Search Results (26,828)

Background/Objectives: Cutaneous lupus erythematosus (CLE) is a complex autoimmune skin disease driven by genetic predisposition, environmental triggers, and immune dysregulation. Environmental factors such as ultraviolet radiation, smoking, and certain drugs can initiate disease onset by inducing keratinocyte apoptosis. The subsequent release of nucleic acids and danger-associated molecular patterns activates pattern recognition receptors (PRRs) on keratinocytes and immune cells, leading to the production of type I and type III interferons (IFNs) and pro-inflammatory cytokines. The objective of this review is to summarize recent advances in understanding the immunopathogenesis of CLE, with particular attention to emerging cellular players and their therapeutic implications. Methods: A narrative review of the recent literature was performed, including experimental, translational, and clinical studies investigating the cellular and molecular mechanisms underlying CLE and novel targeted treatments derived from these findings. Results: Although plasmacytoid dendritic cells (pDCs) have traditionally been considered the major producers of IFN-I, recent data indicate that pDCs in CLE are functionally impaired and are not the primary source. Other cells, such as keratinocytes have emerged as key producers of IFN-I, contributing to a prelesional, IFN-rich microenvironment. This promotes the recruitment and activation of dendritic cells and other inflammatory myeloid subsets, which are now recognized as central players in amplifying local inflammation. Concurrently, T cells infiltrate the skin, where cytotoxic CD8⁺ T cells attack keratinocytes and CD4⁺ T cells further propagate inflammation via cytokine production. B cells and plasma cells produce autoantibodies, forming immune complexes that perpetuate inflammation. Neutrophils release neutrophil extracellular traps (NETs), exposing autoantigens and further stimulating IFN pathways. Macrophages contribute by presenting autoantigens, producing pro-inflammatory mediators, and failing to effectively clear apoptotic cells and immune complexes. Conclusions: The dynamic interplay between the innate and adaptive immune systems sustains the chronic inflammatory state characteristic of CLE. Based on the pathogenetic novelties, new therapeutic agents targeting specific molecules have been developed, which may improve the treatment of this complex disease in the future. Full article

Background/Objectives: The efficacy of ST909, an innate immune cGAS/STING/IRF3 pathway regulator, against ischemic brain injury was investigated, and its pharmacological mechanism was elucidated. Methods: The efficacy and pharmacological mechanism of ST909 in ischemic brain injury were evaluated using the middle cerebral artery occlusion (MCAO) rat model, with brain tissue staining, MRI, behavioral tests (balance beam, screen), and ELISA detection of brain injury markers (neuron-specific enolase [NSE], homocysteine [Hcy], and S100β). Results: ST909 significantly reduces cerebral ischemic area, restores blood–brain barrier integrity, and improves neuronal function, outperforming clinical drugs (3-n-butylphthalide and edaravone) in preclinical models. ST909 markedly reduces neuroinflammation while upregulating neurotrophic factors (e.g., BDNF, NGF) in brain tissue. Through PI3K/Akt pathway activation in microglia, ST909 induces M1-to-M2 phenotype polarization, rebalances the M1/M2 ratio, and enhances secretion of anti-inflammatory cytokines and neurotrophic factors, thereby reducing chronic inflammation and promoting neurological recovery. These findings elucidate ST909’s potential pharmacological mechanism against ischemic brain injury, involving microglial polarization via STING/IRF3 and PI3K/Akt pathway. Conclusions: ST909 has a significant pharmacological effect on improving the ischemic area of the brain and repairing the function of the brain neuronal tissues. Targeting the STING/IRF3 pathway, ST909 exhibits neurorestorative potential in post-ischemic brain injury recovery. Full article

Taraxacum mongolicum Hand.-Mazz (TMHM), a primary source of dandelion, is a globally recognized edible and medicinal plant with significant potential in food, medicine, daily chemical products, and animal husbandry. Although hypoglycemic effects have been reported in other Taraxacum species, the specific hypoglycemic constituents and mechanisms of TMHM are not well understood. The absence of comprehensive multi-target screening methodologies has hindered the elucidation of TMHM’s dual inhibitory effects on α-amylase and α-glucosidase, as well as its associated molecular mechanisms. In this study, a multi-target screening strategy was developed to concurrently evaluate α-amylase and α-glucosidase inhibition, integrating multi-target affinity ultrafiltration coupled with ultra-performance liquid chromatography-tandem mass spectrometry (MTAUF-UPLC-MS/MS), molecular docking, and molecular dynamics (MD) simulations. Using this approach, 13 dual-target inhibitors were identified from TMHM. Moreover, at least 5 of these compounds exhibited anti-diabetic activities comparable to the positive control drug acarbose, suggesting that they are principal bioactive constituents responsible for its hypoglycemic effects. Subsequent investigation of the antioxidant capacities of 7 out of the 13 bioactive compounds revealed that most exhibited more potent antioxidant activities than vitamin C (Vc). Based on these findings, molecular docking and MD simulations further validated that quercetin (8) and kaempferol (15), which demonstrated significant hypoglycemic and antioxidant activities, exhibited particularly strong affinities and stable interactions with α-amylase and α-glucosidase, respectively. In conclusion, these findings underscored the considerable potential of TMHM as a natural source of multifunctional bioactive compounds for nutraceutical, functional, and pharmaceutical applications. This study provided a critical foundation for elucidating the mechanisms underlying TMHM’s anti-diabetic effects and its therapeutic potential in mitigating diabetes-related complications, thereby facilitating future development and utilization. Full article

Intracellular targeting is the missing dimension in contemporary oncology, and nanosecond pulsed electric fields (nsPEFs) uniquely aim to deliver it. By charging membranes on sub-microsecond timescales, nsPEF bypasses plasma-membrane shielding to porate organelles, collapse mitochondrial potential, perturb ER calcium, and transiently open the nuclear envelope. This mechanism reprograms malignant fate while preserving tissue architecture. This review synthesizes the most recent evidence to frame nsPEF as a programmable intracellular therapy, mapping mechanistic design rules that link pulse width, amplitude, repetition, and rise time to specific organelle responses. We outline therapeutic applications, including the induction of apoptosis in resistant tumors, immunogenic cell death with systemic memory, and synergy with checkpoint blockade. We also survey integrations with nanoparticles, calcium, and chemotherapeutic drugs for improved outcomes. We critically appraise safety, selectivity, and scalability, distill translational bottlenecks in dosimetry and standardization, and propose an actionable roadmap to accelerate clinical adoption. Viewed through this lens, nsPEF is not merely another ablation tool but a platform for precision intracellular oncotherapy, capable of drug-sparing efficacy and immune convergence when engineered with rigor. Full article

Background: Cancer therapeutics development has been a challenge in medical and scientific areas due to their toxicity, limited biocompatibility, and unfortunate side effects. However, despite advances in early detection and the study of novel treatments, the mortality rate for breast cancer remains high, making it a significant global health concern. Objectives: In this study, poly(methyl methacrylate) (PMMA) nanoparticles functionalized with acrylic acid (AA), fumaramide (FA), and curcumin (CUR) as chelating and inhibitor agents were synthesized by emulsion polymerization techniques. Methods and Results: Comprehensive physiochemical characterization studies based on gravimetry, dynamic light scattering (DLS), electrophoresis, Fourier transform infrared (FT-IR), ultraviolet–visible (UV–Vis) and photoluminescence (PL) spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM) revealed a pH dependence of nanoparticles that exhibit structural changes upon interaction with calcium (Ca²⁺) and magnesium (Mg²⁺) ions. Calorimetric thermodynamic properties measured by isothermal titration calorimetry (ITC) confirmed chelating coordination and positive cooperativity between the nanoparticles and metal ions. In vitro studies showed the low cytotoxicity of nanoparticles by fibroblast proliferation, and their chelation process was observed by fluorescence microscopy, with the loss of interaction between cells. Conclusions: These results suggest that the functionalized nanoparticles have potential in drug delivery systems (DDS) for targeted breast cancer therapies, providing a promising polymer material for more efficient and less toxic treatments. Full article

Cyclosporine is a selective calcineurin inhibitor used, among other areas, in pediatric gastroenterology as rescue therapy in the treatment of severe ulcerative colitis (ASUC—acute severe ulcerative colitis) in children. The introduction of systemic glucocorticosteroids (GCSs) has significantly reduced mortality in ASUC. However, it should be emphasized that long-term use of these drugs is limited due to the high risk of adverse effects observed during therapy and their limited efficacy. The role of cyclosporine as a second-line therapy is referred to as a ‘rescue therapy,’ which aims to alleviate the symptoms of ASUC, often avoiding life-threatening complications (including toxic megacolon) and postponing the need for urgent colectomy. If colectomy is necessary, this provides time to better prepare the patient nutritionally and psychologically for surgery and to await the effect of slower-acting thiopurine preparations or other chronic treatments; their effectiveness in achieving long-term clinical and endoscopic remission is limited. New therapeutic approaches include cyclosporine as an inducer, which acts as a bridge to new forms of therapy, such as biological drugs, which are used as maintenance preparations in patients. In pediatric patients, there is limited research in the literature on new strategies for the use of cyclosporine. The aim of this review is to assess current evidence on cyclosporine as induction or rescue therapy in pediatric ASUC and explore future integration with biologic and biosimilar strategies, emphasizing its evolving role as a bridging agent toward biologics and novel targeted therapies. Full article

Lipid-polymer hybrid nanoparticles (LPHNPs) are the next-generation nanocarriers that integrate the mechanical strength and sustained-release capacity of polymeric cores with the biocompatibility and high drug-loading efficiency of lipid shells. Various design strategies and architectures that enhance encapsulation efficiency, stability, and targeted delivery of diverse therapeutic agents are reviewed. Commonly employed polymers, lipids, and surfactants that enable controlled drug release and enhanced pharmacokinetic performance are summarized in tabular form, while fabrication methods such as single-step, emulsification-solvent evaporation, and microfluidic techniques are discussed for their scalability and reproducibility. The therapeutic potential of LPHNPs in delivering poorly soluble drugs, phytochemicals, and genetic materials achieving synergistic therapeutic outcomes in oncological applications is comprehensively highlighted. The manuscript also includes details on ligand-based functionalization and the integration of imaging and stimuli-responsive elements to enhance targeted delivery and develop multifunctional theranostic LPHNPs systems. Furthermore, non-oncologic applications of LPHNPs in ocular, topical, and oral delivery are discussed, emphasizing their potential in treating inflammatory, infectious, and autoimmune disorders with sustained release and enhanced therapeutic efficacy. Recent patents focusing on improved biocompatibility, dual-drug encapsulation, and mRNA delivery are summarized. However, challenges such as large-scale production, reproducibility, safety, and regulatory standardization must be addressed through quality by design approaches and advanced manufacturing technologies to fully realize the clinical and commercial potential of next-generation LPHNPs. Full article

Objectives: This study aims to explore the relationship between dental caries and unemployment among U.S. adults who have engaged in illicit drug use, such as cocaine, heroin, and methamphetamine. Methods: The National Health and Nutrition Examination Survey (2015–2018) data were analyzed. The independent variable was severe dental caries (defined as DMFT > 13.99), and the dependent variable was employment status. The sample was categorized into non-users, current users (used in the past year), and former users (used prior to the past year). Covariates included age, education, race, gender, smoking status, family income-to-federal poverty level ratio, and health insurance status. Logistic regression with survey weights was applied to assess associations between severe dental caries and employment status. Results: The total sample (n = 5476) represented 131,848,604 U.S. adults aged 18–59 years, with 4% current users and 12% former users of the specified drugs. Among current users, those with severe caries had higher odds of unemployment (OR = 2.6, p = 0.025) compared to those without severe caries. No significant association was found between severe caries and employment status among former users after controlling for covariates. Conclusions: The study underscores a significant association between severe dental caries and unemployment among U.S. adults who have used illicit drugs in the past year. These findings suggest a potential need for targeted oral health interventions in this population to improve economic well-being. Future research should focus on longitudinal studies to establish causality and explore mechanisms through which dental health may impact employment prospects. Full article

Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Despite therapeutic advances, disease relapse and metastasis remain major challenges and drivers of mortality. Fascin, an actin-bundling protein, promotes BC progression by enhancing drug resistance. However, the role of fascin in proliferation, a hallmark of cancer, and the underlying mechanism remain poorly elucidated. In this study, bioinformatics analysis of publicly available BC datasets, gene manipulation (gain and loss of function) in BC cell lines, flow cytometry, Western blots, and a real-time cell analyzer (RTCA) were employed to assess the role of fascin in proliferation. The clinical relevance of bioinformatics data and in vitro findings was assessed in BC patient samples using immunohistochemistry. FSCN1 expression exhibited a significant correlation with proliferation signature scores in BC datasets. Ectopic expression of fascin in fascin-negative SK-BR-3 and its silencing in fascin-positive MDA-MB-231 BC cell lines demonstrated its direct role in driving proliferation. In-depth bioinformatics analyses revealed a significant correlation between FSCN1 and the cell cycle signature score, particularly the G1-S signature score gene set. Indeed, fascin accelerated the cell cycle progression of synchronized cells from the G to S phase. Mechanistically, fascin upregulated nuclear SKP2 levels and reduced p27 expression—important G1-S cell cycle checkpoint regulators. Immunohistochemistry in samples from 68 patients demonstrated significant correlations between fascin and Ki-67 expression, in addition to SKP2 overexpression and p27 downregulation. Collectively, these data demonstrate the role of fascin as a driver of the G1-S-phase transition during cell cycle proliferation, thereby revealing new opportunities for targeted therapeutic intervention. Full article

Recent advancements in three-dimensional (3D) bioprinting have revolutionized the modeling of skin cancer, enabling the fabrication of high-throughput, patient-specific organoids that recapitulate the structural, functional, and microenvironmental complexity of native tumors. This review focuses on the integration of cutting-edge bioprinting technologies with bioengineered extracellular matrices and patient-derived cells to generate physiologically relevant skin cancer models for diagnostic and personalized medicine applications. Key technological innovations, including novel bioinks, multi-material printing strategies, and biomimetic approaches, are discussed for their ability to replicate tumor-stroma interactions, vascularization, and immune microenvironments. The utility of bioprinted organoids in high-throughput drug screening, mutation-targeted therapy design, and biomarker discovery is critically evaluated. Additionally, we address current challenges in standardization, reproducibility, and clinical translation, highlighting regulatory and quality-control considerations. Collectively, this review emphasizes the transformative potential of 3D bioprinted skin cancer organoids as platforms for precision oncology, bridging bioengineering advances with translational research to accelerate therapeutic development and personalized treatment strategies. Full article

Salivary gland carcinomas (SGCs) are aggressive malignancies with limited treatment options, primarily due to the complexity of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) remodel the extracellular matrix (ECM), enhance cancer cell stemness, and drive drug resistance. This study introduces a decellularized CAF-derived spheroid system as a biomimetic platform to study tumor–stromal interactions in SGC. Multicellular spheroids were generated by co-culturing Medical Research Council cell strain 5 (MRC-5) fibroblasts (fetal lung-derived) with A253 salivary gland cancer cells, producing distinct spatial architecture, with fibroblasts at the core and cancer cells at the periphery. Compared with A253-only spheroids, A253/MRC-5 spheroids exhibited enhanced proliferation and elevated expression of stemness markers (aldehyde dehydrogenase 1 [ALDH1], CD133, cytokeratin 19 [CK19]). MRC-5 spheroids displayed robust ECM and growth factor expression that persisted after decellularization. Decellularized spheroids retained biological activity, enabling A253 cells to develop invasive phenotypes, metabolic reprogramming, and stemness-associated signatures. Transcriptomic analysis revealed a transition from proliferative pathways to stress-adaptive survival programs, mirroring in vivo tumor behavior. Moreover, A253 cells cultured with decellularized fibroblast spheroids exhibited altered cisplatin sensitivity, highlighting the critical role of stromal ECM in therapeutic response. In conclusion, this study establishes decellularized CAF spheroids as a simplified yet biologically relevant TME-mimetic platform. By recapitulating tumor–stromal crosstalk without live co-culture, this system provides a powerful tool for mechanistic studies of salivary gland cancer, preclinical drug screening, and development of stroma-targeted therapies. Full article

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a critical public health threat, particularly in hospital environments where treatment options are limited. Drug repurposing offers a rapid and cost-effective strategy to address antimicrobial resistance. This study evaluates KP46 (tris(8-quinolinolato)gallium(III)), an orally bioavailable gallium-based anticancer agent, for its antimicrobial potential against CRAB. Methods: KP46 was synthesized and characterized using spectroscopic and crystallographic techniques. Its antibacterial activity was assessed against planktonic and biofilm-associated CRAB strains, including multidrug-resistant clinical isolates. Mechanistic studies included intracellular reactive oxygen species (ROS) quantification, membrane integrity assays, and resistance development profiling. Results: KP46 exhibited potent antibacterial activity against both susceptible and carbapenem-resistant A. baumannii strains. It inhibited planktonic growth and disrupted early biofilm formation. KP46 induced intracellular oxidative stress, leading to membrane damage and cell death. Resistance development was significantly slower compared to meropenem, and KP46 retained efficacy against meropenem-resistant isolates. Conclusions: KP46 demonstrates dual-action antimicrobial activity and a low propensity for resistance development, positioning it as a promising candidate for repurposing against CRAB infections. These findings support further preclinical evaluation of KP46 as an orally active therapeutic agent targeting both planktonic and biofilm-associated bacterial populations. resistance development and retained efficacy against meropenem-resistant strains. Full article

Background/Objectives: In the current medical era, Topoisomerase II is recognized as an essential enzyme that regulates DNA topology during critical biological processes such as DNA replication, transcription, and repair. This study aimed to design, synthesize, and biologically evaluate a new series of pyrazolo[3,4-b]pyridines (8a–g, 10a–g, and 12) as potential anticancer agents and Topoisomerase II inhibitors. Methods: The synthesized compounds were subjected to in vitro anticancer screening at the National Cancer Institute (NCI, USA). Active derivatives were further evaluated through a five-dose screening to determine their antiproliferative potency. Selected compounds were examined for their effects on leukemia cell lines (K562 and MV4-11), and mechanistic studies were performed to assess DNA damage, cell cycle distribution, and apoptosis-related protein modulation. Additionally, enzyme inhibition assays were conducted to determine Topoisomerase IIα (TOPIIα) inhibition. Results: Initial single-dose screening identified several active compounds, notably 8b, 8c, 8e, 8f, 10b, 10c, 10e, and 10f. Among these, compound 8c exhibited potent and broad-spectrum antiproliferative activity across the NCI cancer cell line panel, with a GI₅₀ MG-MID value of 1.33 µM (range: 0.54–2.08 µM). The synthesized molecules showed moderate to good anti-leukemic efficacy against K562 and MV4-11 cells. Mechanistic investigations revealed that compound 8c induced DNA damage and S-phase cell cycle arrest, leading to apoptosis as evidenced by the modulation of PARP-1, Bax, XIAP, and Caspases. Furthermore, target-based assays confirmed that compound 8c significantly inhibited the DNA relaxation activity of TOPIIα in a dose-dependent manner, comparable to etoposide. Conclusions: The study highlights compound 8c as a promising pyrazolo[3,4-b]pyridine derivative with potent antiproliferative activity and effective inhibition of Topoisomerase IIα. These findings suggest its potential as a lead scaffold for further optimization in anticancer drug development.. Full article

Background: Despite the emergence of new treatment modalities, including targeted therapies that are of benefit to patients whose tumours carry specific mutations, the prognosis for most patients with cholangiocarcinoma remains poor. Novel therapeutic approaches that can benefit the majority of patients whose tumour cells do not carry targetable mutations are urgently needed. Results: To identify mutation-agnostic treatment approaches, we screened a library of well-tolerated off-patent drugs against cholangiocarcinoma cells and normal biliary epithelial cells. The screen identified Niclosamide as a drug that reduces the viability of multiple cholangiocarcinoma cell lines but has a lesser effect on normal primary biliary epithelial cells. Moreover, Niclosamide treatment reduces the growth of cholangiocarcinoma tumour cells as tumour spheroids in vitro and reduces the growth of cholangiocarcinoma cells as tumours in a xenograft mouse model of this disease. Through a proteasome-dependent mechanism, Niclosamide treatment reduces the expression of the Proline-Rich Homeodomain (PRH) protein, a transcription factor which acts as an oncoprotein in cholangiocarcinoma cells. However, PRH knockout does not alter the sensitivity of cholangiocarcinoma cells to Niclosamide, indicating that this drug is not dependent on PRH to reduce cell viability. Interestingly, the CDK4/6 kinase inhibitor Palbociclib selectively reduces the viability of cholangiocarcinoma cell lines compared to normal biliary epithelial cells and, importantly, Palbociclib synergises with Niclosamide to reduce cholangiocarcinoma cell viability in vitro as well as to reduce tumour growth in a mouse xenograft model. Conclusion: These preclinical results suggest that the combination of Niclosamide and an inhibitor of CDK4/6 is worthy of clinical evaluation as a potential treatment for this disease. Full article

 Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and show notable success in some cancer types such as non-small cell lung cancer, melanoma and colorectal cancers, while they demonstrate relatively low response rate in others, such as esophageal cancers. Due to the heterogeneous nature of the tumor microenvironment and patient-to-patient variability, there remains a need to improve ICI response rates. Combining ICIs with therapies that can overcome resistance is a promising strategy. Compared to de novo drug development, drug repurposing offers a faster and more cost-effective approach to identifying such combination candidates. A variety of computational drug repurposing tools leverage genomics and/or transcriptomic data. As single-cell RNA sequencing (scRNA-seq) technology becomes available, it enables precise targeting of cancer-driving cellular components. In this review, we highlight current computational drug repurposing tools utilizing scRNA-seq data and demonstrate the application of two such tools, scDrug and scDrugPrio, on an esophageal squamous cell carcinoma dataset to identify potential drug candidates for combination with ICI therapy to enhance treatment response. scDrug focuses on predicting tumor cell-specific cytotoxicity, while scDrugPrio prioritizes drugs by reversing gene signatures associated with ICI non-responsiveness across diverse tumor microenvironment cell types. Together, this review underscores the importance of a multi-faceted approach in computational drug repurposing and highlights its potential for identifying drugs that enhance ICI treatment. Future work can expand the application of these strategies to multi-omics and spatial transcriptomics datasets, as well as personalized patient samples, to further refine drug repurposing involving ICI therapy.  Full article