landscape with other approaches such as farnesoid X receptor (FXR) agonists, and propose future paradigms integrating artificial intelligence–driven predictive modeling to optimize patient stratification and therapeutic response in this new era of redox-targeted hepatoprotective therapy. Full article

Chagas disease is caused by the protozoan Trypanosoma cruzi, and its current treatment is limited to the use of two nitroderivatives, benznidazole (Bz) and nifurtimox; however, their toxicity often leads to discontinuation, justifying the search for new therapeutic options. The biological activity of quinones has long shown efficacy towards pathogenic microorganisms. In our previous investigations, two naphthoquinones combining ortho- and para-quinoidal moieties exhibited remarkable trypanocidal activity and presented low toxicity to host cells. Here, these two active compounds were further assessed. On trypomastigotes and epimastigotes, brominated (NQ1) and chlorinated (NQ2) nor-beta-lapachone-derived 1,2,3-triazoles were more active than Bz, presenting IC₅₀/24 h values in the range of 0.8 to 3.1 µM. NQ1-treated epimastigotes showed a mitochondrial impairment and reactive oxygen species (ROS) production under electron microscopy and flow cytometry. The in vitro evaluation of both combinations of compounds with Bz indicated an additive interaction. In vivo, oral treatment with NQ1 reduced parasitemia in an acute model, with no evidence of toxicity. The treatment also led to a reduction in myocarditis, decreasing the PR interval in electrocardiographic analysis and reversing the sinus bradycardia caused by infection. These data suggest that T. cruzi mitochondrion are part of the NQ1 mechanism of action. In vivo, this compound presented moderate trypanocidal and promising anti-inflammatory activity. Its combination with Bz could enhance current therapeutic protocols and should be better explored in the future. Full article

Background/Objectives: Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited therapeutic options restricted to benznidazole and nifurtimox, both associated with significant toxicity and reduced efficacy during chronic infection. Seeking novel, safe, and sustainable chemotherapeutic candidates, two new saturated cardanol-derived phospholipid analogs—LDT10 and LDT119—were rationally designed based on the molecular scaffold of miltefosine and biosourced from cashew nut shell liquid (CNSL). This study aimed to evaluate the pharmacokinetic properties of these compounds in silico and assess their antiparasitic activity, cytotoxicity, and morphological and ultrastructural effects on all developmental forms of T. cruzi in vitro. Materials and Methods: In silico ADMET predictions (SwissADME, pkCSM) were performed to determine bioavailability, pharmacokinetic behavior, CYP inhibition, mutagenicity, and hepatotoxicity. Antiproliferative activity was evaluated in epimastigotes, trypomastigotes, and intracellular amastigotes using dose–response assays and flow cytometry. Cytotoxicity was assessed in HEPG2 and HFF-1 cells using resazurin-based viability assays. Morphological and ultrastructural alterations were investigated through scanning (SEM) and transmission (TEM) electron microscopy. Reactive oxygen species (ROS) generation was quantified with H₂DCFDA after 4 h and 24 h of exposure. Results: In silico analyses indicated favorable drug-like profiles, high intestinal absorption (>89%), absence of mutagenicity or hepatotoxicity, and non-penetration of the blood–brain barrier. LDT10 was not a P-gp substrate, and LDT119 acted as a P-gp inhibitor, suggesting reduced efflux and higher intracellular retention. Both compounds inhibited epimastigote proliferation with low IC₅₀ values (LDT10: 0.81 µM; LDT119: 1.2 µM at 48 h) and reduced trypomastigote viability (LD₅₀ LDT10: 2.1 ± 2 µM; LDT119: 1.8 ± 0.8 µM). Intracellular amastigotes were highly susceptible (IC₅₀ LDT10: 0.48 µM; LDT119: 0.3 µM at 72 h), with >90% inhibition at higher concentrations. No cytotoxicity was observed in mammalian cells up to 20 µM. SEM revealed membrane wrinkling, pore-like depressions, rounded cell bodies, and multiple flagella, indicating cell division defects. TEM showed Golgi disorganization, autophagic vacuoles, mitochondrial vesiculation, and abnormal kinetoplast replication, while host cells remained structurally preserved. Both compounds induced significant ROS production in trypomastigotes after 24 h in a dose-dependent manner. Conclusions: LDT10 and LDT119 exhibited potent and selective in vitro activity against all developmental stages of T. cruzi, with low micromolar to submicromolar IC₅₀/LD₅₀ values, minimal mammalian cytotoxicity, and extensive morphological and ultrastructural damage consistent with disruption of phospholipid biosynthesis pathways. Combined with favorable in silico pharmacokinetic predictions, these CNSL-derived phospholipid analogs represent promising candidates for future Chagas disease chemotherapy and warrant further in vivo evaluation. Full article

Background: Reconstruction of the thigh extensor mechanism following wide excision of a soft-tissue sarcoma is difficult. The aim of this study was to describe the outcomes following complete quadriceps resection for large high-grade soft-tissue sarcomas. Methods: Ten patients with AJCC grade IIIB soft-tissue sarcomas of the anterior thigh were treated with total wide margin quadricectomy, with a mean follow-up of 4 years (range: 51–163 months) in the five surviving patients with conservative surgical procedures. The minimum follow-up period for four of these patients was 8 years. The extensor mechanism was reconstructed with local muscle transfers (eight cases) or a neurotized free flap of the contralateral vastus lateralis (two cases). Results: Four patients died, two due to non-tumor related causes and two due to metastatic disease at 50 months and 43 months. The remaining six were alive and disease-free at the final follow-up. All patients received surgical revision due to wound necrosis. Another patient required an external hemipelvectomy due to early local recurrence of the disease. Functional results of the five patients who remained alive and retained their limb were good or excellent in two cases, acceptable in one, and poor in two, according to their MSTS scores. Average knee flexion was 80° (range: 10–150°). Passive extension was complete in all cases, though no patients achieved it actively. Extensor strength was 2/5 in four patients and 4/5 in the other. Conclusion: Total quadricectomy for high-grade soft-tissue sarcomas of the anterior thigh compartment ensures wide resection margins and local disease control, although local wound complications are common, particularly in older patients. Resection appears to be technically easier if performed distally to proximally in the thigh. Local muscle transfers are more suited for low-demand patients, while neurotized free muscle flaps are mainly an option for young, motivated patients. Full article

Background: Older adults face increased risks of influenza infection and related complications due to declining immunity and reduced vaccine responsiveness. Despite widespread vaccination, only 30–40% mount immune response due to immunosenescence. However, no biomarkers exist to identify potential non-responders, limiting the ability to target vaccine strategies, like high-dose or adjuvanted formulations, to those unlikely to benefit from standard options. Methods: We analysed publicly available baseline bulk RNA sequencing data from peripheral blood mononuclear cells of individuals aged ≥65 years to determine baseline transcriptomic signatures predictive of influenza vaccine response. Using two independent cohorts (discovery and validation), we classified individuals as triple responders (TRs) or triple non-responders (TNRs) based on hemagglutination inhibition assay titers at Day 0 and Day 28 for three components: A/H1N1, A/H3N2, and B/Yamagata. Results: We identified 1152 differentially expressed genes between TRs and TNRs at baseline. TRs exhibited enrichment of genes involved in B cell activation and protein synthesis, while TNRs showed enrichment of genes associated with innate immune responses and platelet activation. A response score derived from gene expression achieved high predictive accuracy in the discovery cohort (area under the curve [AUC] = 0.98). However, performance declined in the validation cohort (AUC = 0.69), and did not outperform clinical predictors, such as baseline titers, sex and vaccine dose. Conclusions: While baseline transcriptomic profiles may reveal mechanistic insights into vaccine responsiveness in the elderly, they offer limited predictive utility. Future work should prioritise higher-resolution or combined cell-specific approaches, such as single-cell RNA-sequencing or flow cytometry. Full article

Invasive pulmonary aspergillosis (IPA), traditionally associated with severe immunosuppression and neutropenia, is increasingly reported among non-neutropenic patients. This epidemiological shift highlights the need for a revised understanding of IPA’s pathogenesis, clinical presentation, and management strategies. The rising incidence in these populations likely reflects improved diagnostic capabilities and recognition of additional predisposing factors. Although profound immunosuppression remains a key risk, even moderate alterations in innate or adaptive immunity can promote Aspergillus spp. invasion. This review summarizes current knowledge and recent advances in the diagnosis and treatment of IPA. Specifically, treatment strategies must be tailored to comorbidities, infection severity, and drug tolerance. Early diagnosis and prompt antifungal therapy are crucial for improving outcomes. Voriconazole remains the first-line treatment, though therapeutic drug monitoring is essential to ensure efficacy and minimize toxicity. Isavuconazole represents an effective alternative, offering comparable efficacy, improved safety, predictable pharmacokinetics, and convenient once-daily dosing. Liposomal amphotericin B serves as a valuable option in severe or refractory cases due to its broad-spectrum activity and reduced nephrotoxicity. Supportive measures—such as respiratory optimization, comorbidity management, and immunomodulatory therapies—are integral to care. Prognosis depends on infection extent, immune status, and timeliness of therapy. Emerging antifungal agents, including olorofim, ibrexafungerp, and fosmanogepix, show promise against resistant Aspergillus species, expanding treatment options. Overall, IPA management in non-neutropenic patients requires a multidisciplinary, patient-centered approach integrating established antifungals, supportive care, and novel therapeutic advances. Full article

Adoptive cellular therapy with donor-derived T cells has always been an attractive strategy after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to reduce the risk of relapse in acute myeloid and lymphoid leukemias. Donor lymphocyte infusion (DLI) is still the best-established option, especially in the preemptive phase when measurable residual disease (MRD) becomes positive and in the prophylactic setting—when MRD is not detectable. However, the clinical benefit of DLI is counterbalanced by the possible onset of graft-versus-host disease (GvHD), which continues to restrict its wide application. To address this challenge, several alternative cell-based strategies have been developed. One of these is represented by cytokine-induced killer (CIK) cells, generated from donor peripheral blood mononuclear cells through stimulation with anti-CD3 antibodies, interferon-γ, and interleukin-2. These cells are characterized by a hybrid phenotype, combining T-cell functions with natural killer-like properties, and exhibit antitumor activity in an MHC-unrestricted manner. CIK cells are generally well tolerated and associated with low toxicity but their efficacy is so far modest. Based on the experience of CAR-T in the treatment of B-cell lymphoid disease, CIK cells have been engineered with chimeric antigen receptors (CAR) developing the CARCIK cells. This novel cellular strategy represents a promising approach in the treatment of acute myeloid and lymphoid leukemia relapsed post-allo-HSCT. This review provides an overview of the current CAR-CIK experiences in the setting of acute leukemias and outlines future directions for their clinical translation. Full article

Hyperpigmentation remains a persistent dermatological challenge with limited treatment options. Among available strategies, tyrosinase inhibition stands out as the current most effective and safest approach for suppressing melanin synthesis. Thiamidol exemplifies a targeted tyrosinase inhibitor developed over a decade of research, guided by rigorous toxicological evaluation. Although it contains a resorcinol moiety, Thiamidol is not a resorcinol derivative and acts through a distinct thiazole 2-amino moiety. In addition to its targeted mode of action of tyrosinase inhibition rather than inactivation, assessments of cytotoxicity and genotoxicity distinguish it from cosmetic and pharmaceutical active ingredients that form highly reactive ortho- or para-quinones. With further exclusion for off-target effects based on pharma profiling and exposure modeling, Thiamidol’s rapid metabolism and absence of bioaccumulation support its safety profile. While an inhibitory mechanism requires repeated application, this characteristic enhances the safety profile and establishes Thiamidol as a cosmetic ingredient rather than a pharmaceutical. In additional to confirmatory clinical studies for efficacy and skin compatibility, a study shows that the use of Thiamidol-containing products does not negatively impact the dermatological diagnostic accessibility of naevi, which is important for skin health monitoring. Full article

Background: Children with congenital heart disease (CHD) are at substantially increased risk for respiratory infections, which occur more frequently and with greater severity than in healthy peers. This heightened vulnerability stems from multifactorial immune impairment, including defects in innate and adaptive immunity, chronic inflammation related to abnormal hemodynamics and hypoxia, reduced thymic function, and genetic syndromes affecting both cardiac and immune development. Viral pathogens—particularly respiratory syncytial virus (RSV), influenza viruses, and SARS-CoV-2—account for most infections, although bacterial pathogens remain relevant, especially in postoperative settings. Methods: This narrative review summarizes current evidence on infection susceptibility in children with CHD, the epidemiology and clinical relevance of major respiratory pathogens, and the effectiveness of available preventive measures. Literature evaluating immunological mechanisms, infection burden, vaccine effectiveness, and passive immunization strategies was examined, along with existing national and international immunization guidelines. Results: Children with CHD consistently exhibit higher rates of hospitalization, intensive care unit admission, mechanical ventilation, and mortality following respiratory infections. RSV, influenza, and SARS-CoV-2 infections are particularly severe in this population, while bacterial infections, though less common, contribute substantially to postoperative morbidity. Preventive options—including routine childhood vaccines, pneumococcal and Haemophilus influenzae type b vaccines, influenza vaccines, COVID-19 mRNA vaccines, and RSV monoclonal antibodies—demonstrate strong protective effects. New long-acting RSV monoclonal antibodies and maternal vaccination markedly enhance prevention in early infancy. However, vaccine coverage remains insufficient due to parental hesitancy, provider uncertainty, delayed immunization, and limited CHD-specific evidence. Conclusions: Respiratory infections pose a significant and preventable health burden in children with CHD. Enhancing the use of both active and passive immunization is essential to reduce morbidity and mortality. Strengthening evidence-based guidelines, improving coordination between specialists and primary care providers, integrating immunization checks into routine CHD management, and providing clear, condition-specific counseling to families can substantially improve vaccine uptake and clinical outcomes in this vulnerable population. Full article

This study explores the sol–gel synthesis, structural characterization, and photocatalytic performance of Ho³⁺-doped TiO₂ nanopowders at two dopant levels (0.5 and 2 mol%). Transparent, homogeneous gels were prepared using titanium (IV) butoxide and holmium (III) nitrate pentahydrate in ethanol, followed by drying and optional annealing at 500 °C. X-ray diffraction confirmed anatase TiO₂ as the dominant crystalline phase, with Ho incorporation suppressing crystal growth and yielding smaller crystallite sizes than undoped TiO₂. FT-IR and UV-Vis spectroscopy verified complete hydrolysis–condensation during gel formation, while diffuse reflectance spectra revealed a red-shifted absorption edge, indicating reduced band gaps. SEM analysis showed nanoscale particles with agglomeration, which intensified after annealing. Photocatalytic activity was tested under UV irradiation using Crystal Violet (anionic dye) and Carmoisine (cationic dye). Annealed Ho-doped powders exhibited markedly higher degradation rates, with the 2 mol% sample achieving the greatest efficiency, particularly against Crystal Violet. These findings demonstrate that Ho³⁺ doping enhances TiO₂’s UV-driven photocatalytic activity by tailoring its structural and optical properties. Full article

The transition toward sustainable transport systems requires decision-support tools that help organizations navigate strategic choices under environmental, economic, and operational constraints. This study introduces the Holistic Multi-Period Fleet Planning Problem (HMPFPP), a nonlinear optimization model designed to support long-term, sustainability-oriented fleet modernization. The model integrates investment costs, operational performance, emission limits, and dynamic demand into a unified analytical framework, enabling organizations to assess the long-term consequences of their decisions. A notable feature of the HMPFPP is the inclusion of outsourcing as a strategic option, which expands the decision space and helps maintain service performance when internal fleet capacity is constrained. An illustrative ten-year scenario demonstrates that the model generates non-uniform but cost-efficient transition pathways, in which legacy vehicles are gradually replaced by cleaner technologies, and temporary fleet downsizing can be optimal during low-demand periods. Outsourcing is activated only when joint emission and budget constraints make fully internal service provision infeasible. Across the tested instance, the HMPFPP is solved within seconds on standard hardware, confirming its computational tractability for exploratory planning. Taken together, these results indicate that data-driven optimization based on the HMPFPP can provide transparent and robust support for sustainable fleet management and transition planning. Full article

Background/Objectives: Chronic bone infections require local antimicrobial delivery to achieve high drug concentrations while limiting systemic toxicity. Silver ion-doped calcium phosphate synthetic bone grafts have been proposed as carriers for local antimicrobial release. This study aimed to evaluate the efficacy and safety of a silver ion-doped synthetic bone graft in patients with chronic osteomyelitis, infected nonunion, or implant-related bone infection. Methods: This retrospective cohort included 12 adults who underwent surgery for chronic osteomyelitis or implant-associated infection. All patients received thorough debridement, removal of infected implants when present, and filling of bone defects with a silver ion-doped calcium phosphate graft. The median age was 38 years, and follow-up was 12 months. Clinical and radiographic outcomes, liver and kidney function tests, and blood silver levels were assessed pre- and postoperatively. Results: Infection eradication was achieved in 11 of 12 patients (90%) at 12 months. Functional recovery, defined as return to normal daily activities, occurred within 3–5 months. Bone union was observed in all but one patient within 3–6 months, and no graft resorption was detected at one year. No significant differences in liver or kidney function tests were found compared with the control group (p > 0.05), and blood silver levels remained within normal limits. Conclusions: At 12-month follow-up, silver ion-doped synthetic bone grafts showed encouraging safety and efficacy in the treatment of chronic osteomyelitis. These findings suggest that silver-doped grafts may represent a useful option for one-stage treatment of osteomyelitis. Full article

This study investigated the effects of alternative sweeteners, allulose (AL), stevia (ST), and xylose (XY), on the physicochemical, antioxidant, textural, and sensory properties of Yanggaeng fortified with Cissus quadrangularis (CQ) powder. Replacing sucrose (SU) with alternative sweeteners significantly affected the proximate composition and overall quality of Yanggaeng. Formulations containing AL, ST, or XY exhibited higher moisture retention and lower carbohydrate content than those containing SU. Colorimetric analysis revealed that Yanggaeng prepared with alternative sweeteners developed a darker coloration and greater browning intensity, likely due to enhanced Maillard reactions during heating. Among the sweeteners tested, AL showed the highest total phenolic content and relatively high antioxidant activity, suggesting potential functional advantages beyond sweetness. Textural analysis indicated that ST enhanced gel strength and elasticity even under high-moisture conditions, whereas AL produced a softer texture, which may be desirable for products requiring reduced firmness. Although consumer preference scores did not differ significantly across most sensory attributes, both ST and AL achieved acceptable overall profiles, with sweetness ratings comparable to those of SU. These findings suggest that CQ-enriched Yanggaeng sweetened with alternative sweeteners can be developed as a promising low-sugar dessert option without compromising quality or consumer acceptability. Full article

Pine wilt disease (PWD), caused by the pine wood nematode (PWN) Bursaphelenchus xylophilus, is a devastating pine disease that is characterized by rapid transmission, high lethality, and limited control options. In our previous study, the fucosyltransferase gene (fut) which encoded fucosyltransferase (FUT) was found to be a putative virulence determinant in PWN, which regulates pathogenicity of nematodes. To investigate the functional role of the fut gene in PWN, a comprehensive analysis was conducted to understand its molecular structure and biological activity. The full-length open reading frame (ORF) of fut was amplified using reverse transcription PCR (RT-PCR) and successfully ligated into the pET-28a expression vector. Heterologous expression of the recombinant FUT was achieved in Escherichia coli Rosetta (DE3) through induction with 1.0 mM isopropyl-β-D-thiogalactoside (IPTG), followed by purification via nickel-nitrilotriacetic acid (Ni-NTA) affinity chromatography. Biochemical characterization revealed that the recombinant FUT exhibited optimal enzymatic activity at 30 °C and pH 8.0, respectively. Furthermore, RNA interference (RNAi) validated by RT-qPCR was used to explore the biological functions of fut in PWN, and results indicated that downregulation of the fut gene could significantly reduce the vitality, reproduction, pathogenicity, development, and lifespan of PWN. Furthermore, gallic acid as an inhibitor of FUT displayed a strong inhibitory effect on recombinant FUT activity and nematicidal activity against PWNs in vitro and could alleviate the wilt symptom of pine seedlings inoculated with PWNs at a concentration of 100 μg/mL, indicating that it has the potential to be a novel nematicide. Collectively, these results establish fut as a critical virulence determinant in PWN and highlight its potential as a molecular target for controlling pine wilt disease. Full article

Vascular dysfunction lies at the core of cardiovascular diseases—the leading cause of global morbidity and mortality. Despite their prevalence, therapeutic options remain limited, in part due to an incomplete understanding of the molecular mechanisms driving vascular pathology. The integrated stress response (ISR), an evolutionarily conserved signaling network activated by diverse stressors, represents a critical but underexplored mechanism in vascular biology. This review examines the dual roles of the core ISR kinases—PERK, GCN2, HRI and PKR—in vascular homeostasis and pathology, including atherosclerosis, pulmonary hypertension, and angiogenesis. We develop a conceptual framework in which the ISR functions as a context-dependent, double-edged sword: while PERK and PKR promote inflammation, apoptosis, and vascular re-modeling, GCN2 mediates protective effects. The outcome of ISR activation is shaped by cell type, stress duration and intensity, and downstream signaling bias (e.g., ATF4 vs. CHOP dominance). We further discuss pharmacological ISR modulators—including 2-aminopurine, C16, salubrinal, halofuginone, GSK2606414, and GSK2656157—which have demonstrated beneficial effects in preclinical models by suppressing inflammation, reducing apoptosis, and attenuating disease progression. Collectively, the ISR emerges as a critical regulatory node in vascular pathophysiology, and its selective, context-aware modulation represents a promising avenue for therapeutic intervention. Full article