Search Results (15,467)

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis. While sorafenib serves as the first-line therapy for advanced HCC, its efficacy is frequently hampered by side effects and the development of drug resistance, necessitating the development of novel agents to enhance HCC sensitivity to sorafenib. In this study, we demonstrate that the antihistamine astemizole significantly enhanced the antitumor efficacy of sorafenib in HCC cell lines. This combination treatment cooperatively inhibited HCC cells’ proliferation and induced cell cycle arrest at the G1 phase, as evidenced by decreased cyclin D1 and p-Rb levels and increased p27 expression. Furthermore, the combination of astemizole and sorafenib synergistically inhibited HCC cells’ migration, invasion, and adhesion. It also reduced F-actin polymerization and the expression of metastasis-regulating proteins, including p-Integrinβ1, FAK, and MMP1. Additionally, the combination treatment suppressed tube formation in HUVECs, accompanied by downregulation of HIF-1α and reduced VEGF secretion. Co-inhibition of Eag1 and the ERK/MAPK signaling pathway may underlie the enhanced anti-HCC effects of sorafenib by astemizole. Collectively, these findings indicate that astemizole significantly enhanced the antitumor activity of sorafenib by inhibiting proliferation, metastasis, and angiogenesis in HCC cells, suggesting its potential as a promising adjuvant to improve sorafenib-based therapy in HCC. Full article

Background/Objectives: This study investigates the induction of cuproptosis in A549 lung cancer cells by doxorubicin (DOX) complexes and the development of pH-responsive bovine serum albumin (BSA)-based nanocarriers for their delivery. We successfully synthesized and characterized two novel complexes: DOX–Cu, where DOX acts as a ligand for Cu(II), and DOX–BTZ, a conjugate formed between DOX and the proteasome inhibitor bortezomib (BTZ). Methods: Spectroscopic and NMR analyses were performed to confirm the formation of the complexes. In vitro assays were conducted to evaluate cytotoxicity in A549 cells, alongside assessment of DLAT aggregation as a marker of cuproptosis. The formulation of DOX into BSA nanoparticles (DOX–Cu@BSA NPs and DOX–BTZ@BSA NPs) was carried out to evaluate potential alleviation of DOX-induced cytotoxicity in cardiomyocytes in vitro. Fluorescence quenching and molecular docking studies were employed to investigate the binding interactions between the complexes and BSA. Cellular uptake experiments were performed to assess nanoparticle internalization into A549 cells. Results: Both complexes exhibited superior cytotoxicity against A549 cells compared to individual components. This enhanced cell death was associated with significant aggregation of dihydrolipoamide S-acetyltransferase (DLAT), a key marker of cuproptosis, suggesting the involvement of this copper-dependent cell death pathway. The BSA nanoparticles displayed favorable characteristics, including uniform size (~190 nm), high encapsulation efficiency (~75–79%), and colloidal stability. Crucially, they exhibited a pH-responsive drug release profile, with significantly accelerated release under acidic conditions (pH 5.7) mimicking the tumor microenvironment. Fluorescence quenching and molecular docking studies revealed strong, spontaneous binding between the complexes and BSA, primarily driven by hydrophobic interactions. Cellular uptake experiments confirmed efficient internalization of the nanoparticles into A549 cells. Conclusions: Collectively, this work offers a proof-of-concept for a strategy of utilizing BSA-based multidrug delivery systems for cuproptosis induction, offering a potential avenue to enhance therapeutic efficacy while reducing systemic toxicity in lung cancer treatment. Full article

HIV-1 protease (PR) is an essential enzyme in the viral life cycle and a primary target of antiretroviral therapies, particularly protease inhibitors (PIs). Understanding the dynamics of viral evolution and the factors governing the emergence or loss of resistance-associated mutations is critical for improving PI efficacy and managing drug resistance in HIV/AIDS treatment. In this study, we investigated the impact of three natural HIV-1 polymorphisms (T12A, L63Q, and H69N), whose prevalence varies depending on treatment status and viral subtype, on the structural stability and conformational dynamics of PR using molecular dynamics (MD) simulations. Three independent 500 ns MD simulations were performed for the native protease and each mutant system. Although none of the mutations disrupts the overall structural integrity of HIV-1 PR, they induce mutation-specific alterations in flexibility and residue interactions. In particular, T12A and H69N exhibit increased structural deviations, especially in the flap regions, along with enhanced conformational fluctuations. In contrast, the L63Q mutation shows a slight reduction in flap flexibility compared to both the native protease and the other mutants. Consistently, the fraction of time spent in open-flap conformations is higher for T12A and H69N and lower for L63Q relative to the native system. Moreover, mutations in the Fulcrum (T12A) and Cantilever (L63Q and H69N) regions do not disrupt the long-range network of correlated motions observed in the native protease, both inter- and intra-monomer, but instead increase the extent of correlated and anti-correlated motions in other regions of PR. Full article

Sensorineural hearing loss (SNHL) can result from genetic mutations, excessive noise exposure, ototoxic drugs, and aging. Glutamate excitotoxicity is one of the underlying mechanisms of SNHL. However, the specific roles of different glutamate receptor subtypes in normal signaling and excitotoxic damage remain unclear. Addressing these questions requires relevant experimental models. This review compares existing protocols for the isolation and cultivation of primary spiral ganglion cells. It also evaluates the utility of this model for studying glutamatergic transmission and glutamate-induced excitotoxicity. A literature search was conducted in PubMed, Scopus, Google Scholar, and Web of Science. We identified 16 relevant English-language articles published since 1990, when the model was first used to study glutamatergic signaling. Our analysis reveals significant heterogeneity in spiral ganglion cell isolation protocols and culture conditions. We highlight major differences in glutamate concentrations and exposure times used to model excitotoxicity. The most significant limitation of this model is the loss of the native microenvironment of auditory neurons, including their dendritic and axonal contacts. Nevertheless, primary spiral ganglion cells serve as a suitable in vitro model for investigating auditory neuron function and pathology. The number of neurons and neurite length serve as reliable indicators of otoprotective effects under conditions of glutamate excitotoxicity. Based on an analysis of the key stages of primary SGC culture establishment, this study proposes approaches to overcome limitations and improve the practice of using this model. A better understanding of the function of glutamate receptors of SGNs and the mechanisms behind glutamate excitotoxicity could help us to develop new treatments for SNHL. This review serves as a practical guide for researchers implementing or optimizing primary SGC cultures. Full article

Background: Lung cancer ranks among the most common and deadly malignant tumors worldwide. Drug resistance is a critical factor hindering the effect of chemotherapy for lung cancer. Exosomes, as intercellular signaling molecule carriers, play an important role in carcinogenesis, metastasis and drug resistance. Our study was aimed at exploring the impact of exosomes derived from docetaxel (DTX)-resistant lung cancer cells on regulating biological behaviors of DTX-sensitive cells, further investigating the molecular mechanisms regarding exosome-mediated intercellular communication. Methods: We extracted and identified the exosomes derived from A549, A549/DTX, H1299 and H1299/DTX cells, and then analyzed the expression of exosomal miR-373-3p between DTX-sensitive and DTX-resistant cells. Cell proliferation and apoptosis experiments were verified using a CCK-8 assay, a colony formation assay, a TUNEL assay and flow cytometry. The molecular interaction between miR-373-3p and PDCD4 was evaluated using a dual-luciferase reporter assay. The function of miR-373-3p was further assessed using an in vivo mouse xenograft model. Results: We found that the exosomal miR-373-3p level from DTX-resistant A549/DTX or H1299/DTX cells significantly exceeded that from DTX-sensitive A549 or H1299 cells. In addition, both exosomes derived from DTX-resistant lung cancer cells and miR-373-3p mimics could promote the proliferation of DTX-sensitive cells and inhibit their apoptosis. Moreover, we identified PDCD4 as a key target gene of miR-373-3p, which could induce the malignant behaviors of DTX-sensitive cells by reducing PDCD4 expression. Conclusions: Our results demonstrated that DTX-resistant lung cancer cells could transfer miR-373-3p to DTX-sensitive cells through exosomes, where miR-373-3p could exert its carcinogenic effect via targeting PDCD4. Full article

Although transplantation of induced oligodendrocyte progenitor cells (iOPCs) is a promising strategy for white matter injury, the therapeutic efficacy of in vitro-generated iOPCs remains limited due to insufficient differentiation potential. Here, we aimed to identify key transcription factors and small-molecule drugs to optimize iOPC quality. Through transcriptome sequencing and bioinformatics analysis, we identified the transcription factor SOX10, which is differentially expressed between endogenous fetal OPCs and exogenous iOPCs. We established lentivirus-mediated SOX10 overexpression in neural stem cells (NSCs) before iOPC induction and performed cellular assays and multi-omics analysis. Early SOX10 overexpression reduced cell migration but promoted maturation into oligodendrocytes and suppressed astrocyte differentiation. Multi-omics analyses revealed that SOX10 overexpression is associated with the extensive redistribution of SOX10 chromatin binding and enrichment of regulatory programs linked to oligodendroglial differentiation, including the activation of the key signaling downstream transcription factors JUN/FOS. Moreover, TSA, Dabrafenib, and Fedratinib effectively upregulated SOX10 and improved iOPC differentiation. This study identifies SOX10 as a core upstream regulator governing the fate of iOPCs, providing a potential strategy for optimizing iOPC induction for future investigation of white matter injury therapy. Full article

Background: Somatostatin receptors (SSTRs) are pivotal diagnostic and therapeutic targets in well-differentiated neuroendocrine neoplasms (NENs). SSTR-directed treatment strategies rely on sufficient SSTR2 expression. Thus, receptor loss during dedifferentiation limits therapeutic efficacy. Preclinical data suggest pharmacologic modulation of SSTRs’ expression. However, there are no robust data on the effect of NEN-specific systemic treatments on SSTRs’ expression and function. Methods: We systematically evaluated the effects of six systemic agents commonly used in NEN therapy—isplatin, etoposide, 5-fluorouracil (5-FU), streptozotocin (STZ), temozolomide (TMZ), and everolimus—on SSTR2 and SSTR5 expression, as well as on uptake of ⁶⁸Ga-DOTATOC, in BON-1 and QGP-1 cells, as well as the MS-18 cell line. Analyses included qRT-PCR, Western blotting, immunohistochemistry, and radiopeptide uptake assays. Results: Systemic agents modulated SSTR expression and radioligand uptake in a drug- and cell line-dependent manner. Etoposide consistently upregulated SSTR2 expression and significantly increased radioligand uptake across all three cell lines. TMZ enhanced SSTR2 expression and uptake in BON-1 cells, but reduced uptake in QGP-1 and MS-18 cells. In contrast, 5-FU, STZ, cisplatin, and everolimus showed heterogeneous, compound- and cell line-specific effects on SSTR2 expression and ⁶⁸Ga-DOTATOC uptake, including both up- and downregulation depending on the model. Conclusions: All agents under investigation affect SSTR expression in vitro, while etoposide is identified as the most consistent enhancer of SSTR2’s expression and function across cellular NEN models. Our findings highlight both the potential and the risks of systemic therapy-induced receptor modulation and therefore support further investigation of treatment sequencing strategies to optimize SSTR-targeted approaches. However, further studies are required to translate these observations to a clinical setting. Full article

Genome editing is widely used and conceptually simple, yet in practice, it is hindered by laborious workflows and high costs. These challenges stem from the difficulty of identifying and isolating cells that contain the desired user-defined modifications, a problem compounded by the wide variability in editing efficiencies across cell types. While homology-directed repair (HDR) provides a mechanism for precise genome modification following nuclease-induced double-strand breaks (DSBs), it is frequently outcompeted by the dominant mutagenic non-homologous end-joining (NHEJ) pathway in mammalian cells. Therefore, we developed a novel enrichment method, Essential HDRescue, to increase the frequency of HDR events at a target site by co-targeting an essential genomic locus. Using both intrinsic positive and negative selection at a common essential gene, we enabled enrichment of precise editing events at a second, unlinked target site. We demonstrated that co-targeting essential genes in cancer cell lines and iPSCs increased HDR rates without the need for an exogenous reporter or selective drug. Analysis of resulting clones revealed that Essential HDRescue produced up to a 6-fold increase in single-allele edits and an ~4-fold increase in homozygous edits relative to single-targeted controls. By harnessing the intrinsic cellular dependencies that arise from DSB repair at essential loci, Essential HDRescue offers a widely applicable method to improve precise genome editing outcomes in mammalian cells, leaving only a minimal, protein-silent scar at the essential gene. Full article

The field of nanoparticle-based biotechnology has undergone substantial advancement, characterized by progress in targeted drug delivery systems, the development of innovative diagnostic and imaging platforms, the expanded adoption of environmentally sustainable (“green”) synthesis approaches, and an increasing emphasis on the integration of emerging technologies such as artificial intelligence and nanorobotics. Conventional nanoparticle synthesis often involves toxic reducing agents; however, recent advances promote eco-friendly green synthesis methods utilizing biological systems such as bacteria, fungi, algae, yeast, plants, and actinomycetes. These biological approaches are safe, sustainable, cost-effective, and capable of producing highly stable Nanoparticles (NPs). The interaction of nanomaterials with biological systems is crucial for developing intracellular and subcellular drug delivery technologies with minimal toxicity, governed by nano–bio interface mechanisms such as cellular translocation, surface wrapping, embedding, and internal attachment. Key factors influencing NP behavior include morphology, size, surface area, surface charge, and ligand chemistry. Magnetic nanoparticles, particularly iron-based forms, exhibit unique superparamagnetic properties that are strongly influenced by particle size, as explained by the Néel relaxation mechanism, in which thermal energy induces flipping of magnetic moments. Nanoparticles demonstrate diverse modes of action, including antimicrobial activity, reactive oxygen species (ROS)-induced cytotoxicity, genotoxicity, and plant growth promotion. NP performance and biological effects are strongly dependent on their size, shape, dosage, and concentration. This critical review article aims to elucidate evolution, classification, preparation methods, and multifaceted applications of nanoparticles Full article

This study concurrently addressed the separation method for carbon dots derived from Glycyrrhizae Radix et Rhizoma Praeparata cum Melle (GRRPM) and the in vitro evaluation of their anti-allergic biological activity. Glycyrrhizae Radix et Rhizoma Praeparata cum Melle Carbon Dots (GRRPM-CDs) were prepared via decoction followed by dialysis, and their properties were characterized using High-Performance Liquid Chromatography (HPLC) and nanomaterial techniques. Anti-allergic activity was evaluated using a C48/80-induced RBL-2H3 mast cell degranulation model. Safety and efficacy were assessed using the CCK-8 assay, direct intervention, and drug-containing serum methods. The release of β-hexosaminidase (β-hex), histamine (HIS), interleukin-4 (IL-4), and tumor necrosis factor-α (TNF-α) was measured by ELISA, and key proteins in the MAPK signaling pathway were analyzed by Western blot. GRRPM-CDs inhibited mast cell degranulation and the release of allergic and inflammatory mediators in a dose-dependent manner. They also significantly downregulated the phosphorylation levels of the JNK, ERK, and p38 proteins in the MAPK signaling pathway. GRRPM-CDs exhibit significant anti-allergic activity, likely via suppression of the MAPK pathway. These findings provide new insights into the bioactive components of processed Glycyrrhiza and suggest potential avenues for developing novel therapies for allergic diseases. Full article

In ovarian cancer, reactive oxygen species (ROS) are both toxic byproducts and mediators of signaling and stress adaptation, such that the same “ROS change” can suppress or promote tumors in vivo. Here, we integratively summarize how ROS modulation reshapes tumor growth, metastasis, and treatment response in ovarian cancer, based on 22 original in vivo-containing studies that were selected from a five-database search of papers published from January 1990 to December 2025. On the antitumor axis, ROS amplification in xenograft models is accompanied by reduced tumor burden and increased markers of cell death, and can operate through diverse death programs beyond apoptosis, including pyroptosis and ferroptosis. ROS-based anticancer effects may vary depending on whether cytoprotective autophagy is co-induced. For example, in models treated with daphnetin, ROS-dependent cell death occurs together with induction of cytoprotective autophagy and the anticancer effect is strengthened when an autophagy inhibitor is added. In a therapeutic context, autophagy may thus function as an adaptive response in tumor cells to partially buffer ROS-induced stress. Conversely, on the pro-tumor axis, ROS can serve as an upstream signal driving inflammatory and metastatic processes. In a peritoneal metastasis model, GPX1 inhibition-induced ROS elevation was linked to increased metastatic burden. In the context of drug resistance, platinum resistance is proposed to be an adaptive state shaped not by the absolute level of ROS alone, but by integrated ROS-sensing and buffering circuits, the DNA damage response (DDR), and NF-κB networks. In vivo, AMPK–ROS axis activation through ACLY inhibition or resetting of drug responsiveness can be connected to tumor suppression and increased sensitivity. Furthermore, ROS modulation is not limited to tumor cell-intrinsic targets: it can also be linked to therapeutic response reprogramming at the tumor microenvironment (TME) level, such as via regulation of acidity/ROS conditions and coupling to macrophage polarization in immunocompetent syngeneic models. Taken together, these lines of in vivo evidence indicate that, in ovarian cancer, ROS should not be interpreted in a binary “increase/decrease” manner, but rather in terms of redox-buffering capacity, the engaged signaling axes (cell death, DDR, metastasis/inflammation), and interactions with TME factors. Full article

Background and Objectives: Idiopathic ventricular arrhythmias commonly occur in patients without structural heart disease and most often present as premature ventricular contractions (PVCs). Although generally considered benign, a high PVC burden may cause symptoms, reduce quality of life, and lead to reversible PVC-induced cardiomyopathy. This study aimed to evaluate long-term outcomes after radiofrequency catheter ablation of idiopathic outflow tract PVCs. Materials and Methods: This single-center retrospective study included 101 patients with idiopathic PVCs who underwent radiofrequency catheter ablation. PVC burden and clinical outcomes were assessed at baseline and during follow-up at 3 months, 12 months, and 5 years. Procedural success, predictors of success, and changes in antiarrhythmic drug therapy were analyzed. Results: During follow-up, a marked reduction in PVC burden was observed compared with baseline values. The median PVC burden decreased from 21.89% at baseline to 0.79% at 3 months, 0.23% at 12 months, and 0.09% at the 5-year follow-up after ablation. Acute procedural success was achieved in 88.1% of patients. Long-term success at 5 years was observed in 80.2% of patients. The use of antiarrhythmic drugs decreased during follow-up. Left ventricular ejection fraction remained stable, with no significant difference between baseline and 5-year values. Monomorphic PVC morphology and procedural success at 12 months were identified as independent predictors of long-term success. Conclusions: Radiofrequency catheter ablation provides effective and sustained reduction in PVC burden in patients with idiopathic outflow tract PVCs, with high acute success rates, durable long-term outcomes, and reduced reliance on antiarrhythmic drug therapy. Full article

Background/Objectives: Hepatic diseases frequently present with ocular manifestations that aid diagnosis, provide prognostic data, and guide therapy. Despite the clear utility of the liver–eye axis, the literature lacks reviews that categorize these manifestations by etiology. This review evaluates current evidence to identify ocular findings that serve as clinical tools for diagnosis, prognosis, and therapeutic monitoring of hepatic pathologies. Methods: A narrative review was conducted using PubMed and Google Scholar to identify English-language articles addressing ocular manifestations associated with liver disease. The primary search encompassed publications from 2000 to 2025, with inclusion of select foundational works published prior to 2000 when they represented seminal studies establishing diagnostic criteria, pathophysiological mechanisms, or natural history data not superseded by subsequent research. Search terms included combinations of liver, hepatic, hepatitis, cirrhosis, cholestasis, eye, ocular, retina, cornea, sclera, conjunctiva, ophthalmic manifestations, and specific disease names. All study designs were eligible. Society guidelines, systematic reviews, and studies from high-impact journals were prioritized. The final selection comprised 59 references representing the most authoritative sources across the spectrum of hepatic conditions. Results: A spectrum of ocular findings linked to distinct hepatic conditions was identified. Manifestations with established clinicopathologic associations were categorized into congenital and acquired etiologies. Congenital liver pathologies included metabolic disorders (Wilson disease, galactosemia, lysosomal storage disorders) and syndromic/genetic causes (Alagille syndrome, hereditary hemochromatosis). Acquired liver diseases encompassed infectious (hepatitis B/C), drug-induced and iatrogenic (interferon, immune checkpoint inhibitors), nutritional (vitamin A deficiency), neoplastic (metastatic hepatocellular carcinoma), and cirrhotic causes. Conclusions: Specific ocular signs raise clinical suspicion for underlying liver disease and warrant targeted hepatic evaluation. Recognizing these associations facilitates earlier diagnosis and improves outcomes. Systematic screening for these signs is supported in at-risk populations, and prospective validation studies should establish their sensitivity and specificity. Full article

Chalcones, a subclass of flavonoid-derived phenolic compounds, have demonstrated promising anthelmintic activity against parasitic nematodes. This study aimed to obtain insights into the biological effects a cis/trans mixture of chalcone and its geometric isomer, trans-chalcone, using RNA sequencing in the model organism Caenorhabditis elegans. Fourth-stage larvae (L4) were exposed to cis/trans-chalcone or trans-chalcone for 3 h, and total RNA was extracted for high-throughput sequencing. Transcriptomic analysis revealed that exposure to cis/trans-chalcone and trans-chalcone induced pronounced modulation of genes involved in lipid metabolism and repression of collagen and structural genes, potentially leading to defective extracellular matrix maintenance, thereby suggesting these combined effects as potential mechanisms underlying their anthelmintic activity. Also, metabolic and stress response pathways, with several genes implicated in detoxification and cellular defense, were markedly upregulated. These findings provide new insights into the molecular mechanisms affected by chalcones, advancing our understanding of their anthelmintic potential and supporting future drug development efforts. Full article

Background: Ponatinib (PON), an effective tyrosine kinase inhibitor for leukemias harboring the T315I mutation, is limited by severe cardiotoxicity, including myocardial infarction and heart failure. Here, we investigated the therapeutic potential of Bone Morphogenetic Protein-7 (BMP-7), an anti-inflammatory growth factor, in a murine model of PON-induced cardiotoxicity. Methods: C57BL/6J mice were distributed into experimental groups receiving PON (25 mg/kg cumulative dose) either alone or with BMP-7 (600 μg/kg cumulative dose), along with a corresponding control group. Cardiac analyses included molecular and histological assessments. Results: PON administration induced a marked increase in monocyte infiltration and M1 macrophage polarization. These inflammatory events led to the upregulation of the pyroptotic cascade, leading to activation of the TGF-β1/SMAD2/3 signaling axis. In contrast, BMP-7 significantly attenuated these pathological responses by suppressing inflammation-induced pyroptosis and the TGF-β1/SMAD2/3 signaling axis. Conclusions: These findings identify inflammation-induced pyroptosis as a central driver of the pathological changes in PON-induced cardiotoxicity. Notably, our work highlights BMP-7’s capacity to inhibit these disease-related alterations. Collectively, these results expand on the current knowledge of the mechanistic framework of PON-induced cardiotoxicity, while also emphasizing BMP-7 as a promising therapeutic candidate with potential translational relevance. Full article