Search Results (10,322)

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by a block of differentiation and uncontrolled expansion of myeloid progenitor cells. Standard treatment includes intensive induction chemotherapy, typically with cytarabine and anthracycline, followed by consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. However, these approaches are often associated with relapse and treatment-related toxicity. Accumulating evidence highlights a critical role for epigenetic dysregulation in driving disease initiation, progression, and therapeutic resistance. In this review, we examine an integrated framework of epigenetic regulation in AML, encompassing DNA methylation, histone post-translational modifications, chromatin remodeling, and RNA-mediated epigenetics. We discuss how alterations in key epigenetic regulators, such as DNMT3A, TET2, IDH1/2, EZH2, and histone-modifying enzymes, reshape the transcriptional and epigenetic landscape of leukemic cells. Particular emphasis is placed on epigenetically defined AML subtypes, including NPM1-mutated, DNMT3A-mutated, and KMT2A-rearranged AML, which illustrate distinct mechanisms of transcriptional and epigenetic dysregulation and confer unique therapeutic vulnerabilities. We further summarize current and emerging therapeutic strategies, ranging from conventional chemotherapy to molecularly targeted agents, epigenetic drugs, and immunotherapeutic approaches. Despite these advances, durable responses remain limited, highlighting the need to better understand epigenetic mechanisms to overcome resistance and improve patient outcomes. Full article

Pulmonaria rubra (Boraginaceae) is a widely distributed plant in Bulgaria, yet its phytochemical profile and therapeutic potential have remained unexplored. P. rubra methanol extract (PRE) was evaluated through phytochemical profiling and in vitro neuroprotective and antioxidant assays. Rat brain synaptosomes, mitochondria and microsomes were treated with PRE alone, and in combination with 6-hydroxydopamine and tert-butyl hydroperoxide as toxic agents. The extract exhibited concentration-dependent protective effects in all subcellular models. Additionally, it was tested on hMAOA/B and different isoforms of CYP450 enzymes, but it did not show any activity in the tested conditions. In the UHPLC-HRESIMS analysis, 26 secondary metabolites were identified, mainly hydroxycinnamic acids and caffeoyl oligomers, flavonoids, a lignan (globoidnan A), and the terpenoid glycoside roseoside. Seven compounds were identified via UHPLC-UV method using reference compounds: rosmarinic acid, rutin, quercetin-3-O-glucoside, astragalin, apigenin-7-O-glucoside, apigenin-7-O-glucuronide and alcesefoliside, with the latter two being reported for the first time in genus Pulmonaria. The quantity of rosmarinic acid in PRE was 4.35%, distinguishing the compound as the main bioactive molecule in the species. Characterized by its high content of rosmarinic acid, P. rubra represents a highly viable candidate for subsequent development into standardized phytopharmaceuticals targeting oxidative stress-related neurodegenerative diseases. Full article

Bispecific antibodies (bsAbs) have emerged as a novel therapeutic class in oncogene-driven non-small-cell lung cancer (NSCLC), designed to simultaneously target multiple signaling pathways and overcome resistance mechanisms associated with tyrosine kinase inhibitors (TKIs). Unlike small-molecule TKIs, bsAbs enable dual receptor blockade and immune effector engagement, offering a mechanistically distinct advantage in the context of tumor heterogeneity and bypass signaling. This review summarizes the structural and biological principles underlying bsAb design, with a focus on clinically approved agents such as amivantamab (EGFR/MET) and zenocutuzumab (HER2/HER3) and a growing pipeline of investigational agents. We evaluate key clinical evidence from Phase I-III trials including CHRYSALIS, PAPILLON, MARIPOSA, MARIPOSA-2 and eNRGy, and compare the efficacy, toxicity, and CNS penetration profile of bsAbs relative to TKIs and antibody–drug conjugates (ADCs). While bsAbs demonstrate meaningful clinical activity, particularly in TKI-resistant disease and molecularly defined subsets such as EGFR exon 20 insertions and NRG1 fusions, their limitations, including intravenous administration, increased immune-mediated and thromboembolic toxicity, currently preclude replacement of TKIs in most settings. Collectively, available evidence supports a complementary role for bsAbs within evolving multimodal treatment paradigms, particularly in combination strategies. Future directions include biomarker-driven patient selection, improved drug engineering and integration into adaptive therapeutic sequencing frameworks. Full article

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two main neurodegenerative diseases and cause disability and death in patients worldwide. Neurodegeneration is characterized by a progressive loss of neuronal function and structure, causing enormous impairment in cognitive–motor function. Magnolol and honokiol are isomeric biphenyl neolignans and have exhibited neuroprotective activity in previous studies. Hence, we assessed and compared honokiol, magnolol, and mixtures of honokiol and magnolol in honokiol/magnolol molar ratios of 1:3, 1:1, and 3:1 in terms of their neurotoxicity, using the cell counting kit-8 (CCK-8) assay, and of their neuroprotective effect on intracellular reactive oxygen species (iROS) against amyloid-beta (Aβ)- and 1-methyl-4-phenylpyridinium ion (MPP⁺)-induced neurotoxicity in SH-SY5Y cells, using the 2′,7′-dichlorodihydrofluorescein diacetate (H₂DCF-DA) assay. The results showed that honokiol (H) and magnolol (M) at 0.1 μM and the mixtures of honokiol and magnolol in H/M ratios of 1:3, 1:1, and 3:1 at 0.0001 μM exhibited a significant neuroprotective effect of reducing iROS in SH-SY5Y cells where neurotoxicity was induced by Aβ- and MPP⁺ (p-value with respect to Aβ-treated cells < 0.005 and p-value with respect to MPP⁺-treated cells < 0.0001). Moreover, magnolol and honokiol possess antioxidant properties according to computational molecular analysis with Highest Occupied Molecular Orbital (HOMO)- Lowest Unoccupied Molecular Orbital (LUMO) prediction, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and Ferric Reducing Antioxidant Power (FRAP) assays. The mixtures of honokiol and magnolol exerted synergistic neuroprotective ability at all ratios while showing better antioxidation ability than that of pure magnolol alone but comparable to that of pure honokiol alone. Drug-likeness, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction, and toxicity profiles showed that both compounds are promising neuroprotective agents and that one of the possible targeting mechanisms is the ROS-mediated oxidative stress pathway. Additional neuronal cell lines and in vivo models are required to determine similar effects or other protective mechanisms involving the neuroprotective ability of honokiol and magnolol. Full article

Introduction: Toxic epidermal necrolysis in children is a life-threatening emergency requiring prompt withdrawal of the culprit drug, transfer to an experienced center, and intensive supportive care. Case Report: An 11-year-old girl developed toxic epidermal necrolysis involving 90 percent of total body surface area after exposure to a nonsteroidal anti-inflammatory drug, with concomitant viral positivity. At the referring pediatric hospital, on day 2 the patient received high-dose intravenous immunoglobulin 2 g/kg and a single infusion of infliximab 5 mg/kg. She was transferred on day 6 to our Burn Unit. Histopathology confirmed complete epidermal loss. Treatment included IgM- and IgA-enriched intravenous immunoglobulin over 72 h and methylprednisolone 0.74 mg/kg/day for 30 days. Cryopreserved amniotic membrane was applied to trunk and limbs, and fluorescent light energy to the face. Complete re-epithelialization occurred within 14 days without complications. Pain resolved rapidly, with a Visual Analog Scale score of 0 on day 2. At 6 months, skin and mucosae were intact with only transient dyschromia. Conclusions: In this child with extensive toxic epidermal necrolysis and high predicted mortality, IgM/IgA-enriched immunoglobulin, low-dose corticosteroid and early staged cryopreserved amnion were associated with infection-free, complete re-epithelialization and full functional recovery. Full article

Animal venoms represent an extraordinary, yet largely untapped, biochemical reservoir for oncological drug discovery. This review provides a comprehensive analysis of venom-derived enzyme inhibitors as emerging anticancer agents, emphasizing their chemical diversity, structure–activity relationships (SAR), molecular targets, and mechanistic pathways. Venom-derived peptides and proteins exhibit exceptional binding affinity and structural rigidity, characteristics frequently enforced by conserved disulfide networks. This specific architecture allows them to selectively modulate critical cancer-associated enzymes, including matrix metalloproteinases, phospholipases A₂, serine proteases, and kinases. Inhibiting these highly specific targets successfully disrupts tumour angiogenesis, extracellular matrix remodelling, and metastatic dissemination, while simultaneously inducing apoptosis through unique pathways such as reactive oxygen species generation. Modern computational approaches, encompassing deep learning algorithms, molecular docking, and molecular dynamics simulations, are substantially accelerating and transforming the discovery pipeline by rapidly mapping intricate peptide–receptor interactions and guiding rational drug design. Translating these potent molecules into clinical therapeutics remains heavily challenged by pharmacokinetic instability, rapid proteolytic degradation, and systemic toxicity. The integration of computationally optimized scaffolds with advanced targeted delivery platforms, such as nanocarriers and liposomal encapsulation, offers a highly viable strategy to overcome these barriers, ultimately paving the way for next-generation, venom-inspired cancer therapies. Full article

Microphysiological Systems (MPS) have emerged as a transformative platform in biomedical research, enabling the investigation of disease mechanisms, drug screening, and toxicity prediction by closely simulating human physiological functions. However, the rapid advancement of MPS technology has raised a series of complex ethical challenges. These include the sourcing and application of human-derived stem cells, the protection of donors’ personal and genetic data, the potential for brain organoids to develop consciousness-like characteristics, and the challenges to species boundaries posed by human–animal chimera research. Meanwhile, although regulatory authorities encourage innovation, specialized certification standards and ethical review guidelines for MPS are yet to be fully established. The lack of technical standardization and a coherent ethical governance framework remain a major bottleneck hindering the broader application and industrialization of MPS. This review systematically outlines the key ethical issues facing MPS, compares the evolution and differences in international ethical regulatory frameworks, and discusses strategies for addressing these challenges—including the establishment of dynamic ethical governance mechanisms, harmonization of international standards, and the promotion of benefit-sharing and public engagement. Finally, we highlight the need to develop a scientific, unified, and actionable ethical governance system that balances technological innovation with responsible translation, supporting the sustainable development of MPS technology. Full article

Objective: To analyze the evolving epidemiological characteristics of pediatric poisoning from 2019 to 2024 in Southwest China, explore the changing patterns of pediatric poisoning in the post-pandemic era, and provide a reference for poisoning prevention and the development of effective prevention and treatment strategies. Methods: This study included 3923 cases of pediatric poisoning treated at the Emergency Department of West China Second University Hospital, Sichuan University. Clinical data such as gender, age, poisonous substance, and cause of poisoning were described. The chi-square trend test was used to analyze annual changes, and multivariate Poisson regression was employed to identify risk factors for hospitalization and for intentional poisoning in children. Results: The total number of cases increased significantly from 544 in 2019 to 1006 in 2024. A marked “polarization” pattern was observed: among children aged 1–3 years, unintentional ingestion of household chemicals predominated (n = 2332), whereas among adolescents aged 12–14 years, intentional self-poisoning cases surged by 580%, with the toxic agents shifting mainly to psychotropic prescription drugs. From 2019 to 2024, the proportions of intentional poisoning, psychotropic drug poisoning, psychiatric comorbidity, and delayed presentation all increased significantly. Poisson regression indicated that the post-pandemic period, psychiatric comorbidity, and exposure to psychotropic drugs were risk factors for intentional poisoning. Conclusions: Following the COVID-19 pandemic, mental health problems among adolescents have become increasingly prominent, and pediatric poisoning has exhibited a bipolarization pattern. Clinical prevention and control strategies should shift from simple emergency treatment to early intervention, psychological screening, and comprehensive prevention, so as to reduce health damage to children and the societal disease burden. Full article

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed worldwide for their analgesic, antipyretic, and anti-inflammatory properties. However, their long-term use is associated with substantial gastrointestinal (GI) toxicity. Although upper GI injury has traditionally received greater attention, NSAID-induced enteropathy is now increasingly recognized as a common yet underdiagnosed condition. Advances in small-bowel imaging, particularly capsule endoscopy, have demonstrated that mucosal injury of the small intestine occurs in up to 70–80% of chronic NSAID users and may also develop after short-term exposure in otherwise healthy individuals, often without overt clinical symptoms. When symptoms do occur, NSAID-induced enteropathy is characterized by non-specific clinical manifestations and may lead to severe complications in approximately 1% of cases. The pathogenesis of NSAID-induced enteropathy is multifactorial and more complex than that underlying upper GI damage. It involves prostaglandin depletion, increased intestinal permeability, bile acid-mediated toxicity, enterohepatic recirculation of NSAIDs, and, importantly, interactions with the gut microbiota. Concomitant therapies, particularly proton pump inhibitors, may further aggravate small-bowel injury by promoting intestinal dysbiosis. Growing evidence supports a relevant contributory role for the gut microbiota as both a mediator and a modulator of NSAID-induced toxicity, affecting epithelial barrier function, oxidative stress, immune responses, and bile acid metabolism. This review provides an overview of current knowledge of NSAID-induced enteropathy, with a particular emphasis on the microbiota-driven mechanisms underlying mucosal injury. By integrating emerging microbiota-targeted therapeutic approaches, we propose a management algorithm that may help modify disease progression in a condition that remains frequently overlooked in clinical practice. Full article

Quantum Dots (QDs) are nanoparticles that are highly desirable for biomedical applications such as drug delivery, cellular tracking, and imaging due to their fluorescent and tunable optical properties. However, the biochemical mechanism of their interaction with intracellular proteins that regulate cytoskeletal organization remains poorly understood. While previous studies have shown QDs’ ability to interact with actin and alter actin dynamics, their impacts on actin-binding proteins have not been explored. In this study, we investigated the interaction between CdSe/ZnS QDs and the actin-binding protein, α-actinin, and assessed its impact on actin cytoskeletal organization. Our results demonstrated a strong interaction between QDs and α-actinin, which impeded an α-actinin-mediated filamentous actin (F-actin) bundling, as well as compromised the activity of α-actinin in preventing actin depolymerization. Furthermore, the physics-based modeling and simulations carried out at physiological temperatures supported these findings by identifying stable interaction surfaces between QDs and α-actinin. This study provides mechanistic insight into nanoparticle–protein interactions and highlights the potential cytoskeletal toxicity associated with it. Full article

Rhodococcus equi (R. equi) primarily induces fatal pulmonary and extrapulmonary pyogenic granulomatous infections in foals, imposing substantial economic burdens on the equine industry. The emergence and spread of multidrug-resistant (MDR) R. equi have led to a therapeutic impasse in clinical settings. Although vaccination is a proven strategy against MDR pathogens, no commercial vaccine is currently available for R. equi. In this study, we employed a bioinformatics approach to systematically identify and prioritize antigenic epitopes derived from R. equi for multi-epitope vaccine design. Using ABCPred, NetMHCpan EL, and IEDB servers, 27 MHC-I and 9 MHC-II epitopes were selected from five previously validated R. equi vaccine candidates: ABC transporter, PBD2, NlpC/P60, Esterase, and M23. These epitopes were coupled with distinct peptide linkers to construct six multi-epitope vaccine constructs, designated V1–V6. The physicochemical properties, antigenicity, immunogenicity, and toxicity of the six vaccine constructs were analyzed, and the V3 and V4 constructs were ultimately selected. Using the HDOCK and Gromacs tools, the intermolecular interactions, binding affinity, and thermal stability of the V3 and V4 constructs with the equine MHC molecules EQCA-I and EQCA-II were evaluated. The results confirm that V3 and V4 exhibit strong binding affinity to EQCA-I and EQCA-II, with stable conformations following binding, indicating theoretical potential to induce humoral and cellular immunity in foals. Recombinant plasmids for V3 and V4 were constructed, and the V3 and V4 proteins were successfully prepared, confirming the feasibility of prokaryotic expression for these vaccine constructs. Immunization assays in SPF BALB/c mice showed that the multi-epitope vaccines elicited robust antigen-specific IgG antibody responses, reflecting preliminary humoral immunogenicity. However, these murine data have translational limitations, as they cannot fully represent equine immune responses. The findings establish a crucial theoretical foundation for the advancement of vaccines targeting R. equi while offering a reference for the design of vaccines against other drug-resistant microbial pathogens. Full article

Amino alcohols are a class of compounds bearing both amino and hydroxyl groups, ubiquitous in natural products and extensively utilized as key structural motifs in pharmaceuticals and functional materials. Owing to their structural diversity, inherent chirality, and high reactivity, they exhibit significant application value in the pharmaceutical field, materials industry, and organic synthesis. Compared with chemical synthesis, which suffers from limitations such as insufficient enantioselectivity, dependence on precious metal catalysts, and environmental concerns, biosynthesis offers core advantages of high stereoselectivity, mild reaction conditions, and environmental sustainability. This review systematically delineates the diverse applications of amino alcohols in the pharmaceutical field (e.g., anti-HIV, antimalarial, and antitumor drugs), materials industry (e.g., polymer modification and metal corrosion protection), and organic synthesis (e.g., chiral ligands and catalysts). Particular emphasis is placed on the biosynthetic strategies and pathways of representative amino alcohols, including ethanolamine, (2S,3R)-2-amino-1,3,4-butanetriol, (R)-3-amino-1-butanol, sphingosine, and metaraminol, as well as the metabolic engineering design principles and downstream processing technologies for amino alcohol biosynthesis. Although current biosynthetic approaches still face bottlenecks in enzyme catalytic efficiency, substrate tolerance, cofactor regeneration, product toxicity, and thermodynamic equilibrium, substantial improvements in synthetic efficiency and stereoselectivity have been achieved through protein engineering, metabolic engineering, in situ product removal, and multi-enzyme cascade optimization. This review aims to provide systematic theoretical references and technical insights for the green and efficient biomanufacturing of amino alcohols. Full article

Peritoneal metastasis (PM) is the most frequent and lethal pattern of dissemination in gastrointestinal malignancies. Despite advances in systemic chemotherapy, outcomes remain poor because the unique biology of PM, characterized by poor vascularization and the peritoneal–plasma barrier (PPB), limits drug penetration and contributes to treatment resistance. To address these challenges, several locoregional treatment strategies have been developed, including cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). However, their widespread adoption is constrained by invasiveness, strict patient selection, and inconsistent survival benefits. Normothermic intraperitoneal and systemic treatment (NIPS) has emerged as a practical and less invasive alternative, particularly in East Asia. Through an implanted intraperitoneal port, NIPS enables repeated drug administration, providing sustained regional exposure while imposing minimal procedural burden. Importantly, it can be readily integrated with systemic chemotherapy, making it suitable for long-term multimodal treatment. Among available agents, paclitaxel (PTX) is particularly well suited for intraperitoneal administration because of its prolonged retention within the peritoneal cavity and limited systemic absorption. These pharmacokinetic properties allow high local drug concentrations with relatively low systemic toxicity. Consequently, PTX-based NIPS represents a biologically rational and clinically feasible treatment strategy for PM. This review summarizes the pharmacological rationale, clinical evidence, and emerging innovations in drug formulation and delivery that may further enhance the efficacy of PTX-based intraperitoneal chemotherapy for this challenging disease. Full article

Neuroinvasive free-living amoebae (FLA), particularly Naegleria fowleri and Acanthamoeba spp., are responsible for rare but devastating infections of the central nervous system (CNS). Approximately 480 cases of primary amoebic meningoencephalitis (PAM) and fewer than 200 well-documented cases of Acanthamoeba-associated granulomatous amoebic encephalitis (GAE) have been reported worldwide. Mortality rates frequently exceed 90%. PAM typically develops following exposure to warm freshwater contaminated with N. fowleri and progresses rapidly in otherwise healthy individuals. In contrast, GAE usually follows a more indolent course and occurs predominantly in immunocompromised hosts. Despite their distinct clinical courses, both infections are characterized by CNS invasion, amoeba-mediated tissue destruction, blood–brain barrier (BBB) disruption, and host inflammatory responses. These processes drive neuroinflammation, neuronal injury, and neurological deterioration. Early diagnosis remains challenging because clinical manifestations are nonspecific and disease progression can be either fulminant or initially subtle. Therapeutic management is hindered by poor CNS drug penetration, limited efficacy of currently available therapies, treatment-related toxicity, and the absence of standardized treatment protocols or controlled clinical trials. This narrative review critically synthesizes current evidence on CNS invasion, neuroinflammation, neuropathology, diagnostic challenges, and therapeutic strategies in neuroinvasive FLA infections. It also highlights key translational priorities, including earlier diagnosis, standardized treatment protocols, stronger clinical evidence, and improved CNS-targeted drug delivery. Full article

Cancer immunotherapy has reshaped oncology, yet durable benefit remains limited for many patients because antitumor responses are constrained by multiple biological and clinical barriers. A targeted narrative review was conducted using peer-reviewed literature indexed in PubMed, Scopus, and Web of Science from January 2020 to April 2026, with additional landmark studies from earlier years included for essential mechanistic context. Priority was given to clinical, translational, and high-impact review articles examining combination strategies built on immune checkpoint blockade and related immune platforms. The evidence was synthesized by the main barriers each strategy aims to overcome, including poor immune priming, immune exclusion, immunosuppressive tumor microenvironments, adaptive resistance, and limited treatment durability. Across recent studies, combination immunotherapy is increasingly moving away from empiric regimen construction toward biologically rational approaches that integrate checkpoint blockade with chemotherapy, radiotherapy, antiangiogenic therapy, targeted agents, antibody–drug conjugates, bispecific antibodies, vaccines, and cellular platforms. Increasing emphasis has also been placed on integrated biomarkers that combine tumor-intrinsic, immune, spatial, and dynamic features to improve patient selection. At the same time, growing regimen complexity continues to raise challenges related to overlapping toxicity, sequencing, polypharmacy, and multidisciplinary implementation. Overall, the field is evolving toward mechanism-matched, biomarker-guided, and clinically manageable strategies that may broaden and refine the benefit of cancer immunotherapy. Full article