Int J Mol Sci. 2025 Jan 18;26(2):793. doi: 10.3390/ijms26020793.

ABSTRACT

The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function.

PMID:39859507 | DOI:10.3390/ijms26020793

Int J Mol Sci. 2025 Jan 15;26(2):686. doi: 10.3390/ijms26020686.

ABSTRACT

SARS-CoV-2 viral entry requires membrane fusion, which is facilitated by the fusion peptides within its spike protein. These predominantly hydrophobic peptides insert into target membranes; however, their precise mechanistic role in membrane fusion remains incompletely understood. Here, we investigate how FP1 (SFIEDLLFNKVTLADAGFIK), the N-terminal fusion peptide, modulates membrane stability and barrier function across various model membrane systems. Through a complementary suite of biophysical techniques-including electrophysiology, fluorescence spectroscopy, and atomic force microscopy-we demonstrate that FP1 significantly promotes pore formation and alters the membrane's mechanical properties. Our findings reveal that FP1 reduces the energy barrier for membrane defect formation and stimulates the appearance of stable conducting pores, with effects modulated by membrane composition and mechanical stress. The observed membrane-destabilizing activity suggests that, beyond its anchoring function, FP1 may facilitate viral fusion by locally disrupting membrane integrity. These results provide mechanistic insights into SARS-CoV-2 membrane fusion mechanisms and highlight the complex interplay between fusion peptides and target membranes during viral entry.

PMID:39859399 | DOI:10.3390/ijms26020686

Int J Mol Sci. 2025 Jan 7;26(2):448. doi: 10.3390/ijms26020448.

ABSTRACT

Mitophagy, an essential process within cellular autophagy, has a critical role in regulating key cellular functions such as reproduction, metabolism, and apoptosis. Its involvement in tumor development is complex and influenced by the cellular environment. Here, we conduct a comprehensive analysis of a mitophagy-related gene signature, composed of PRKN, PINK1, MAP1LC3A, SRC, BNIP3L, BECN1, and OPTN, across various cancer types, revealing significant differential expression patterns associated with molecular subtypes, stages, and patient outcomes. Pathway analysis revealed a complex interplay between the expression of the signature and potential effects on the activity of various cancer-related pathways in pan-cancer. Immune infiltration analysis linked the mitophagy signature with certain immune cell types, particularly OPTN with immune infiltration in melanoma. Methylation patterns correlated with gene expression and immune infiltration. Mutation analysis also showed frequent alterations in PRKN (34%), OPTN (21%), PINK1 (28%), and SRC (15%), with implications for the tumor microenvironment. We also found various correlations between the expression of the mitophagy-related genes and sensitivity in different drugs, suggesting that targeting this signature could improve therapy efficacy. Overall, our findings underscore the importance of mitophagy in cancer biology and drug resistance, as well as its potential for informing treatment strategies.

PMID:39859167 | DOI:10.3390/ijms26020448

Medicina (Kaunas). 2025 Jan 13;61(1):105. doi: 10.3390/medicina61010105.

ABSTRACT

Background and Objectives: The pathophysiology of arrhythmogenic cardiomyopathy (ACM), previously known as arrhythmogenic right ventricular cardiomyopathy (ARVC), and its specific biological features remain poorly understood. High-throughput plasma proteomic profiling, a powerful tool for gaining insights into disease pathophysiology at the systems biology level, has not been used to study ACM. This study aimed at characterizing plasmatic protein changes in patients with ACM, which were compared with those of healthy controls, and at exploring the potential role of the identified proteins as biomarkers for diagnosis and monitoring. Materials and Methods: Blood samples were collected from six ACM patients, four patients with other cardiomyopathies, and two healthy controls. Plasma was processed to remove high-abundance proteins and analyzed by two-dimensional gel electrophoresis. Differential protein expressions were assessed using PDQuest software, Bio-Rad US version 8.0.1. Results: The analysis revealed several proteins with altered expressions between ACM patients and controls, including plakophilin-2, junctional plakoglobin, desmoplakin, desmin, transmembrane protein 43, and lamin A/C. Conclusions: The plasma proteomic profiling of ACM suggests that ACM is a distinct disease entity characterized by a unique dysregulation of desmosomal proteins. The identification of plasma biomarkers associated with ACM underscores their potential to improve diagnostic accuracy and facilitate early intervention strategies. Further exploration of mutations in desmosomal proteins and their phosphorylation states may provide deeper insights into the pathophysiology of ACM.

PMID:39859087 | DOI:10.3390/medicina61010105

Microorganisms. 2025 Jan 16;13(1):176. doi: 10.3390/microorganisms13010176.

ABSTRACT

Antibiotic resistance is on the WHO's top 10 list of global public health threats due to its rapid emergence and spread but also because of the high morbidity and mortality associated with it. Amongst the main species driving this phenomenon is A. baumannii, a member of the ESKAPE group of medical assistance-associated infections causing species famous for its extensively drug-resistant phenotypes. Our findings note a 91.52% frequency of extensively drug-resistant carbapenem-resistant A. baumannii (XDR CRAB) phenotype amongst clinical isolates from multiple hospitals in two major cities from northwestern and central Romania, harboring multiple antibiotic resistance genes such as blaOXA-23-like in 108 (91.5%) isolates, blaOXA-24/40-like in 88 (74.6%) isolates, blaNDM in 29 (25%) isolates, ArmA in 75 (63.6%) isolates, and ant(3″)-I in 69 (58.5%) isolates and sul1 in 113 (95.76%) isolates. The isolates, although nearly identical in phenotype, displayed different genotypical profiles, with varying degrees of similarity across hospitals and cities, raising the possibility of both local outbreaks of a single clone and widespread dissemination of resistant isolates.

PMID:39858944 | DOI:10.3390/microorganisms13010176

Genes (Basel). 2024 Dec 29;16(1):37. doi: 10.3390/genes16010037.

ABSTRACT

Background/Objectives: Salivary gland carcinomas encompass a broad group of malignant lesions characterized by varied prognoses. Stem cells have been associated with the potential for self-renewal and differentiation to various subpopulations, resulting in histopathological variability and diverse biological behavior, features that characterize salivary gland carcinomas. This study aims to provide a thorough systematic review of immunohistochemical studies regarding the expression and prognostic significance of stem cell markers between different malignant salivary gland tumors (MSGTs). Methods: The English literature was searched via the databases MEDLINE/PubMed, EMBASE via OVID, Web of Science, Scopus, and CINHAL via EBSCO. The Joanna Briggs Institute Critical Appraisal Tool was used for risk of bias (RoB) assessment. Meta-analysis was conducted for markers evaluated in the same pair of diseases in at least two studies. Results: Fifty-four studies reported the expression of stem cell markers, e.g., c-KIT, CD44, CD133, CD24, ALDH1, BMI1, SOX2, OCT4, and NANOG, in various MSGTs. Low, moderate, and high RoB was observed in twenty-five, eleven, and eighteen studies, respectively. Meta-analysis revealed an outstanding discriminative ability of c-KIT for adenoid cystic carcinoma (AdCC) over polymorphous adenocarcinoma [P(LG)A] but did not confirm the prognostic significance of stem cell markers in MSGTs. Conclusions: This study indicated a possible link between stem cells and the histopathological heterogeneity and diverse biological behavior that characterize the MSGTs. c-KIT might be of diagnostic value in discriminating between AdCC and P(LG)A.

PMID:39858584 | DOI:10.3390/genes16010037

Genes (Basel). 2024 Dec 25;16(1):11. doi: 10.3390/genes16010011.

ABSTRACT

BACKGROUND/OBJECTIVES: A prominent endophenotype in Autism Spectrum Disorder (ASD) is the synaptic plasticity dysfunction, yet the molecular mechanism remains elusive. As a prototype, we investigate the postsynaptic signal transduction network in glutamatergic neurons and integrate single-cell nucleus transcriptomics data from the Prefrontal Cortex (PFC) to unveil the malfunction of translation control.

METHODS: We devise an innovative and highly dependable pipeline to transform our acquired signal transduction network into an mRNA Signaling-Regulatory Network (mSiReN) and analyze it at the RNA level. We employ Cell-Specific Network Inference via Integer Value Programming and Causal Reasoning (CS-NIVaCaR) to identify core modules and Cell-Specific Probabilistic Contextualization for mRNA Regulatory Networks (CS-ProComReN) to quantitatively reveal activated sub-pathways involving MAPK1, MKNK1, RPS6KA5, and MTOR across different cell types in ASD.

RESULTS: The results indicate that specific pivotal molecules, such as EIF4EBP1 and EIF4E, lacking Differential Expression (DE) characteristics and responsible for protein translation with long-term potentiation (LTP) or long-term depression (LTD), are dysregulated. We further uncover distinct activation patterns causally linked to the EIF4EBP1-EIF4E module in excitatory and inhibitory neurons.

CONCLUSIONS: Importantly, our work introduces a methodology for leveraging extensive transcriptomics data to parse the signal transduction network, transforming it into mSiReN, and mapping it back to the protein level. These algorithms can serve as potent tools in systems biology to analyze other omics and regulatory networks. Furthermore, the biomarkers within the activated sub-pathways, revealed by identifying convergent dysregulation, illuminate potential diagnostic and prognostic factors in ASD.

PMID:39858558 | DOI:10.3390/genes16010011

Biomolecules. 2025 Jan 9;15(1):89. doi: 10.3390/biom15010089.

ABSTRACT

Amylin and amyloid β belong to the same protein family and activate the same receptors. Amyloid β levels are elevated in Alzheimer's disease. Recent studies have demonstrated that amylin-based peptides can reduce the symptoms of Alzheimer's disease in animal models. Replica exchange molecular dynamics simulation machine learning, as well as other computational analyses, were applied to improve the understanding of the amino acid residues in these amylin-based peptides. Comparisons were made between amylin, amylin-based peptides, and amyloid β. These studies converged on amylin residues 10Q, 28S, 29S, 30T, 31N, 32V, 33G, 34S, and 35N (residues 10 and 28-35) being ranked highest, meaning that they were the most likely to be involved in activating the same targets as amyloid β. Surprisingly, the amyloid β signaling domain most closely matched amylin residues 29-35 in the simulated structures. These findings suggest important residues that are structurally similar between amylin and amyloid β and are thus implicated in the activation of the amylin receptor.

PMID:39858483 | DOI:10.3390/biom15010089

Biomolecules. 2024 Dec 24;15(1):1. doi: 10.3390/biom15010001.

ABSTRACT

This study examines the prevalence and the mechanisms of antibiotic resistance in Pseudomonas aeruginosa isolates collected from healthcare units in Northwestern Transylvania, Romania, between 2022 and 2023. Given the alarming rise in antibiotic resistance, the study screened 34 isolates for resistance to 10 antibiotics, 46 ARGs, and integrase genes using PCR analysis. The results reveal a concerning increase in multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates over the two-year period. Notably, the prevalence of ARGs encoding resistance to sulfonamides and beta-lactams, particularly sul1 and blaOXA-50, has shown a significant rise. Furthermore, the study detected the emergence of new resistance mechanisms in the same time interval. These include target protection and even more specific mechanisms, such as metallo-beta-lactamases or enzymes involved in the methylation of 23S rRNA. Statistical analysis further confirmed the correlation between Class I integrons and several ARGs, underscoring the role of horizontal gene transfer in the dissemination of resistance. These findings emphasize the urgent need for updated treatment strategies and monitoring programs to effectively combat the spread of ARGs in clinical settings.

PMID:39858396 | DOI:10.3390/biom15010001

Antioxidants (Basel). 2025 Jan 11;14(1):80. doi: 10.3390/antiox14010080.

ABSTRACT

Glucosinolates (GSLs) are nitrogen/sulfur-containing glycosides widely present in the order of Brassicales, particularly in the Brassicaceae family. Camelina (Camelina sativa (L.) Crantz) is an oilseed plant belonging to this family. Its seeds, in addition to a distinctive fatty acid composition, contain three aliphatic GSLs: glucoarabin, glucocamelinin, and homoglucocamelinin. Our study explored the impact of these GSLs purified from Camelina press cake, a by-product of Camelina oil production, on yeast chronological aging, which is the established model for simulating the aging of post-mitotic quiescent mammalian cells. Supplementing yeast cells with GSLs extends the chronological lifespan (CLS) in a dose-dependent manner. This enhancement relies on an improved mitochondrial respiration efficiency, resulting in a drastic decrease of superoxide anion levels and an increase in ATP production. Furthermore, GSL supplementation affects carbon metabolism. In particular, GSLs support the pro-longevity preservation of TCA cycle enzymatic activities and enhanced glycerol catabolism. These changes contribute positively to the phosphorylating respiration and to an increase in trehalose storage: both of which are longevity-promoting prerequisites.

PMID:39857414 | DOI:10.3390/antiox14010080

J Clin Med. 2025 Jan 9;14(2):377. doi: 10.3390/jcm14020377.

ABSTRACT

Background: Rigid bronchoscopy (RB) is the gold standard for managing central airway obstruction (CAO), a life-threatening condition caused by both malignant and benign etiologies. Anesthetic management is challenging as it requires balancing deep sedation with maintaining spontaneous breathing to avoid airway collapse. There is no consensus on the optimal anesthetic approach, with options including general anesthesia with neuromuscular blockers or spontaneous assisted ventilation (SAV). Methods: This case series presents our anesthetic protocol using remifentanil-propofol-ketamine total intravenous anesthesia (TIVA) with SAV in four patients with airway obstructions. Muscle relaxants were avoided in all cases. Results: Ketamine's ability to preserve respiratory drive and airway reflexes, along with its bronchodilating properties, made it ideal for managing CAO. All procedures successfully restored airway patency without complications or drug-related side effects. Conclusions: Our findings suggest that remifentanil-propofol-ketamine TIVA combined with SAV is a viable anesthetic approach for therapeutic RB, offering effective sedation, maintaining airway patency, and minimizing perioperative complications.

PMID:39860383 | DOI:10.3390/jcm14020377

Molecules. 2025 Jan 10;30(2):260. doi: 10.3390/molecules30020260.

ABSTRACT

Drug development faces significant financial and time challenges, highlighting the need for more efficient strategies. This study evaluated the druggability of the entire human proteome using Fpocket. We identified 15,043 druggable pockets in 20,255 predicted protein structures, significantly expanding the estimated druggable proteome from 3000 to over 11,000 proteins. Notably, many druggable pockets were found in less studied proteins, suggesting untapped therapeutic opportunities. The results of a pairwise pocket similarity analysis identified 220,312 similar pocket pairs, with 3241 pairs across different protein families, indicating shared drug-binding potential. In addition, 62,077 significant matches were found between druggable pockets and 1872 known drug pockets, highlighting candidates for drug repositioning. We repositioned progesterone to ADGRD1 for pemphigus and breast cancer, as well as estradiol to ANO2 for shingles and medulloblastoma, which were validated via molecular docking. Off-target effects were analyzed to assess the safety of drugs such as axitinib, linking newly identified targets with known side effects. For axitinib, 127 new targets were identified, and 46 out of 48 documented side effects were linked to these targets. These findings demonstrate the utility of pocket similarity in drug repositioning, target expansion, and improved drug safety evaluation, offering new avenues for the discovery of new indications and side effects of existing drugs.

PMID:39860130 | DOI:10.3390/molecules30020260

Int J Mol Sci. 2025 Jan 13;26(2):622. doi: 10.3390/ijms26020622.

ABSTRACT

To enhance the treatment of tumors that are resistant to radio- and chemotherapy while minimizing the side effects of radiochemotherapy, researchers are continuously seeking new active compounds for use in combination with radiotherapy. Therefore, the aim of our study was to examine the cytotoxic and radiosensitizing effects of an extract from St. John's Wort (Hypericum perforatum), referred to as HP01, on human epithelial tumor cells in vitro. The growth of MCF-7 (breast carcinoma) and HT-29 (colon carcinoma) cells was examined under the influence of HP01. In combination with radiation, the effects of HP01 on cytotoxicity and long-term survival were assessed using a colony formation assay. The number of DNA double-strand breaks was analyzed using the γH2AX assay, while cell cycle distribution was examined via flow cytometry. A growth-inhibiting and cytotoxic effect was observed for both tumor cell lines starting at a concentration of 10 µg/mL HP01. Treatment with HP01 resulted in an inhibition of clonogenic survival of tumor cells after ionizing radiation (6 Gy). The number of DNA double-strand breaks (DSBs) in tumor cells increased with HP01 treatment, but the repair of radiation-induced DNA DSBs was not affected. Cell cycle analysis revealed that HP01, in addition to radiation, enhanced G2/M arrest in MCF-7 and HT-29 cells. Overall, HP01 not only showed a growth-inhibiting effect but also demonstrated a radiosensitizing effect on human tumor cells for the first time. We conclude that the HP01-induced G2/M accumulation of cells may be the main rationale for the drug-induced radiosensitivity. It is therefore a promising candidate for combined therapy in tumor diseases and warrants further investigation.

PMID:39859336 | DOI:10.3390/ijms26020622

Medicina (Kaunas). 2025 Jan 14;61(1):123. doi: 10.3390/medicina61010123.

ABSTRACT

Background and Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but their use is associated with a spectrum of immune-related adverse events (irAEs), including endocrine disorders. This study aims to investigate the incidence, timing, treatment modalities, and impact of ICI-related endocrine side effects in cancer patients. Materials and Methods: This retrospective study analyzed 139 cancer patients treated with ICIs between 2016 and 2022. Data regarding endocrine irAEs, including hypothyroidism, hyperthyroidism, hypophysitis, and diabetes mellitus, were collected. The study examined the timing of irAE onset, management approaches, and the association between irAEs and treatment outcomes. Results: The most common endocrine irAE was hypothyroidism (65.5%), followed by hyperthyroidism (2.3%), hypophysitis (8.6%), and diabetes mellitus (0.7%). These disorders typically emerged within the first six months of ICI therapy. Most cases were managed conservatively or with hormone replacement therapy. Patients who developed endocrine irAEs exhibited a higher objective response rate (ORR) and clinical benefit rate (CBR) compared to those without irAEs. Conclusions: Endocrine dysfunction is a significant toxicity of ICI therapy. Early recognition, prompt diagnosis, and appropriate management are crucial to minimize their impact on patient health and quality of life. This study highlights the potential association between irAEs and improved clinical outcomes. Further research is needed to elucidate the underlying mechanisms and identify predictive biomarkers for irAE development.

PMID:39859105 | DOI:10.3390/medicina61010123

Diagnostics (Basel). 2025 Jan 17;15(2):205. doi: 10.3390/diagnostics15020205.

ABSTRACT

Drug-induced gingival overgrowth is associated with various systemic diseases, including epilepsy. Among antiepileptic medications, phenytoin is commonly reported to cause this condition. In contrast, sodium valproate (VPA), another widely used antiepileptic drug, rarely induces gingival overgrowth. This difference in side effects highlights the variability in drug-induced oral complications among different antiepileptic medications. This case study presents a patient who developed significant gingival overgrowth after using VPA for over 10 years. The study aims to identify VPA as the causative agent and observe changes during long-term administration and after dose reduction. Our findings demonstrate that even long-standing gingival overgrowth can improve rapidly following discontinuation of the causative medication, providing valuable insights for managing similar cases in the future.

PMID:39857089 | DOI:10.3390/diagnostics15020205

BMC Cancer. 2025 Jan 24;25(1):139. doi: 10.1186/s12885-025-13566-6.

ABSTRACT

BACKGROUND: Patients who developed immune-related adverse events (irAEs) could benefit more from treatment with immune checkpoint inhibitors (ICIs) than those who did not develop irAEs. This study was designed to assess whether the occurrence of irAEs or their characteristics are correlated with survival in advanced patients treated with ICIs.

METHODS: This retrospective cohort study enrolled a panel of cancer patients who received ICIs at a single institute. Kaplan‒Meier curves were generated to describe progression-free survival (PFS) and overall survival (OS) in patients with irAEs or specific irAE characteristics.

RESULTS: A total of 238 patients were enrolled, 83 (34.9%) of whom developed at least one irAE. Overall, irAE development was associated with prolonged OS (not reached vs. 17.8 months, P < 0.001), PFS (8.7 vs. 4.8 months, P = 0.003), and an improved objective response rate (24.1% vs. 10.3%, P = 0.005). Furthermore, only skin or endocrine toxicities were associated with improved OS and PFS. On the basis of the results from organ-specific irAEs, the first development of skin or endocrine toxicities as protective irAEs rather than other irAEs was an independent indicator for predicting OS (P < 0.001) and PFS (P < 0.001). A protective irAE burden score based on organ-specific irAEs was further developed to show the significant protective effect of total irAEs on patient outcomes.

CONCLUSIONS: Not all irAEs are associated with prolonged survival. The identification of organ-specific irAEs is useful for stratifying patients who actually respond to and benefit from ICIs across different cancer types.

PMID:39856626 | DOI:10.1186/s12885-025-13566-6

J Neurol Sci. 2025 Mar 15;470:123395. doi: 10.1016/j.jns.2025.123395. Epub 2025 Jan 14.

ABSTRACT

OBJECTIVE: Rare neurologic diseases (RNDs) are difficult to diagnose and treat due to their low prevalence and complex nature. This survey evaluated awareness and current care status of RNDs among esteemed neurologists affiliated with the World Federation of Neurology (WFN).

METHODS: A 34-question survey was distributed to renowned neurologists, including delegates from national neurology societies in the WFN Assembly, various WFN committees, and members of the Rare Neurologic Diseases Specialist group. Responses were stratified by geographical regions, including Africa, the Americas, Asia/Oceania, and Europe, and into four income groups based on the World Bank Indicator. Descriptive statistics summarized responses, stratified by geographical regions or income groups, and significant differences were assessed by Fisher's exact test.

RESULTS: Of 190 invited neurologists, 64 responded (34 % response rate). Among respondents, 89 % agreed that RND patients should receive timely and effective care on par with more common neurological conditions. Additionally, 77 % of respondents overall thought most RNDs could be accurately diagnosed in their country. However, there were significant differences in the perceived ability of respondents' country of practice to diagnose RNDs by region, specifically in Africa (25 %), and by income of country of practice, specifically in the lower-income group (17 %).

CONCLUSIONS: This global survey highlights varying RND diagnosis and care by country socioeconomic status, suggesting potential disparities in resources and preparedness. To improve outcomes and quality-of-life for RND patients, efforts should focus on improving diagnostic capabilities, fostering collaboration among neurology centers, and promoting education on the unique challenges and treatment options of RNDs.

PMID:39855013 | DOI:10.1016/j.jns.2025.123395

Vaccines (Basel). 2024 Dec 29;13(1):19. doi: 10.3390/vaccines13010019.

ABSTRACT

Safeguarding patients from emerging infectious diseases demands strategies that prioritise patient well-being and protection. Immunobridging is an established trial methodology which has been increasingly employed to ensure patient protection and provide clinicians with swift access to vaccines. It uses immunological markers to infer the effectiveness of a new drug through a surrogate measure of efficacy. Recently, this method has also been employed to authorise novel drugs, such as COVID-19 vaccines, and this article explores the concepts behind immunobridging trials, their advantages, issues, and significance in the context of COVID-19 and other infectious diseases. Our goal is to improve awareness among clinicians, patient groups, regulators, and health leaders of the opportunities and issues of immunobridging, so that fewer patients are left without protection from infectious diseases, particularly from major pathogens that may emerge.

PMID:39852798 | PMC:PMC11768488 | DOI:10.3390/vaccines13010019

Eur J Pharm Biopharm. 2025 Jan 22:114636. doi: 10.1016/j.ejpb.2025.114636. Online ahead of print.

ABSTRACT

Recent developments in pharmacogenetics have emphasised the importance of customised medication, driving interest in technologies like FDM 3D-printing for tailored drug delivery. FDM 3D-printing is a promising technique for the on-demand manufacturing of customised oral dosage forms, providing flexibility in terms of shape and size, dose and drug release profiles. This study investigates the fabrication and characterisation of 3D-printed oral dosage forms using PEO as the primary polymer and PEG 6 K as a plasticiser. Firstly, the printability of the PEO filaments with different propranolol hydrochloride concentrations was explored using the hot-melt extrusion technology. The influence of the propranolol hydrochloride concentrations on the mechanical properties of the filaments was examined was then examined after which surface characteristics, including roughness and wettability, were evaluated. Dissolution imaging was used to visualise the effects of drug content on the swelling and dissolution characteristics of the PEO-based 3D-printed tablets. Results showed a reduction in the flexural stress of the filaments with increasing drug load. It was also observed that increasing the drug load led to higher surface roughness and lower contact angles of the 3D-printed PEO tablets, implying increased surface hydrophilicity. The swelling behaviour of the tablets increased with higher drug concentrations, resulting in a larger gel layer formation. When comparing the drug release percentages, the release rate was higher in the 10 mg propranolol tablets, suggesting that a lower drug content led to a faster release. The greater gel layer of the 40 mg PPN tablets hindered the drug release by acting as a diffusion barrier, while the 10 mg PPN tablets, with less swelling and gel formation, experienced a faster drug release. These findings show the importance of drug content in modifying the surface properties, swelling behaviour, and drug release profiles of 3D-printed PEO tablets. The study also demonstrates the novel use of dissolution imaging for 3D-printed dosage forms, providing valuable quantitative and qualitative insights into swelling dynamics and channel formation to optimise 3D-printed tablets for drug delivery systems.

PMID:39855578 | DOI:10.1016/j.ejpb.2025.114636

Epilepsy Behav. 2025 Jan 23;164:110272. doi: 10.1016/j.yebeh.2025.110272. Online ahead of print.

ABSTRACT

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy marked by drug-resistant seizures and profound cognitive and behavioral impairments, with nearly 95% of individuals affected by moderate to severe intellectual disability. This review comprehensively explores the cognitive and behavioral impacts of current treatment options for LGS, including antiseizure medications (ASMs), neuromodulation strategies, the ketogenic diet, and surgical interventions. Given the limited availability of LGS-specific data for several ASMs, the evidence base is supplemented with findings from general epilepsy populations and individuals with epilepsy and intellectual disabilities. The evidence reveals that ASMs exert varied cognitive and behavioral effects in LGS. Medications such as valproate, lamotrigine, cannabidiol, fenfluramine, levetiracetam, brivaracetam, felbamate, and rufinamide generally support cognitive stability, while topiramate and zonisamide are associated with cognitive challenges. Behavioral outcomes also vary: stability is observed with valproate, lamotrigine, rufinamide, cannabidiol, and fenfluramine, whereas medications like levetiracetam, perampanel, brivaracetam, clobazam, and zonisamide can increase aggression or irritability. Nonpharmacological therapies, particularly when they reduce seizure frequency, typically provide greater cognitive and behavioral stability, with some offering improvement. Early intervention-especially through surgical options-appears most beneficial for preserving cognitive function. Additionally, therapies such as the ketogenic diet and neuromodulation may provide independent cognitive benefits beyond seizure control. This review emphasizes the importance of personalized treatment strategies, integrating cognitive and behavioral evaluations in therapy selection. Key components include baseline cognitive and behavioral assessments, followed by regular follow-up evaluations, particularly after therapy changes. Consideration of minimizing ASM polytherapy, careful evaluation of drug-drug interactions, pharmacogenomic implications, and the need for therapeutic drug monitoring in cases of cognitive adverse effects is essential. Future research should focus on developing assessment tools tailored to the unique needs of individuals with LGS, utilizing connectivity measures to assess intervention impacts, and advancing precision therapeutics to improve cognitive and behavioral outcomes.

PMID:39854829 | DOI:10.1016/j.yebeh.2025.110272