Search Results (18,268)

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of cancer with poor clinical outcomes. There is a critical need to identify novel, druggable targets for TNBC to improve therapy response and patient outcomes. Due to their roles in critical processes driving cancer progression, kinases have been a major focus of drug discovery efforts. The role of extracellular signal-regulated kinase 5 (ERK5) in mediating TNBC extracellular matrix (ECM) has previously been described in 2D culture and in vivo. Here, we characterized the impact of ERK5 on breast cancer biology in 2D culture, 3D spheroids, and our 3D breast adipose-macrophysiological system (BA-MaPS). Methods: We assessed migration changes in MDA-MB-231 parental and ERK5-knockout (ERK5-ko) cells cultured in the three in vitro models using transwell, scratch, and spheroid pseudo-migration assays. Differential gene expression among these cell lines in the three platforms was assessed by RNA sequencing and pathway analysis. Stromal remodeling of adipocytes and matrix was evaluated by H&E and Masson’s Trichrome. Results: Across the in vitro models, ERK5 deletion impaired TNBC cell migration. ERK5-mediated transcriptomic changes included genes associated with epithelial-to-mesenchymal transition (EMT) and migration, with further analysis showing significant alterations in core and associated matrisome. Histological staining corroborated the downregulation of collagen with ERK5 depletion in the BA-MaPS. The NFκB pathway was significantly upregulated only in the ERK5-ko 2D-cultured cells, not in 3D spheroids nor the BA-MaPS model. Conclusions: These results indicate a link between ERK5 and TNBC progression through regulation of TME remodeling, EMT, and cell motility. Differences in 2D culture, 3D spheroid, and BA-MaPS underscore the importance of using physiologically relevant models in breast cancer research. Full article

Intravenous thrombolysis with recombinant tissue-type plasminogen activator (tPA) remains a keystone of acute ischemic stroke treatment but in a subset of patients is complicated by angioedema, a potentially life-threatening adverse event largely mediated by bradykinin signaling. The unpredictable and idiosyncratic nature of this reaction has long suggested an underlying genetic contribution, yet its molecular architecture has remained poorly characterized. We hypothesized that alteplase-associated angioedema represents a multigenic susceptibility phenotype, arising from the convergence of rare genetic variants across multiple interacting physiological systems rather than from a single causal variant. To explore this hypothesis, we performed clinical exome sequencing in a cohort of 11 patients who developed angioedema following alteplase administration. Rather than identifying a shared pathogenic variant, we observed distinct yet convergent patterns of genetic vulnerability, allowing patients to be grouped according to dominant, but overlapping, biological axes. These included alterations affecting bradykinin regulation (e.g., ACE, SERPING1, XPNPEP2), endothelial structure and hemostasis (e.g., VWF, COL4A1), neurovascular and calcium signaling (e.g., SCN10A, RYR1), and vascular repair or remodeling pathways (e.g., PSEN2, BRCA2). Notably, many of the identified variants were classified as Variant of Uncertain Significance (VUS) or likely benign significance in isolation. However, when considered within an integrated, pathway-based framework, these variants can be interpreted as capable of contributing cumulatively to system level fragility, a phenomenon best described as “contextual pathogenicity”. Under the acute biochemical and proteolytic stress imposed by thrombolysis, this reduced physiological reserve may allow otherwise compensated vulnerabilities to become clinically manifest. Together, these findings support a model in which severe alteplase-associated angioedema appears as an emergent property of interacting genetic networks, rather than a monogenic disorder. This systems level perspective underscores the limitations of gene centric interpretation for adverse drug reactions and highlights the potential value of pathway informed, multi-genic approaches to risk stratification. Such frameworks may ultimately contribute to safer, more personalized thrombolytic decision, while providing a conceptual foundation for future functional and translational studies. Full article

Cyclodextrins and chitosan are biomaterials largely used as pharmaceutical excipients due to their biocompatibility, biodegradability, and low/absent toxicity, associated with a number of favorable properties. In particular, cyclodextrins complexation is mainly utilized to improve the physicochemical and biological properties of drugs, including solubility, stability, and bioavailability, and to reduce their irritating effect. Nevertheless, some disadvantages related to the fast removal of the complex from blood circulation after in vivo administration, and possible competition effects for interaction with cyclodextrin between the complexed drug and other molecules present in the biological environment, can reduce their efficacy as drug carriers. On the other hand, chitosan is widely employed to take advantage of its mucoadhesive, controlled/targeted release, and permeation-enhancing properties. However, its almost complete insolubility in water and poor affinity towards hydrophobic molecules (as most drugs are) are considered its main drawbacks, which could strongly limit its applicability. Due to the several beneficial properties of both cyclodextrins and chitosan, their joint use could provide additional favorable effects in drug delivery and help overcome their disadvantages, in particular by combining the complexing/solubilizing ability of the former towards hydrophobic molecules with the mucoadhesive and controlled/targeted release properties of the latter. The present review is intended to provide a critical and comprehensive summary of the main relevant investigations performed in the last twenty-five years regarding the applications and possible advantages that can be obtained by the combined use of cyclodextrins and chitosan in the development of more effective drug delivery systems. Full article

Glioblastoma multiforme (GBM) is characterized by aggressive growth, extensive vascularization, high metabolic malleability, and a striking capacity for therapy resistance. Current treatments involve surgical resection and concomitant radiation therapy and chemotherapy, prolonging survival times marginally due to the therapy resistance that is built up by the tumor cells. A growing body of research has identified exosomes as critical enablers of therapy resistance. These nanoscale vesicles enable GBM cells to disseminate oncogenic proteins, nucleic acids, and lipids that collectively promote angiogenesis, maintain autophagy under metabolic pressure, and suppress apoptosis. As interest grows in targeting tumor communication networks, exosome-based therapeutic strategies have emerged as promising avenues for improving therapeutic outcomes in GBM. This review integrates current insights into two complementary therapeutic strategies: inhibiting exosome biogenesis and secretion, and engineering exosomes as precision vehicles for the delivery of anti-tumor molecular cargo. Key molecular regulators of exosome formation—including the endosomal sorting complex required for transport (ESCRT) machinery, tumor susceptibility gene 101 (TSG101) protein, ceramide-driven pathways, and Rab GTPases—govern the sorting and release of factors that enhance GBM survival. Targeting these pathways through pharmacological or genetic means has shown promise in suppressing angiogenic signaling, disrupting autophagic flux via modulation of autophagy-related gene (ATG) proteins, and sensitizing tumor cells to apoptosis by destabilizing mitochondria and associated survival networks. In parallel, advances in exosome engineering—encompassing siRNA loading, miRNA enrichment, and small-molecule drug packaging—offer new routes for delivering therapeutic agents across the blood–brain barrier with high cellular specificity. Engineered exosomes carrying anti-angiogenic, autophagy-inhibiting, or pro-apoptotic molecules can reprogram the tumor microenvironment and activate both the intrinsic mitochondrial and extrinsic ligand-mediated apoptotic pathways. Collectively, current evidence underscores the potential of strategically modulating endogenous exosome biogenesis and harnessing exogenous engineered therapeutic exosomes to interrupt the angiogenic and autophagic circuits that underpin therapy resistance, ultimately leading to the induction of apoptotic cell death in GBM. Full article

Acute respiratory distress syndrome (ARDS) is a common condition among intensive care unit patients and is associated with high mortality. Currently, there are no unified therapeutic strategies, including for the use of systemic glucocorticosteroid (GCS) therapy, in the management of ARDS of various etiologies. Using our previously developed non-surgical and reproducible model of unilateral total diffuse alveolar damage (ARDS/DAD) in the left lung of ICR mice, we investigated the effects of GCS with different durations of action and administration regimens on lung function recovery. Our data show that repeated-course administration of dexamethasone promoted complete normalization of respiratory function, as well as restoration of aeration and perfusion of the left lung in mice following ARDS/DAD induction. In contrast, a single administration of the same drug or the use of a prolonged-release formulation, despite exhibiting anti-inflammatory effects, did not provide adequate lung tissue recovery and, in some cases, even exacerbated injury. These results underscore that in ARDS therapy, not just the use but the specific dosing regimen of glucocorticoids is critically important for driving complete functional and structural lung repair. Full article

Background/Objectives: Nutraceuticals, including short-chain fatty acids (SCFAs) and antioxidants (AOXs), are nutrient-derived bioactive compounds considered as potential treatments for metabolic-associated steatotic liver disease (MASLD). However, in vitro studies of their effects are limited by inconsistent experimental conditions, including differences in cell lines, methods of steatosis induction, and culture media, and by reliance on qualitative rather than quantitative assessments. Here, we systematically evaluate the anti-steatotic potential of eight commonly used nutraceuticals—three SCFAs (butyrate, acetate, and propionate) and five AOXs (resveratrol, curcumin, berberine, chlorogenic acid, and vitamin E)—using a standardized in vitro approach. Methods: Following a systematic literature review to identify common experimental conditions, we developed an assay to validate steatosis induction and quantified the effects of the nutraceuticals. For our studies we used the HepG2 liver cancer cell line and the Fa2N-4 immortalized hepatocyte cell line. Steatosis was modeled by stimulating cells with free fatty acids and fructose for 48 h. Nutraceuticals were added either concurrently with steatotic stimulation, to assess preventive effects, or after 24 h to assess therapeutic effects. Anti-steatotic drugs (resmetirom, semaglutide, obeticholic acid, and a DGAT2 inhibitor) were included as positive controls. Intracellular triglyceride levels were measured to quantify steatosis. Results: A systematic review of 46 studies revealed large differences in culture conditions, steatosis induction, and nutraceutical assessment. In our experiments, most nutraceuticals did not reduce intracellular triglycerides, with the exception of vitamin E. Surprisingly, butyrate, berberine, and curcumin increased triglyceride accumulation. Resmetirom was the only drug that significantly decreased triglycerides, while obeticholic acid, semaglutide, and the DGAT2 inhibitor showed minimal or inconsistent effects. Fa2N-4 cells were generally more sensitive than HepG2 cells, showing larger absolute changes in triglyceride levels in response to both nutraceuticals and resmetirom. Conclusions: We established a standardized in vitro assay to evaluate the anti-steatotic potential of nutraceuticals. Using this system, we found that SCFAs and AOXs did not consistently reduce intracellular triglycerides, highlighting the need for quantitative assessments and careful validation when studying anti-steatotic interventions in vitro. Full article

Background/Objectives: Sulfated polysaccharides from Spirulina platensis have shown various promising biological activities, but their anticancer effects in lung cancer models remain poorly characterized. In this study, sulfated polysaccharide-rich fractions (SPPs) were tested on A549 non-small cell lung cancer (NSCLC) cells to evaluate their cytotoxic, oxidative, and immunomodulatory activity. Methods: The potential of SPPs to interfere with A549 cell viability, to modulate intracellular reactive oxygen species (ROS) levels, to produce pro-inflammatory effects, and to induce apoptosis was evaluated. Co-administration experiments were also performed using Gefitinib, a drug commonly used in NSCLC therapy. Non-cancerous human bronchial epithelial cells (16HBE) were included to assess the ability of SPPs to selectively target tumoral cells. Results: Our findings show that SPPs significantly reduced A549 cell viability in a concentration-dependent manner and increased ROS levels. This effect was associated with apoptotic DNA fragmentation and modulation of apoptosis-related genes, including upregulation of BAX and CASP-9, and downregulation of BCL-2, MTOR, and BIRC5. SPPs also induced a controlled pro-inflammatory response by increasing ACE2, NF-κB1, and CCL2 expression while reducing COX-2 levels. In co-administration experiments with Gefitinib, a cancer drug used to treat NSCLC, enhanced cytotoxic and pro-apoptotic effects were observed. Importantly, at active concentrations (150–250 µg/mL) SPPs were not found to produce cytotoxicity or apoptosis in 16HBE cells. Conclusions: Overall, these findings suggest that SPPs may selectively target NSCLC cells by promoting redox imbalance, apoptosis, and immune response, without affecting healthy cells, supporting their potential as natural adjuvants in lung cancer treatment. Full article

This study evaluated long-term trends in the prevalence of use of atypical and typical antipsychotic drugs (APDs), both as classes of drugs and as individual drugs, among adult inpatients in the United States (US). The Health Facts^® database developed by Cerner Corporation was used to analyze the prevalence of APD use among adult inpatients aged 18 years or older who were administered at least one antipsychotic medication order during hospitalization between 1 January 2000 and 31 December 2016. The prevalence of APD use was standardized by age, sex, race, and census region. Typical and atypical antipsychotic treatment patterns in the US differed over this period. While the use of atypical APDs increased overall, the use of typical antipsychotic medications decreased, but remained more prevalent. Overall, haloperidol and prochlorperazine were the two most administered antipsychotic medications throughout the study period. From 2000 to 2011, prochlorperazine and haloperidol were the first- and second-most prescribed typical APDs, respectively; haloperidol became the most administered antipsychotic of this class as of 2012. Quetiapine was the most administered atypical antipsychotic medication, followed by risperidone and olanzapine until 2014, after which olanzapine was the second-most administered atypical APD. There was a notable decline in the use of atypical antipsychotics medications between 2005 and 2008, which may reflect the impact of the Food and Drug Administration’s warnings and the American Diabetes Association’s consensus position, but only for a short time. The usage patterns observed in this study support existing evidence of substantial off-label use of antipsychotic drugs in the US. Full article

Pain is an unpleasant but essential sensory experience that serves as a protective mechanism, yet it can also manifest maladaptively in a wide range of pathological conditions. Current analgesic strategies rely heavily on opioid medications and non-steroidal anti-inflammatory drugs (NSAIDs); however, concerns regarding addiction, tolerance, and dose-limiting adverse effects highlight the urgent need for safer and more effective therapeutics. Voltage-gated sodium (Na_v) channels, which govern the initiation and propagation of action potentials, have emerged as promising targets for mechanism-based analgesic development. In particular, the Na_v1.7–Na_v1.9 subtypes have attracted substantial interest owing to their enrichment in the peripheral nervous system—despite broader expression elsewhere—and their central roles in nociception, offering the potential for non-addictive, subtype-selective pain modulation. This review summarizes the physiological roles of these channels in nociception, examines how disease-associated mutations shape pain phenotypes, and highlights recent advances in drug discovery targeting Na_v1.7 and Na_v1.8. The recent FDA approval of VX-548 (suzetrigine), a first-in-class and highly selective Na_v1.8 inhibitor, marks a major milestone that validates peripheral Na_v channels as clinically actionable targets for analgesia. We also discuss the remaining challenges and emerging opportunities in the pursuit of next-generation, mechanism-informed analgesics. Full article

(1) Background: Drug–drug interactions (DDIs) are a frequent cause of medication-related harm, particularly in ambulatory care. Community pharmacists are uniquely positioned to identify and manage these risks. This study assessed DDI knowledge, practices, and barriers among community pharmacists in the Jazan Region, Saudi Arabia. (2) Methods: A structured, self-administered questionnaire was distributed to community pharmacists. The survey assessed DDI knowledge using 26 clinically relevant drug pairings and included questions on professional behavior, training exposure, software use, and educational needs. Descriptive and inferential statistics were applied to identify associations between knowledge scores and demographic or practice-related variables. (3) Results: A total of 219 pharmacists participated in the study. The mean knowledge score was (9.63 ± 4.58) out of 26, reflecting suboptimal to moderate awareness. Female pharmacists demonstrated significantly higher DDI knowledge scores than males (10.74 ± 5.4 vs. 9.08 ± 4.2; p = 0.016). Knowledge scores also differed significantly by academic qualification (p < 0.001), with PharmD holders scoring higher than B. Pharm and postgraduate degree holders. Pharmacists with less than 10 years of experience had significantly higher scores compared with those with longer practice duration (p = 0.002). Additionally, pharmacists who graduated from Saudi institutions scored higher than those trained outside Saudi Arabia (10.22 ± 4.7 vs. 8.44 ± 4.2; p = 0.005). Pharmacists who had received professional development training and those who attended workshops regularly also scored significantly higher. Familiarity with guidelines showed a positive trend. Reported barriers to effective DDI counseling included time constraints, limited patient understanding, and poor collaboration with prescribers. Self-rated awareness of DDIs was positively associated with actual knowledge scores. Pharmacists expressed strong preferences for workshops, online courses, and webinars as future training formats. (4) Conclusions: Pharmacists in the Jazan Region demonstrate moderate awareness of DDIs, with variation influenced by training, experience, and qualifications. Enhancing access to structured professional development and integrating clinical decision support tools could strengthen pharmacists’ role in preventing DDIs in community practice. Full article

Background: The profound heterogeneity of glioblastoma and the often-limited efficacy of conventional treatments, including arsenic trioxide (ATO), underscore the urgent and critical demand for innovative combination strategies specifically designed to overcome treatment resistance. Methods: We evaluated the therapeutic effects of ATO as a single agent and in combination with the MNK1 inhibitor AUM001 across patient-derived xenograft (PDX) models and investigated molecular determinants of sensitivity and synergy. Our results demonstrated that GBM models resistant to ATO, particularly those of the mesenchymal subtype, are more likely to show synergistic cytotoxicity when AUM001 is added. The combination significantly reduces the frequency of glioblastoma stem cells (GSCs) compared to either drug alone, especially in ATO-resistant models. Results: These observations suggest that targeting the MNK1 pathway in conjunction with ATO is a promising strategy to specifically eradicate GSCs, which are major drivers of GBM recurrence and therapeutic failure. Transcriptomic analyses revealed that ATO sensitivity correlated with activated translation-related pathways and cell cycle processes, while synergistic responses to the combination were driven by distinct molecular signatures in different GBM subtypes. Overall, synergistic response to the combination therapy is more associated with cellular organization, amino acid transmembrane transporter activity, ion channels, extracellular matrix organization and collagen formation. Conclusions: Our findings highlight that specific molecular pathways and their activities, including those involving translation, cell cycle and ion transport, appear to modulate the synergistic efficacy of the ATO and AUM001 combination, thereby offering potential biomarkers for improved patient stratification in future GBM clinical trials of such ATO-based treatments. Full article

Background and Objectives: Hand joint deformity remains a main cause impairing quality of life in rheumatoid arthritis (RA). This study aimed to investigate the association between biologic and targeted-synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) treatment and the prevalence of hand joint deformity in RA patients. Materials and Methods: This cross-sectional analysis included RA patients recruited between 2019 and 2024. Hand joint deformity was defined as the presence of specific deformity in any of 28 hand joints, including the metacarpophalangeal (MCP) joints I-V, proximal interphalangeal (PIP) joints I-V, and distal interphalangeal (DIP) joints II-V. The key exposure was the use of b/tsDMARDs. Multivariable logistic regression was used to assess the association between b/tsDMARDs treatment and hand joint deformity. Results: A total of 1083 RA patients with a mean age of 52.6 ± 12.4 years and a median disease duration of 5 (2,11) years were included. Hand joint deformity was present in 25.4% (275/1083) of patients. The top three deformed joint locations were PIP V (12.9%, 140/1083), PIP III (11.6%, 126/1083), and PIP IV (10.9%, 118/1083). The top three deformity types were ulnar deviation of MCP II-V (8.0%, 87/1083), boutonniere deformity of II-V fingers (6.8%, 74/1083), and swan neck deformity of II-V fingers (6.7%, 73/1083). In total, 17.4% (188/1083) of patients had received b/tsDMARDs. After 1:1 propensity score matching for age, sex, and disease duration, the prevalence of deformity was significantly lower in patients treated with conventional medicine (csDMARDs and/or GCs) add-on b/tsDMARDs compared to those treated with conventional medicine (27.1% vs. 61.7%, p < 0.001). Multivariable logistic regression analysis showed that b/tsDMARDs use was independently associated with a lower prevalence of hand joint deformity after adjusting for confounding factors (OR = 0.211, 95%CI: 0.129–0.345, p < 0.001). Conclusions: The use of b/tsDMARDs was independently associated with a lower prevalence of hand joint deformity in RA. Full article

Non-AIDS-defining cancers (NADCs) have emerged as an increasingly prominent cause of non-AIDS-related morbidity and mortality among people living with HIV (PLWH). However, the scarcity of NADC clinical samples, compounded by privacy and security constraints, continues to present formidable obstacles to advancing pathological and clinical investigations. In this study, we adopted a joint analysis strategy and deeply integrated and analyzed transcriptomic data from 12,486 PLWH and cancer patients to systematically identify potential key regulators for 23 NADCs. This effort culminated in NADCdb—a database specifically engineered for NADC pathological exploration, structured around three mechanistic frameworks rooted in the interplay of immunosuppression, chronic inflammation, carcinogenic viral infections, and HIV-derived oncogenic pathways. The “rNADC” module performed risk assessment by prioritizing genes with aberrant expression trajectories, deploying bidirectional stepwise regression coupled with logistic modeling to stratify the risks for 21 NADCs. The “dNADC” module, synergized patients’ dysregulated genes with their regulatory networks, using Random Forest (RF) and Conditional Inference Trees (CITs) to identify pathogenic drivers of NADCs, with an accuracy exceeding 75% (in the external validation cohort, the prediction accuracy of the HIV-associated clear cell renal cell carcinoma model exceeded 90%). Meanwhile, “iPredict” identified 1905 key immune biomarkers for 16 NADCs based on the distinct immune statuses of patients. Importantly, we conducted multi-dimensional profiling of these key determinants, including in-depth functional annotations, phenotype correlations, protein–protein interaction (PPI) networks, TF-miRNA-target regulatory networks, and drug prediction, to deeply dissect their mechanistic roles in NADC pathogenesis. In summary, NADCdb serves as a novel, centralized resource that integrates data and provides analytical frameworks, offering fresh perspectives and a valuable platform for the scientific exploration of NADCs. Full article

Pathological scars are fibrotic lesions that result from aberrant wound healing following tissue injury, such as burns. They are frequently associated with disfigurement and dysfunction, thereby severely impairing the quality of life of affected patients. Current clinical treatments, including surgery, laser therapy, and corticosteroid injections, are often characterized by limited efficacy, high recurrence rates, and undesirable side effects, including skin atrophy. Furthermore, the dense structure and excessive extracellular matrix (ECM) deposition in scar tissue present a significant barrier to effective drug penetration, thereby further limiting therapeutic efficacy. In recent years, biomaterial-based drug delivery systems, which integrate sustained drug release with minimally invasive transdermal technologies, have emerged as a promising strategy to overcome the limitations of traditional therapies. This review systematically outlines the pathogenesis and molecular mechanisms of pathological scars, summarizes established and emerging treatments, and highlights the application strategies and future prospects of novel biomaterial-based drug delivery systems for managing this condition. Full article

Oral squamous cell carcinoma (OSCC) remains a major therapeutic challenge due to aggressive progression, high recurrence, and limited selectivity of current treatments. In this study, a series of seven 4-amino-2-substituted tetrahydrobenzothieno[2,3-d]pyrimidines were evaluated for their cytotoxic, antiproliferative, and mechanistic effects against oral cancer cell lines with different metastatic potential (HSC-3 and SCC-9), alongside non-tumorigenic keratinocytes (HaCaTs). Several compounds demonstrated selective anticancer activity, with Compounds 5 and 6 showing the most favorable balance between potency and selectivity. Antiproliferative assays revealed effective inhibition of cancer cell growth, while clonogenic assays confirmed a pronounced reduction in long-term survival, particularly in highly metastatic HSC-3 cells. Mechanistic studies indicated that the anticancer effects are associated with S-phase cell cycle arrest, apoptosis induction, and profound disruption of the actin cytoskeleton. In silico ADME and drug-likeness analyses supported the lead-like properties of the most active derivatives. Overall, these findings identify thienopyrimidine derivatives as promising scaffolds for the development of targeted therapies against OSCC and warrant further optimization and in vivo evaluation. Full article