Search Results (38,510)

Diabetes mellitus is primarily caused by the loss or malfunction of insulin-producing β-cells, and although current therapies improve glycemic control, they do not restore physiologic insulin secretion. Advances in stem cell biology and organoid engineering have led to the development of pancreatic organoids and induced pluripotent stem cell (iPSC)-derived β-cells as promising platforms for disease modeling, drug testing, and regenerative medicine. Pancreatic organoids generated from ductal, acinar, or progenitor populations can recapitulate key anatomical and functional features of native pancreatic tissue, enabling studies of development, injury, and regeneration. In parallel, improvements in iPSC differentiation protocols have produced β-like cells capable of insulin secretion in response to glucose, although achieving full functional maturity remains a challenge. Bioengineering strategies, including biomaterial scaffolds, microfluidic platforms, endothelial co-culture systems, three-dimensional bioprinting, and CRISPR-based genome editing, have enhanced the stability, vascular compatibility, and functional performance of both organoid and iPSC-derived systems. Despite these advances, variability in differentiation efficiency, limited β-cell maturity, and poor long-term survival continue to hinder clinical translation. Together, pancreatic organoids and iPSC-derived β-cells represent complementary platforms that advance fundamental research and support the development of β-cell replacement therapies, with ongoing integration of bioengineering approaches expected to accelerate progress toward reproducible, scalable, and clinically relevant β-cell regeneration. Full article

Enteroviruses represent important human pathogens, posing a substantial disease burden, particularly in children under 5 years of age. Enteroviruses are the primary causative agents of hand-foot-and-mouth disease (HFMD) and are strongly associated with acute flaccid myelitis (AFM), with severe cases potentially resulting in significant neurological complications. Inactivated vaccines against EV-A71 based on the C4 genotype are currently available. However, there are no licensed direct antiviral agents for severe cases. By focusing on viral proteins and host factors, researchers have made great strides in the creation of antiviral medications that target enteroviruses. However, several viral candidates failed to progress in clinical development due to limited efficacy or side effects. This review discusses key findings in enterovirus antiviral research, analyzes the advantages and limitations of each drug target, and highlights knowledge gaps that need to be addressed to advance further development in this field. Full article

Background/Objectives: The emergence of methicillin-resistant Staphylococcus aureus (MRSA) necessitates innovative strategies to overcome conventional resistance mechanisms. This study investigated the potential of the natural flavonolignan silibinin (SIL) as an antivirulence agent against S. aureus, with a particular emphasis on its putative multi-target antibacterial activity and its capacity to potentiate the effects of ciprofloxacin (CIP). Methods: The antibacterial and antivirulence properties of SIL were assessed using both in vitro and in silico approaches. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined, and its synergistic interaction with CIP was evaluated using checkerboard assays. Inhibition of biofilm formation, as well as disruption of established biofilms, was assessed using an MTT-based viability assay. Staphyloxanthin (STX) inhibition was examined through pigment extraction and spectrophotometric quantification of pathway intermediates. Molecular docking studies were conducted to predict the binding affinities of the compounds to key bacterial targets, while safety was evaluated through haemolytic and cytotoxicity assays. Results: SIL exhibited weak to moderate direct antibacterial activity (MICs of 256–512 µg/mL), which is characteristic of many natural product scaffolds. Notably, SIL potentiated the activity of CIP, reducing its MIC by up to fourfold against selected resistant strains of S. aureus. SIL significantly inhibited biofilm formation and disrupted established mature biofilms in a strain-dependent manner. In vitro metabolic profiling and in silico analyses provided mechanistic insights into the effects of SIL on STX biosynthesis. Precursor accumulation data suggest inhibition at the diapophytoene desaturase (CrtN) catalytic step, representing a potential mechanism not previously reported for flavonolignans. Molecular docking studies further predicted favourable binding affinities for CrtM and other key targets. Importantly, SIL exhibited no haemolytic activity and low cytotoxicity in macrophages at synergistic concentrations. Conclusions: This study provides evidence that SIL functions as a dual-action agent, potentiating ciprofloxacin efficacy while reducing STX production and inhibiting biofilm formation, thereby impairing key virulence mechanisms of S. aureus. These findings, together with its favourable safety profile, provide a strong rationale for the development of silibinin-based topical adjuvants to combat drug-resistant Staphylococcus infections in humans. Full article

Siponimod, a selective sphingosine 1-phosphate (S1P) receptor modulator, represents a next-generation therapeutic drug for active secondary progressive multiple sclerosis. This study conducted in-depth forced degradation studies of siponimod in solid state subjected to acidic, alkaline, oxidative, photolytic, and thermal conditions, in compliance with ICH guidelines Q1A (R2) and Q3A (R2). An HPLC method was developed to quantify siponimod and separate its degradation products (DPs). The DPs were characterized using LC-HRMS/MS and LC-MSⁿ techniques. Moreover, the toxicological profiles of siponimod and its DPs were evaluated through the in silico tools ProTox 3.0 and ADMETlab 3.0, with molecular docking and dynamics simulations assessing their binding to the S1P1 receptor. Siponimod was stable to light but degraded under acidic, alkaline, oxidative, and thermal stress, producing five products: DP-1 (acidic), DP-2/3 (oxidative), DP-4 (hydrolytic), and DP-5 (thermal). The toxicity prediction suggested that neither siponimod nor its DPs exhibited carcinogenic or mutagenic potential, and the molecular modeling analysis revealed that DP-2 and DP-3 demonstrated favorable binding affinities, with stable dynamic profiles and thermodynamic properties that closely resembled those of siponimod. As far as we know, this is the first study on the structural elucidation of the DPs of siponimod by LC-HRMS/MS and LC-MSⁿ. Full article

Introduction: Tuberculous aneurysm of the thoracic aorta (TBAA) is an extremely rare but potentially fatal manifestation of tuberculosis (TB). Clinical presentation may include hemoptysis in the absence of parenchymal lung abnormalities. Case report: We presented a 62-year-old male with cough, chest pain, and minimal hemoptysis. Diagnostic evaluation confirmed an aneurysm of the descending thoracic aorta at a site previously treated with endovascular repair, with no imaging findings suggestive of pulmonary TB. Bronchoscopy revealed blood in the main bronchi without an identifiable endobronchial source. The diagnosis of TB was established by polymerase chain reaction (PCR) testing of bronchial aspirate obtained during bronchoscopy. Emergency surgical intervention was recommended because of an impending aortic rupture, but the patient declined surgery. Standard antituberculous therapy was initiated, and the patient subsequently developed drug-induced liver injury, prompting temporary cessation of treatment. The clinical course was later complicated by the development of an aortoesophageal fistula (AEF), with significant implications for prognosis. Conclusions: Early recognition of TBAA, along with a multidisciplinary approach that integrates advanced diagnostic modalities, timely vascular intervention, and carefully managed antituberculous therapy, is essential to reduce mortality and optimize treatment outcomes. Full article

Background/Objectives: Pericardial effusion (PEf) is a frequent finding after cardiac surgery. Progression to cardiac tamponade (CT) is a rare but life-threatening complication. Current evidence remains limited due to insufficient data on prevalence, progression predictors and management strategies. Methods: We retrospectively analyzed anamnestic, clinical, laboratory, echocardiographic and therapeutic data from 2662 patients (74 ± 11 years) admitted to the Cardiac Rehabilitation ward between 2022 and 2024. Results: Among 2152 (81%) cardiac surgery patients, 382 (18%) developed PEf: 58% mild, 38% moderate, and 4% severe. Patients developing PEf tended to be younger and more frequently male. In addition, PEf development was seen more commonly after aortic and combined surgeries. All patients with severe PEf or CT had undergone surgery via sternotomy, whereas minithoracotomy was inversely associated with PEf severity. Postoperative complications occurred in 92% of PEf patients, mainly due to arrhythmia, hemodynamic deterioration, or heart failure. Overall outcome was favourable in 98% of patients. CT occurred in eight patients (2%). Anticoagulation therapy was more frequent among patients who developed PEf or CT. Preventive colchicine was prescribed in only 16% of cases. No PEf-specific therapy was administered in 56% of PEf patients, while corticosteroids and nonsteroidal anti-inflammatory drugs were used in 28% and 8% of cases, respectively, without surgical wound complications. No PEf recurrences were observed during follow up (517 ± 424 days). Conclusions: PEf is a common complication after cardiac surgery, more frequently in young males, usually of mild or moderate severity. The majority of these cases resolve using either a conservative or pharmacological approach, predominantly via corticosteroids. Patients undergoing aortic surgery, experiencing postoperative complications (especially arrhythmias), and receiving anticoagulation therapy were associated with severe PEf or CT. Despite guideline recommendations, colchicine remains markedly underutilized. Full article

Hearing loss is detrimental to human health, and currently, more than 1.5 billion people are affected by hearing loss. Active military personnel and construction workers are examples of individuals in the workplace who are exposed to loud noise and are at serious risk of hearing loss. While there is currently no therapy for hearing loss, evidence supports investigating the enhancement of the Medial Olivocochlear (MOC) System, an efferent pathway for hearing that serves as a gain-control for hearing loss protection. Selectively modulating the α9α10 nicotinic acetylcholine receptor (nAChRs) found within this pathway is promising for the development of a new drug class. In this review article, we present the most current findings related to the therapeutic targeting of α9α10 nAChRs for hearing loss. We discuss the loss- or gain-of-function of the receptor, evaluate the known modulators of the receptor, examine their clinical relevance, and discuss their chemical and physical properties. Investigation of this novel pathway may aid in the development of a therapeutic for hearing loss. Full article

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative maxillofacial disorder marked by progressive cartilage degradation and subchondral bone resorption, severely compromising patients’ quality of life. Intra-articular injection (IA), a standard route for conservative therapy, offers clinical advantages in safety and efficacy; however, outcomes remain limited due to short drug retention, poor tissue penetration, and variable agent efficacy, necessitating repeated administration. To overcome these limitations, fisetin-loaded poly (lactic-co-glycolic acid) nanoparticles (FST-PNP) were developed as a localized drug delivery system (DDS) for TMJOA treatment. Physicochemical analyses showed FST-PNP had uniform spherical morphology, excellent dispersibility, stability, high encapsulation efficiency, and substantial drug loading capacity. An in vitro study demonstrated more sustained and stable release from FST-PNP than free fisetin. The in vivo IA administration of FST-PNP preserved mandibular condylar osteochondral structures in TMJOA models. Notably, FST-PNP suppressed the expression of metalloproteinase-13 and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5) as catabolic enzymes and downregulated p16 and p21 as senescence markers, indicating synergistic anti-inflammatory and anti-senescent effects. These findings highlight FST-PNP as a DDS integrating controlled-release with multifaceted therapeutic actions, providing a promising strategy for IA therapy of TMJOA. Full article

Carbapenems comprise a class of β-lactam antibiotics with broad-spectrum hydrolytic activity and are often reserved as last-line agents for the treatment of serious multidrug-resistant (MDR) bacterial infections. Clinically important nosocomial MDR Gram-negative bacteria (GNB) include Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Carbapenem resistance among these organisms is predominantly mediated by the production of β-lactamases called carbapenemases, such as K. pneumoniae carbapenemase (KPC), New Delhi metallo-β-lactamase (NDM), imipenemase (IMP), Verona integron-encoded metallo-β-lactamase (VIM), and selected oxacillinase (OXA)-type carbapenemases. These enzymes degrade carbapenems, significantly compromising their clinical efficacy. To address escalating antimicrobial resistance, novel next-generation β-lactamase inhibitors (BLIs), partnered with established β-lactams (BLs), have been approved or are currently under development to inhibit carbapenemase activity. The present narrative review aims to synthesize the most current information on the major carbapenemases and discusses recently approved and investigational BL/BLI combination therapies in terms of their mechanisms of action, spectrum of activity, gaps in coverage, and available clinical and in vitro evidence. Development of resistance to novel BL/BLI combinations is also examined. Comparative analysis of inhibitory spectra and microbiological coverage indicates a continued need for metallo-β-lactamase inhibitors with direct pan-inhibitory activity, pathogen-specific BL/BLI regimens for carbapenem-resistant A. baumannii, and carbapenemase-targeted agents effective in the context of non-enzymatic resistance mechanisms. Treatment-emergent resistance to novel BL/BLIs and limitations in activity profiles underscore the critical need for continued innovation in pipeline development, vigilant global and local surveillance of carbapenemase epidemiology, and robust antimicrobial stewardship strategies to aid in preserving the efficacy of the antibacterial drug armamentarium. Full article

Background/Objectives: Population pharmacokinetic (PopPK) modeling in NONMEM requires iterative, expertise-dependent workflows. Naïve zero-shot prompting of general-purpose large language models (LLMs) typically produces NONMEM code that fails to execute. This study introduces PKGPT, a recursive agentic LLM system designed to automate NONMEM-based PopPK model development and benchmarks its performance against human expert models. Methods: PKGPT, powered by Google’s Gemini 3.0 Flash, embeds pharmacometrics expertise into phase-specific expert-agent prompts orchestrated across five sequential phases: base model establishment, structural diagnostics, overfitting reduction, random-effects optimization, and covariate analysis. The system recursively executes NONMEM, parses outputs, and iteratively refines control streams. PKGPT was evaluated on three public datasets (warfarin, theophylline, and tobramycin) and benchmarked against independently developed human expert models. Results: PKGPT consistently produced executable, converging NONMEM models across all three datasets. In warfarin, both PKGPT and the human expert selected a one-compartment oral structure (ADVAN2), but the expert achieved a lower OFV (294.41 vs. 484.43) via covariate scaling. In theophylline, PKGPT produced parameter estimates close to the expert solution (Ka = 1.59 vs. 1.46 h⁻¹; CL = 0.0399 vs. 0.0404 L/h/kg). In tobramycin, PKGPT correctly identified a two-compartment structure but produced physiologically implausible peripheral volume estimates (V2 = 149 L vs. expert’s 13.2 L). Across datasets, PKGPT did not identify clinically established covariates, and run-to-run reproducibility was variable. Conclusions: PKGPT substantially improves the robustness and usability of LLM-generated NONMEM code compared with naïve zero-shot prompting, accelerating model drafting and iterative refinement, but physiological plausibility and clinical interpretability still require a human-in-the-loop oversight. Full article

This study focuses on the production and characterization of polyvinyl alcohol (PVA)-chitosan (CS)-based nanoparticles loaded with vitamin E (VitE) and ephedrine (Ep) via electrospraying for intranasal drug delivery in narcolepsy treatment. The nanoparticles were successfully synthesized using optimized parameters (15.5 kV voltage, 0.3 mL/h flow rate, 25 G needle size, and 14 cm distance). Scanning electron microscopy (SEM) analysis confirmed the formation of spherical particles with an average size of 350–500 nm, while energy-dispersive X-ray spectroscopy (EDS) mapping revealed a homogeneous elemental distribution with oxygen (51.74%), silicon (24.48%), carbon (6.47%), zinc (6.08%), and aluminum (3.82%). Fourier-transform infrared (FTIR) spectra demonstrated the successful encapsulation of VitE and Ep through characteristic peaks at 3285 cm⁻¹ (OH stretching), 1731 cm⁻¹ (C=O stretching), and 1086 cm⁻¹ (C-O-C stretching). In vitro drug release analysis indicated a controlled and sustained release profile, with cumulative VitE and Ep release reaching 78.6% and 84.3%, respectively, over 48 h in phosphate-buffered saline (PBS, pH 7.4). Antioxidant activity assessment using the DPPH assay confirmed an R² value of 18.84 µg/mL, demonstrating significant free radical scavenging potential. The antibacterial activity, tested via the disk diffusion method, exhibited inhibition zones of 18.31 ± 5.8 mm (E. coli) and 21.51 ± 1.57 mm (S. aureus), confirming strong antimicrobial properties. These findings suggest that the developed electrosprayed PVA/CS nanoparticles loaded with VitE and Ep offer a promising intranasal delivery system with enhanced bioavailability, controlled release, antioxidant capacity, and antibacterial properties, making them a viable candidate for narcolepsy treatment. Full article

Background/Objectives: Research has shown a high prevalence of co-occurring trauma-related disorders and cocaine use disorder (CUD). However, there remains a need for preclinical studies to determine how traumatic event exposure influences vulnerability to CUD development and relapse. In this study, we assessed the impact of traumatic event exposure using a threat conditioning (TC) paradigm, which models traumatic event exposure through associative threat learning on cocaine-seeking behavior in adult male and female rats. Methods: Adult male and female rats were exposed to a single TC session. After TC, the rats underwent cocaine self-administration (SA), extinction training, cue-primed reinstatement, and cocaine-primed reinstatement testing. A parallel cohort was subjected to a sucrose SA cohort to assess whether TC altered non-drug reward seeking in the form of sucrose SA. Results: In the cocaine cohort, stressed male rats exhibited greater cue- and cocaine-primed reinstatement relative to non-stressed males, whereas no reinstatement differences emerged in female rats. In the sucrose cohort, stressed females displayed increased sucrose pellet delivery during self-administration compared to non-stressed females, but no differences were observed during sucrose reinstatement in either male or female rats. Conclusions: These findings indicate that trauma exposure prior to cocaine use influences cocaine relapse-related behavior, as well as non-drug reward reinforcement earning, in a sex-specific manner. Overall, these results highlight the value of associative stress models such as TC for studying trauma–addiction comorbidity and the need to investigate the neurobiological mechanisms driving these sex-specific outcomes. Full article

Background/Objective: In lung cancer treatment, increasing the concentration of antitumor drugs at the tumor site, enhancing efficacy, and reducing systemic toxicity are significant challenges. This study aims to develop an intelligent responsive polymer micelle system (GPDD) that achieves efficient accumulation and controlled release of drugs at lung tumor sites through targeted and pH-responsive design. Methods: The GPDD system is formed by the self-assembly of GE11-PEG-hyd-DOX conjugates and co-loads free DOX. This system utilizes the targeting effect of the GE11 peptide with the epidermal growth factor receptor (EGFR) to accumulate at the tumor site, while the hydrazone bond serves as a pH-responsive linker that breaks in the acidic tumor microenvironment, triggering drug release. Experiments employed CCK-8 cytotoxicity assays and tumor-bearing nude mouse models (strain not specified) for in vitro and in vivo evaluations. Results: In vitro experiments showed that GE11-modified GPDD effectively inhibited tumor cell growth. In tumor-bearing nude mouse experiments, GPDD demonstrated more significant tumor suppression effects and lower systemic toxicity compared to free DOX and unmodified PDD. Conclusions: The GPDD nanocarrier integrates targeting and pH responsiveness, improving antitumor efficacy and reducing side effects, with translational potential. The novelty of the study lies in its dual-functional design and co-loading strategy, providing new insights for tumor-targeted delivery systems. Full article

Background/Objectives: Magnetic nanoparticles have emerged as powerful tools for biomedical imaging, targeted drug delivery, and hyperthermia therapy. Magnetic particle imaging (MPI) is among the most promising technologies built around its properties: a radiation-free, quantitative tomographic modality that detects superparamagnetic iron oxide nanoparticles (SPIONs) directly against a biologically silent background. This review synthesizes MPI’s physical principles, nanoparticle design strategies, and preclinical applications within the broader landscape of magnetic material engineering for biomedical use. Methods: A systematic review was conducted covering MPI signal generation and image reconstruction, nanoparticle core synthesis and surface coating approaches, and preclinical applications, spanning cell tracking, oncological imaging, vascular perfusion, neuroimaging, and MPI-guided theranostics. Studies were selected to provide quantitative benchmarks and direct comparisons with competing modalities where available. Results: MPI delivers signal-to-background ratios above 1000:1, iron-mass linearity at R² ≥ 0.99, regardless of tissue depth, and acquisition rates up to 46 volumes per second. Tracer architecture—encompassing single-core particles, multicore nanoflowers, and stimuli-responsive cluster designs—is the primary determinant of sensitivity, environmental robustness, and theranostic capability. Preclinical results include detection of cell populations in the low thousands, earlier ischaemia identification than diffusion-weighted MRI, real-time drug release quantification, and spatially confined tumour hyperthermia. Three translational bottlenecks are identified: the absence of a clinically approved tracer with optimal relaxation dynamics, hardware performance losses when scaling to human-bore systems, and overestimation of passive tumour accumulation in murine models. Conclusions: MPI illustrates how progress in magnetic material design directly expands clinical imaging and theranostic possibilities. Successful translation will require indication-driven, interdisciplinary development that integrates materials science, scanner engineering, and regulatory strategy in parallel. Full article

Quality by design (QbD) is a systematic approach focused on achieving consistent, predictable quality based on predefined objectives. Unlike traditional methods, QbD prioritizes risk assessment and management, which significantly enhances the robustness of the analytical method. In this study, we initiated factor screening using a three-factor, two-level design to evaluate three independent variables: flow rate, pH, and mobile phase composition. To further investigate the interaction of these variables, we employed Central Composite Design (CCD). This allows us to apply response surface methodology to the Critical Analytical Attributes (CAAs), specifically retention time, peak area, and symmetry factor, by conforming to the method’s robustness. The combination of pregabalin and duloxetine hydrochloride (HCl) dosage form was determined using a straightforward, exact, specific, and accurate reverse-phase HPLC approach. The results showed retention times of 3.265 min and 4.318 min for duloxetine HCl and pregabalin, respectively. Pregabalin demonstrated linearity from 100 to 200 μg/mL (R² = 0.998), whilst duloxetine HCl demonstrated linearity between 20 and 120 μg/mL (R² = 0.997). Lower LOD values of 0.925 µg/mL and 0.853 μg/mL and LOQ values of 2.809 μg/mL and 2.587 μg/mL of pregabalin and duloxetine HCl, respectively, suggest good sensitivity for the technique. The drug content of the commercial formulation may thus be determined using the recommended method. This technique can be used for standard quality control studies to simultaneously estimate pregabalin and duloxetine HCl. The novelty of the present studies lies in the development of a robust RP-HPLC method for simultaneous estimation of pregabalin and duloxetine HCl using a systematic AQbD approach, enhancing robustness, reproducibility, and reliability, making it highly suitable for routine quality control and regulatory applications. Full article