Search Results (1,224)

Resistance to imatinib remains a therapeutic challenge, largely driven by point mutations within the kinase domain of the BCR-ABL, among which the T315I substitution constitutes the most clinically significant barrier. Ponatinib effectively inhibits this mutant form but is limited by dose-dependent cardiovascular toxicity, prompting efforts to develop safer and more selective agents. Recent advances highlight aminopyrimidine-derived scaffolds and their evolution into thienopyrimidines, oxadiazoles, and pyrazines with improved activity against BCR-ABL^T315I. Further progress has been achieved with benzothiazole–picolinamide hybrids incorporating a urea-based pharmacophore, which benefit from strategic hinge-region substitutions and phenyl linkers that enhance potency. Parallel research into dual-mechanism inhibitors, including Aurora and p38 kinase modulators, demonstrates additional opportunities for overcoming resistance. Combination strategies, such as vorinostat with ponatinib, provide complementary therapeutic avenues. Natural-product-inspired approaches utilizing fungal metabolites provided structurally diverse scaffolds that could engage sterically constrained mutant kinases. Hybrid molecules derived from approved TKIs, including GNF-7, olverembatinib, and HG-7-85-01, exemplify rational design trends that balance efficacy with improved safety. Molecular modeling continues to deepen understanding of ligand engagement within the T315I-mutated active site, supporting the development of next-generation inhibitors. In this review, we summarized recent progress in the design, optimization, and biological evaluation of small molecules targeting the BCR-ABL^T315I mutation. Full article

Extracellular vesicles (EVs) are emerging as key factors in maintaining cellular homeostasis, critical mediators of intercellular communication, potential biomarkers, and therapeutic tools. While small EVs have been extensively characterized, the molecular signatures of large EVs (including those generated during regulated cell death pathways) remain poorly defined. Here, we investigated the characteristics of large EVs released during apoptosis and pyroptosis by human monocytic cell lines (THP-1 and U937). Apoptosis was induced by staurosporine and blocked using the pan-caspase inhibitor Q-VD-OPh, whereas pyroptosis was triggered by LPS/nigericin and inhibited with a selective NLRP3 inhibitor. We found that both forms of regulated cell death markedly enhanced the release of large EVs. Both apoptotic and pyroptotic large EVs showed increased Annexin V binding and decreased CD9 expression compared with those released by healthy cells. Large EVs derived from apoptotic and pyroptotic cells exhibited distinct proteomic profiles. Pyroptotic large EVs carried interacting protein networks of RNA-binding proteins and chromatin-associated proteins many of which are known damage-associated molecular patterns or alarmins. In contrast, we found that a subpopulation of apoptotic large EVs was characterized by the presence of dsDNA, and active caspase-3/7. Together, our data shed light on the specific protein cargo of large EVs released by cells during apoptosis and pyroptosis. This study identifies candidate markers of large EVs released by dying cells and may enhance our understanding of the role of EVs in regulated cell death. Full article

Thrips are cosmopolitan agricultural pests and important vectors of plant viruses, and the increasing coexistence of multiple morphologically similar species has intensified the demand for species-specific molecular identification. However, traditional morphological identification and PCR assays using universal primers are often inadequate for mixed-species samples and field-adaptable application. In this study, we developed a species-specific molecular identification framework targeting a polymorphism-rich region of the mitochondrial cytochrome c oxidase subunit I (COI) gene, which is more time-efficient than sequencing-based COI DNA barcoding, for four economically important thrips species in southern China, including the globally invasive Frankliniella occidentalis. By aligning COI sequences, polymorphism-rich regions were identified and used to design four species-specific primer pairs, each containing a diagnostic 3′-terminal nucleotide. These primers were combined with a PBS-based DNA extraction workflow optimized for single-insect samples that minimizes dependence on column-based purification. The assay achieved a practical detection limit of 1 ng per reaction, demonstrated species-specific amplification, and maintained reproducible amplification at DNA inputs of ≥1 ng per reaction. Notably, PCR inhibition caused by crude extracts was effectively alleviated by fivefold dilution. Although the chemical identities of the inhibitors remain unknown, interspecific variation in inhibition strength was observed, with T. hawaiiensis exhibiting the strongest suppression, possibly due to differences in lysate composition. This integrated framework balances target specificity, operational simplicity, and dilution-mitigated inhibition, providing a field-adaptable tool for thrips species identification and invasive species monitoring. Moreover, it provides a species-specific molecular foundation for downstream integration with visual nucleic acid detection platforms, such as the CRISPR/Cas12a system, thereby facilitating the future development of portable molecular identification workflows for small agricultural pests. Full article

Inflammatory Bowel Diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated disorders marked by persistent and recurrent inflammation of the gastrointestinal tract. Over the past two decades, major advances in understanding the immunologic and molecular pathways that drive intestinal injury have transformed the therapeutic landscape. This progress has enabled the development of novel biologics and small-molecule agents that more precisely target dysregulated immune responses, thereby improving clinical outcomes and quality of life for many patients. Despite these therapeutic advances, IBD remains a highly heterogeneous condition. Patients differ widely in disease phenotype, progression, and response to specific treatments. Consequently, selecting the most effective therapy for an individual patient requires careful consideration of clinical features, molecular markers, and prior treatment history. The shift toward personalized, prediction-based treatment strategies aims to optimize the timing and choice of therapy, minimize unnecessary exposure to ineffective drugs, and ultimately alter the natural course of disease. In this review, we provide a comprehensive overview of current evidence guiding drug positioning in IBD, with particular emphasis on biologic therapies and small-molecule inhibitors. We also examine emerging biomarkers, clinical predictors of response, and real-world factors that influence therapeutic decision-making. Finally, we discuss the challenges and limitations that continue to hinder widespread implementation of personalized strategies, underscoring the need for further research to integrate precision medicine into routine IBD care. Full article

As a natural flavonoid, the flavonoid luteolin is characterized by its powerful antioxidant and anti-inflammatory effects. While its precise mechanisms require further elucidation, existing evidence confirms its efficacy in ameliorating myocardial ischemia–reperfusion injury (MIRI). This research was designed to investigate the mechanism through which luteolin protects against MIRI. We established MIRI rat models through the ligation of left anterior descending coronary artery (LAD). To evaluate the cardioprotective effects of luteolin, echocardiographic analysis was performed, Hematoxylin and Eosin (HE) staining, and serum cardiac injury markers creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH). Cardiac vascular permeability was determined using Evans blue staining. To mimic ischemia–reperfusion injury, endothelial cells (ECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Endothelial cell barrier function was evaluated through F-actin phalloidin staining and FITC-Dextran fluorescence leakage experiments. To elucidate the molecular mechanism, FOXP1 small interfering RNA (siRNA) and NLRP3 inhibitor MCC950 were administered. In MIRI rats, luteolin significantly improved cardiac function and preserved endothelial barrier integrity. These effects were associated with upregulation of FOXP1 and suppression of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. In OGD/R-treated endothelial cells, luteolin restored barrier function and cell viability. The protective effects of luteolin were abolished after FOXP1 silencing. Pharmacological NLRP3 inhibition (MCC950) mirrored luteolin’s protection. Our study indicates that luteolin enhances endothelial barrier function and attenuates MIRI via the FOXP1-NLRP3 pathway. The current study provides a potential drug for MIRI treatment. Full article

Background: In melanoma diagnostics key molecular markers, such as BRAF, NRAS, and KIT mutations also paved the way for targeted therapies. Immunotherapies, including immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1/PD-L1, have revolutionized treatment, improving survival outcomes for advanced-stage melanoma patients. Despite these advances, challenges such as resistance to targeted therapies and variability in patient responses to immunotherapy remain critical issues. The purpose of the project is to characterize the molecular landscape of a set of 28 malignant melanomas using next-generation sequencing, identify the prevalence and nature of class 3–5 variants (e.g., NRAS, BRAF, KIT, TP53), assess the genetic complexity and molecular patterns, and use these insights to inform personalized therapies and optimize patient stratification for potential combination strategies (targeted therapy followed by immunotherapy). Methods: We analyzed a set of malignant melanoma of the skin of 17 women (61%) and 11 men (39%) at the age of 23 to 85 years (median: 63 years) by tumor-only next generation sequencing. Results: 22/28 cases (79%) present a pathogenic or likely pathogenic variant with an allelic frequency of ≥5%. In total 42 distinct somatic pathogenic or likely pathogenic variants with an allelic frequency of ≥5% could be detected. The most frequent pathogenic molecular alteration in these melanomas were found in NRAS (25%) and BRAF (25%). The most frequent molecular alteration of unknown significance was found in FANDC2 (46%), NOTCH3 (39%), ARID1A (32%), PMS2 (32%), POLE (29%), NOTCH1 (29%), TSC2 (25%), SMARCA4 (25%), ATR (25%) and TERT (21%). Conclusions: While NRAS and BRAF were the most frequent actionable alterations (each 25%), a broad spectrum of variants of unknown significance (e.g., FANDC2, NOTCH3, ARID1A, PMS2, POLE, NOTCH1, TSC2, SMARCA4, ATR and TERT) also predominates, underscoring the genetic complexity of melanoma. These variants complicate clinical decision-making because their contribution to tumorigenesis, therapeutic response, and prognosis remains uncertain. Nevertheless, these variants also offer a valuable resource for future research, as they may uncover novel pathogenic mechanisms or therapeutic targets once their significance is elucidated. Integrating comprehensive genetic profiling with immunologic markers can enhance patient stratification and support rational, potentially synergistic strategies, such as combining targeted therapies with immunotherapy, to optimize clinical outcomes. This study is limited due to a small cohort and limited available clinical data. Larger cohort studies and prospective clinical trials are necessary to validate and explore the interplay between molecular and immune biomarkers as well as general biological mechanism in paving therapeutic way in melanoma. Full article

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk, particularly in aging populations. Postmenopausal osteoporosis (PMOP) remains the most common primary form and results from abrupt estrogen deficiency after menopause, which disrupts bone remodeling by accelerating the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis, suppressing Wnt/β-catenin signaling, and promoting inflammatory cytokine production. In contrast, drug-induced osteoporosis (DIOP) encompasses a heterogeneous group of secondary bone disorders arising from pharmacologic exposures. Glucocorticoids suppress osteoblastogenesis, enhance osteoclast activity, and increase reactive oxygen species; long-term bisphosphonate therapy may oversuppress bone turnover, resulting in microdamage accumulation; denosumab withdrawal triggers a unique rebound surge in RANKL activity, often leading to rapid bone loss and multiple vertebral fractures. Medications including aromatase inhibitors, SSRIs, proton pump inhibitors, heparin, and antiepileptic drugs impair bone quality through diverse mechanisms. Standard antiresorptive agents remain first-line therapies, while anabolic agents such as teriparatide, abaloparatide, and romosozumab provide enhanced benefits in high-risk or drug-suppressed bone states. Transitional bisphosphonate therapy is essential when discontinuing denosumab, and individualized treatment plans—including drug holidays, lifestyle interventions, and monitoring vulnerable patients—are critical for optimizing outcomes. Emerging approaches such as small interfering RNA (siRNA)-based therapeutics, anti-sclerostin agents, digital monitoring technologies, and regenerative strategies show promise for future precision medicine management. Understanding the distinct and overlapping molecular mechanisms of osteoporosis is essential for improving fracture prevention and long-term skeletal health. Full article

Background/Objectives: Immunotherapy has improved outcomes for selected patients with advanced non-small-cell lung cancer (NSCLC), yet the predictive value of individual biomarkers such as PD-L1 remains limited. Systemic inflammatory indices derived from routine blood tests may complement molecular and immunohistochemical features, offering a broader view of host–tumor immunobiology. Methods: We conducted a retrospective study of 298 patients with stage IIIB–IV NSCLC treated with immune checkpoint inhibitors (ICIs) at a tertiary oncology center between 2022 and 2024. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune–inflammation index (SII) were collected alongside PD-L1 expression and molecular alterations (EGFR, KRAS, ALK, TP53). Patients were stratified into inflammatory–molecular clusters integrating these parameters. Associations with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan–Meier and multivariate Cox analyses. Results: Four distinct inflammatory–molecular clusters demonstrated significantly different outcomes (p < 0.001). Patients with low NLR and high PD-L1 expression (Cluster A) showed the highest ORR (41%), longest median PFS (13.0 months), and OS (22.5 months). The EGFR/ALK-driven, inflammation-dominant cluster (Cluster C) exhibited poor response (ORR 7%) and shortest survival (PFS 4.3 months). High NLR (HR 2.12), PD-L1 < 1% (HR 1.91), and EGFR mutation (HR 2.36) independently predicted shorter PFS. A combined model incorporating NLR, PD-L1, and molecular status outperformed individual biomarkers (AUC 0.82). Conclusions: Integrating systemic inflammatory indices with PD-L1 expression and molecular alterations identifies clinically meaningful NSCLC subgroups with distinct immunotherapy outcomes. This multidimensional approach improves prediction of ICI response and may enhance real-world patient stratification, particularly in settings with limited access to extended molecular profiling. Full article

Acute kidney injury (AKI) is a critical clinical syndrome characterized by a rapid decline in renal function, frequently resulting from ischemia, nephrotoxicity, or sepsis. It represents a major global health burden due to its high morbidity and mortality and its strong association with progression to chronic kidney disease. In this study, we identified a novel small-molecule TLR4 inhibitor, DB03476, via structure-based virtual screening targeting the intracellular TIR domain of murine Tlr4. Molecular dynamics simulations confirmed that DB03476 stabilizes Tlr4 without altering its global conformation. In a murine ischemia–reperfusion-induced AKI model, DB03476 administration significantly attenuated renal inflammation, macrophage infiltration, and apoptosis and suppressed the TLR4/MyD88/NF-κB pathway. Moreover, DB03476 exhibited cross-species efficacy by binding conserved residues in human TLR4 with high affinity. Functional validation using human kidney organoids confirmed its protective effects against inflammatory challenge. These results demonstrate DB03476 as a promising therapeutic agent for AKI through selective inhibition of TLR4-mediated inflammatory responses. Full article

Lineage plasticity, the ability of cancer cells to alter their differentiated state through transcriptional and epigenetic reprogramming, has emerged as a key mechanism of therapeutic resistance across cancers. This adaptive process can manifest in multiple ways, including epithelial–mesenchymal transition, acquisition of stem-like features, and histological transformation, the most striking and clinically apparent example. In EGFR-mutant lung adenocarcinoma (LUAD), lineage plasticity is increasingly recognized as a prevalent mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs). Among its visible manifestations, histologic transformation into small-cell lung cancer (SCLC) is the most frequent, while squamous transformation and other phenotypic shifts also occur. Transformed tumors typically retain the initiating EGFR mutation but lose EGFR dependence, acquire neuroendocrine features, and display aggressive clinical behavior with poor clinical outcomes compared with both de novo SCLC and non-transformed LUAD. Recent studies show that plasticity arises through combined genomic, transcriptomic, and epigenetic reprogramming, often foreshadowed by molecular alterations before overt histological change. Spatial and single-cell profiling reveal heterogeneous trajectories and intermediate states, while functional models and multi-omics approaches have begun to identify therapeutic vulnerabilities distinct from both de novo EGFR-mutated SCLC and classical EGFR-mutated LUAD. Thus, lineage plasticity, whether manifested as histologic transformation or through more subtle epigenetic reprogramming, represents a formidable resistance mechanism in NSCLC. Defining its molecular basis and temporal dynamics will be essential for early detection, prognostication, and the development of tailored therapies. Full article

Background: Durvalumab, a PD-L1 inhibitor used as consolidation therapy after chemoradiation in unresectable stage III non–small cell lung cancer (NSCLC), can induce immune-related adverse events, among which immune-mediated pneumonitis represents one of the most severe. Differentiating checkpoint inhibitor pneumonitis (CIP) from infectious pneumonia is challenging due to overlapping clinical and radiologic findings. Case presentation: We describe a 67-year-old woman with stage III lung adenocarcinoma treated with chemotherapy, radiotherapy, and durvalumab, who presented with progressive dyspnea and extensive bilateral ground-glass opacities on CT imaging. Laboratory tests revealed leukopenia and elevated inflammatory markers. Despite broad-spectrum antibiotic and antiviral therapy, her condition worsened, requiring high-flow nasal cannula oxygen therapy. Multiplex molecular testing on sputum identified human metapneumovirus (HMPV), while blood cultures and urinary antigens for Streptococcus pneumoniae and Legionella pneumophila were negative. A pulmonology consultation raised suspicion for severe durvalumab-induced pneumonitis exacerbated by viral infection. High-dose methylprednisolone (2 mg/kg/day) followed by a four-week taper led to gradual clinical and radiologic resolution. Durvalumab was permanently discontinued. Discussion: To our knowledge, this is the first reported case of HMPV-associated pneumonitis in a patient receiving durvalumab. This case highlights the potential synergistic interplay between viral infection and immune checkpoint blockade, resulting in severe lung injury. Comprehensive microbiologic evaluation, including molecular diagnostics, is essential to guide therapy and distinguish infectious from immune-mediated causes. Conclusions: Early recognition of mixed infectious and immune-mediated pneumonitis, and timely corticosteroid therapy are critical to achieving favorable outcomes and preventing irreversible pulmonary damage. Full article

Pain is a dominant symptom in acute pancreatitis, yet high-level evidence guiding optimal analgesic management in acute pancreatitis has been limited. Emerging evidence suggests a role of non-steroidal anti-inflammatory drugs, including cyclooxygenase-2 inhibitors, and opioids in the management of pain in acute pancreatitis patients. Based on a narrative review of the current literature, we provide an overview of available evidence, give an update on recent studies, and propose a treatment algorithm for pain management in acute pancreatitis, considering pharmacological and non-pharmacological modalities, patient comorbidities, and disease severity. Existing studies are generally limited by small sample sizes, heterogeneity in outcomes, unidimensional pain assessments, and a lack of understanding for the pathophysiology of pain in acute pancreatitis. Future trials should focus on multicentre collaboration, comprehensive pain evaluation, adequate sample sizes, and understanding the complex molecular mechanisms of acute pancreatitis pain. Full article

The renin–angiotensin–aldosterone system (RAAS) is essential for controlling blood pressure and maintaining fluid balance, driving significant structural changes throughout the cardiovascular system, including the heart and blood vessels. As a result, the RAAS is a key therapeutic target for various chronic cardiovascular diseases, ranging from arterial hypertension (AH) to heart failure (HF). In this review, one of our objectives is to describe the new evidence over the last 4 years regarding the RAAS. Moreover, we pay attention to the structure and function of the angiotensin II type 1 receptor (AT1R) and its role in hypertension, as well as define its active site. Later, we discuss the most potent, selective inhibitors of AT1 receptors, based on in vitro and in vivo experiments, from 2020 to 2024. Large peptide molecules, small non-peptide-like molecules, and sartan derivatives are analyzed. The low IC₅₀ values of the entities that do not resemble sartans showcase the vast chemical space that can be explored for the creation of more potent antihypertensive medications. We have also employed computational chemistry tools in order to identify key molecular interactions between the compounds of the literature studied in order to elucidate the underlying reasons why these different molecules exhibit variations in their binding energies and overall potency. Full article

Background: Glioblastoma is the most common and malignant primary brain tumor in adults, with current treatment presenting limited effectiveness. Therapeutic resistance stems largely from its marked molecular and cellular heterogeneity. Multitarget small molecules (MSMs) have emerged as a promising strategy for treating complex diseases such as cancer. In the present work, we generated a novel family of indole-based MSMs engineered to inhibit histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs) while simultaneously acting as histamine H₃ receptor (H3R) antagonists and sigma-1 receptor (S1R) agonists. Methods: To accomplish this, we combined selected pharmacophoric moieties from the parent compounds Contilisant and the HDAC pan-inhibitor Belinostat. Nine MSMs were synthesized. Results: Most of them showed cytotoxic activity in glioma cells. Among them, three molecules (MTP142, MTP156 and MTP150) were prioritized based on potency; these compounds impaired glioma stem cell (GSC) activity and were predicted to cross the blood–brain barrier. In vivo and multi-omic analyses centered on MTP150 showed significant tumor growth inhibition, both as monotherapy and in combination with temozolomide (TMZ). Transcriptomic and proteomic profiling of patient-derived GSCs revealed MTP150-induced disruption of cell cycle regulation pathways. Conclusions: Our data reveal the efficacy of a novel family of MSMs in the pre-clinical setting of glioblastoma. Full article