Search Results (948)

Membrane transporters play a crucial role in any cell. Identifying the substrates they translocate across membranes is important for many fields of research, such as metabolomics, pharmacology, and biotechnology. In this study, we leverage recent advances in deep learning, such as amino acid sequence embeddings with protein language models (pLMs), highly accurate 3D structure predictions with AlphaFold 2, and structure-encoding 3Di sequences from FoldSeek, for predicting substrates of membrane transporters. We test new deep learning features derived from both sequence and structure, and compare them to the previously best-performing protein encodings, which were made up of amino acid k-mer frequencies and evolutionary information from PSSMs. Furthermore, we compare the performance of these features either using a previously developed SVM model, or with a regularized feedforward neural network (FNN). When evaluating these models on sugar and amino acid carriers in A. thaliana, as well as on three types of ion channels in human, we found that both the DL-based features and the FNN model led to a better and more consistent classification performance compared to previous methods. Direct encodings of 3D structures with Foldseek, as well as structural embeddings with ProstT5, matched the performance of state-of-the-art amino acid sequence embeddings calculated with the ProtT5-XL model when used as input for the FNN classifier. Full article

Efflux is one of the key mechanisms used by Gram-negative bacteria to reduce internal antibiotic concentrations. These active transport systems recognize and expel a wide range of toxic molecules, including antibiotics, thereby contributing to reduced antibiotic susceptibility and allowing the bacteria to acquire additional resistance mechanisms. To date, unlike other resistance mechanisms such as enzymatic modification or target mutations/masking, efflux is challenging to detect and counteract in clinical settings, and no standardized methods are currently available to diagnose or inhibit this mechanism effectively. This review first outlines the structural and functional features of major efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. It then explores various strategies used to curb their activity, with a particular focus on efflux pump inhibitors under development, detailing their structural classes, modes of action, and pharmacological potential. We discuss the main obstacles to their development, including the structural complexity and substrate promiscuity of efflux mechanisms, the limitations of current screening methods, pharmacokinetic and tissue distribution issues, and the risk of off-target toxicity. Overcoming these multifactorial barriers is essential to the rational development of less efflux-prone antibiotics or of efflux pump inhibitors. Full article

Objectives: To assess the role of a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program of isavuconazole in preventing under- or overexposure with the intent of improving efficacy and safety outcomes in the critically ill patients. Methods: This retrospective study included critical patients receiving intravenous isavuconazole for prophylaxis or treatment of invasive fungal infections (IFI) and undergoing at least one TDM-guided ECPA in the period 1 March 2021–31 March 2025. Desired isavuconazole exposure was defined as trough concentrations (C_min) of 1.0–5.1 mg/L. Efficacy outcome was assessed by means of bronchoalveolar (BAL) galactomannan (GM) index, breakthrough IFI, and 30-day mortality rate, whereas safety was assessed by means of hepatic test disturbances (HTD). Univariate analysis was carried out for assessing potential variables associated with isavuconazole under- or overexposure and for comparing features of solid organ transplant (SOT) recipients vs. non-SOT patients. Proportions of isavuconazole C_min underexposure, desired exposure, and overexposure were assessed at different timepoints from starting therapy. Trends over time of HTD in relation to isavuconazole exposure were assessed separately in patients having HTD or not at baseline. Results: Overall, 32 critical patients were included. A total of 166 TDM-guided ECPAs were provided. Median (IQR) average isavuconazole C_min was 3.5 mg/L (2.1–4.6 mg/L). Proportions of ECPAs with isavuconazole C_min under- and overexposure were 4.2% (7/166) and 16.3% (27/166), respectively. Patients experiencing underexposure had higher body mass index (30.1 vs. 25.5 kg/m²; p < 0.001). Trends of isavuconazole C_min under- and overexposure changed over time, significantly decreasing the former (10.5% <7 days vs. 4.3% 7–28 days vs. 0.0% >28 days; p < 0.001) and increasing the latter (5.3% <7 days vs. 12.8% 7–28 days vs. 29.3% >28 days; p < 0.001). HTD occurred in 15/32 patients, most of whom (10/15) were affected just at baseline. Patients with transient or persistent overexposure trended toward a higher risk of HTD compared to those without (33.3% vs. 8.3%; p = 0.11). Conclusions: A real-time TDM-guided approach could be a valuable tool for optimizing isavuconazole exposure, especially whenever dealing with obese patients or with prolonged treatment. Full article

Ricinus communis (Euphorbiaceae), commonly known as the castor oil plant, is prized for its versatile applications in medicine, industry, and agriculture. It features large, deeply lobed leaves with vibrant colours, robust stems with anthocyanin pigments, and extensive root systems for nutrient absorption. Its terminal panicle-like inflorescences bear monoecious flowers, and its seeds are enclosed in prickly capsules. Throughout its various parts, R. communis harbours a diverse array of bioactive compounds. Leaves contain tannins, which exhibit astringent and antimicrobial properties, and alkaloids like ricinine, known for anti-inflammatory properties, as well as flavonoids like rutin, offering antioxidant and antibacterial properties. Roots contain ellagitannins, lupeol, and indole-3-acetic acid, known for anti-inflammatory and liver-protective effects. Seeds are renowned for ricin, ricinine, and phenolic compounds crucial for industrial applications such as biodegradable polymers. Pharmacologically, it demonstrates antioxidant effects from flavonoids and tannins, confirmed through minimum inhibitory concentration (MIC) assays for antibacterial activity. It shows potential in managing diabetes via insulin signalling pathways and exhibits anti-inflammatory properties by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Additionally, it has anti-fertility effects and potential anticancer activity against cancer stem cells. This review aims to summarize Ricinus communis’s botanical properties, therapeutic uses, chemical composition, pharmacological effects, and industrial applications. Integrating the current knowledge offers insights into future research directions, emphasizing the plant’s diverse roles in agriculture, medicine, and industry. Full article

Background/Objectives: Tension-type headache (TTH) is the most prevalent form of primary headache. The etiology of TTH is not yet fully understood, although it is associated with the presence of myofascial trigger points (MTPs) in cervical and facial muscles. Dry needling (DN) therapy has emerged as an effective and safe non-pharmacological option for pain relief, but there are a lack of systematic reviews focused on its specific characteristics in TTH. The aim of this paper is to examine the characteristics and methodologies of DN in managing TTH. Methods: A scoping review was conducted with inclusion criteria considering studies that evaluated DN interventions in adults with TTH, reporting target muscles, diagnostic criteria, and technical features. The search was performed using PubMed, Embase, Scopus, and the Web of Science, resulting in the selection of seven studies after a rigorous filtering and evaluation process. Results: The included studies, primarily randomized controlled trials, involved a total of 309 participants. The most frequently treated muscles were the temporalis and trapezius. Identification of MTPs was mainly performed through manual palpation, although diagnostic criteria varied. DN interventions differed in technique. All studies included indicated favorable outcomes with improvements in headache symptoms. No serious adverse effects were reported, suggesting that the technique is safe. However, heterogeneity in protocols and diagnostic criteria limits the comparability of results. Conclusions: The evidence supports the use of DN in key muscles such as the temporalis and trapezius for managing TTH, although the diversity in methodologies and diagnostic criteria highlights the need for standardization. The safety profile of the method is favorable, but further research is necessary to define optimal protocols and improve reproducibility. Implementing objective diagnostic criteria and uniform protocols will facilitate advances in clinical practice and future research, ultimately optimizing outcomes for patients with TTH. Full article

Intimal hyperplasia (IH) compromises the patency of arteriovenous fistula (AVF) vascular access in patients with end-stage kidney disease. Uncontrolled cell proliferation and migration, driven by inflammation, shear stress and surgery, are well-known triggers in IH. Recently, microRNAs (miRNAs) have emerged as regulators of core mechanisms in cardiovascular diseases and as potential markers of IH. This study was aimed at identifying a specific miRNA panel in failed AVFs and clarifying the miRNA involvement in IH. miRNA profiling performed in tissues from patients with IH (AVFs) and normal veins (NVs) highlighted a subset of four miRNAs significantly deregulated (hsa-miR-155-5p, hsa-miR-449a-5p, hsa-miR-29c-3p, hsa-miR-194-5p) between the two groups. These miRNAs were analyzed in tissue-derived cells (NVCs and AVFCs), human aortic smooth muscle cells (HAOSMCs) and human umbilical vein endothelial cells (HUVECs). The panel of hsa-miR-449a-5p, hsa-miR-155-5p, hsa-miR-29c-3p and hsa-miR-194-5p was up-regulated in AVFCs, HAOSMCs and HUVEC under inflammatory stimuli. Notably, overexpression of hsa-miR-449a-5p exacerbated the proliferative, migratory and inflammatory features of AVFCs. In vitro pharmacological modulation of these miRNAs with pioglitazone, particularly the down-regulation of hsa-miR-155-5p and hsa-miR-29c-3p, suggested their involvement in IH pathogenesis and a potential translational application. Overall, these findings provide new insights into the pathogenesis of AVF failure, reinforcing the miRNA contribution to IH detection and prevention. Full article

Epilepsy remains a major therapeutic challenge, with approximately one-third of patients experiencing drug-resistant epilepsy (DRE) despite the availability of multiple antiseizure medications (ASMs). This review aims to evaluate emerging ASMs—cenobamate, fenfluramine, ganaxolone, ezogabine (retigabine), and perampanel—with a focus on their mechanisms of action, pharmacological profiles, and potential role in precision medicine. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify preclinical and clinical studies evaluating the pharmacodynamics, pharmacokinetics, efficacy, and safety of the selected ASMs. Relevant trials, reviews, and mechanistic studies were reviewed to synthesize the current understanding of their application in DRE and specific epilepsy syndromes. Each ASM demonstrated unique mechanisms targeting hyperexcitability, including the modulation of γ-aminobutyric acid receptor A (GABA-A) receptors, sodium and potassium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptors), and serotonin systems. These mechanisms correspond with specific pathophysiological features in syndromes such as Dravet and Lennox–Gastaut. Evidence from clinical trials supports their use as adjunctive therapies with generally favorable tolerability, though adverse events and variable efficacy profiles were noted. The mechanistic diversity of these emerging ASMs supports their value in personalized epilepsy management, particularly in treatment-resistant cases. While the promise of precision medicine is evident, further studies are required to address challenges related to long-term safety, cost, and equitable access. Full article

Exocarpium Citrus grandis is a traditional Chinese medicinal and edible herb whose pharmacological efficacy is closely tied to its aging duration. The accurate discrimination of aging years is essential for quality control but remains challenging due to limitations in current analytical techniques. This study proposes a novel feature-optimized classification framework that integrates hyperspectral imaging (HSI) with a Broad Learning System (BLS). Bilateral spectral data (side A and side B) were collected to capture more comprehensive sample information. A combination of normalization (NOR) preprocessing and the Iterative Variable Importance for Spectral Subset Selection Algorithm (iVISSA) was found to be optimal. The NOR–iVISSA–BLS model achieved classification accuracies of 94.09 ± 1.01% (side A) and 95.10 ± 0.82% (side B). Furthermore, cross-validation between the two sides (A→B: 94.92%, B→A: 94.11%) confirmed the model’s robustness and generalizability. This dual-side spectral validation strategy offers a rapid, nondestructive, and reliable solution for the vintage authentication of Exocarpium Citrus grandis, contributing to the modernization of quality control in medicinal foodstuffs. Full article

Cognitive impairment is a prevalent and disabling feature of multiple sclerosis (MS), significantly impacting patients’ quality of life (QoL) and psychological well-being. Despite its clinical relevance, there are currently no approved pharmacological treatments for cognitive deficits in MS, highlighting the need for effective non-pharmacological interventions. This narrative review explores evidence from studies evaluating the efficacy of cognitive re-education (CR) approaches (including traditional, group-based, computer-assisted, virtual reality, and innovative methods such as music therapy) on cognitive and QoL outcomes in people with MS. The findings demonstrate that while CR consistently influences cognitive domains such as memory, attention, and executive function, its effects on QoL are more variable and often depend on intervention type, duration, and individual patient characteristics. Notably, integrative approaches like virtual reality and music therapy show promising results in enhancing both cognitive performance and psychosocial well-being. Several studies report that cognitive gains are accompanied by improvements in mental health and functional QoL, particularly when interventions are tailored to individual needs and delivered within multidisciplinary frameworks. However, some interventions yield only limited or transient QoL benefits, underlining the importance of personalized, goal-oriented strategies that address both cognitive and psychosocial dimensions. Further research is needed to optimize intervention strategies and clarify the mechanisms linking cognitive and QoL outcomes. Full article

Monoterpene indole alkaloids (MIAs) exhibit diverse structures and pharmacological effects. Annotating MIAs in herbal medicines remains challenging when using liquid chromatography combined with high-resolution mass spectrometry (LC-HRMS). This study introduced a new annotation strategy employing LC-HRMS to efficiently identify MIAs in herbal medicines. Briefly, MS² spectra under multiple collision energies (MCEs/MS²) helped capture high-quality product ions across a range of mass-to-charge (m/z) values, revealing key MS² features such as diagnostic product ions (DPIs), characteristic cleavages (CCs), and neutral/radical losses (NLs/RLs). Next, feature-based molecular networking (FBMN) was created to map the structural relationships among MIAs across large MS datasets. Potential MIAs were then graded and annotated through systematic comparison with known biosynthetic pathways (BPs), derived skeletons, and their characteristic substituents. The MCEs/MS²-FBMN/BPs workflow was first applied to annotate MIAs in the alkaloids from the leaf of Alstonia scholaris (ALAS), a new botanical drug for respiratory diseases. A total of 229 MIAs were systematically annotated and classified, forming a solid basis for future clinical research on ALAS. This study offers an effective strategy that enhances the structural annotation of MIAs within complex herbal medicines. Full article

Boronic acids are an important class of molecules diversely used in organic synthesis, catalysis, medicinal chemistry, and for the design of functional materials. Particularly, aryl boronic acids in the solid state are known to exhibit pharmaceutical and photoluminescent properties for antimicrobial, sensing, and drug delivery applications. Furthermore, the phenazine molecule is known for its diverse pharmacological properties, including antibiotic activity. In the case of molecular crystalline solids, it is well established that understanding noncovalent interactions remains key to designing or engineering their functional properties. While both aryl boronic acids and phenazine molecules individually represent an important class of compounds, their co-assembly in the crystalline state is of interest within the context of supramolecular chemistry and crystal engineering. Herein, we report the supramolecular features of two newly synthesized cocrystals, which are composed of para-F/CF₃-substituted phenylboronic acids, respectively, and phenazine, as demonstrated by structure analysis by single-crystal X-ray diffraction. Full article

Background: Patients with obesity seeking bariatric surgery often display high rates of depressive symptoms, which are linked to worse clinical and surgical outcomes. A comprehensive evaluation of depression-related features in this population is lacking. Therefore, this study investigated clinical and psychopathological factors associated with depressive symptoms’ severity in 946 outpatients with obesity undergoing pre-surgical evaluation. Methods: The sample (45.1 ± 12 years) was subdivided according to Patient Health Questionnaire-9 (PHQ-9) into ‘absent’, ‘mild’, and ‘moderate-to-severe depression’ groups, which were compared for sociodemographic characteristics, childhood trauma, and emotional dysregulation. Assessments included the Childhood Trauma Questionnaire-Short-Form (CTQ-SF) and Difficulties in Emotion Regulation Scales (DERS). Inflammatory levels were evaluated through the Systemic Immune-inflammatory Index (SII). Multinomial logistic regression and correlations were performed to evaluate predictors of depression severity and their interrelationship. Results: Beyond sociodemographic and clinical differences, patients with moderate-to-severe depression displayed higher childhood trauma, emotional dysregulation, and inflammatory levels. Logistic regression with 95% confidence intervals showed that higher CTQ-SF scores were significantly associated with moderate-to-severe vs. absent depression (p = 0.005, 95% CI: 1.02–1.09), while elevated DERS scores were a risk factor for both moderate-to-severe vs. mild (p < 0.001, 95% CI: 1.04–1.11) and vs. absent depression (p < 0.001, 95% CI: 1.11–1.18). Additionally, PHQ-9 was significantly correlated with CTQ-SF, DERS, and SII. Conclusions: A worse clinical picture was observed in patients with moderate-to-severe depression, and significant interactions were found between psychopathology and inflammatory indexes. Emotional dysregulation was primarily associated with depression severity. These preliminary results support the implementation of rigorous pre-operative screening to identify and deliver targeted psychotherapeutic/pharmacological interventions aimed at improving clinical and post-surgical outcomes. Full article

Background: The COVID-19 pandemic has had a profound impact on pediatric mental health, contributing to a global surge in psychiatric emergencies among children and adolescents. This study aimed to evaluate trends in pediatric emergency department (PED) visits for three key psychiatric conditions—anxiety disorders (ADs), self-injury behaviors (SIBs), and psychomotor agitation (PMA)—before and after the onset of the COVID-19 pandemic. Methods: We conducted a retrospective observational study at a tertiary pediatric hospital in Italy, analyzing all psychiatric presentations to the PED from 1 January 2018 to 31 December 2024. The data were divided into pre-COVID and post-COVID periods and included patient demographics, recurrence of visits, clinical features, hospital admissions, and pharmacological management. Diagnoses were confirmed by chart review. Results: Of 233,867 total PED visits, 1082 were due to primary psychiatric concerns. A marked increase in visits was observed postCOVID: SIB incidence rose from 3.6 to 15.1 per 10,000 visits (p < 0.0001), PMA from 9.4 to 17.8 (p < 0.0001), and AD from 17.7 to 21.6 (p = 0.018). SIB cases showed increased recurrence (from 3.4% to 27.4%, p = 0.004) and greater pharmacological intervention, whereas PMA was associated with a rise in heteroaggression (from 14.3% to 39.8%, p < 0.0001). Pharmacological treatment remained largely consistent, with benzodiazepines and neuroleptics most frequently used. The emerging use of intranasal ketamine was noted in select cases. Conclusions: This study highlights the increasing burden of pediatric psychiatric emergencies in the wake of the COVID-19 pandemic. The findings underscore the urgent need to implement standardized emergency care protocols, strengthen outpatient mental health services, and develop pediatric-specific pharmacological guidelines to improve outcomes in this vulnerable population. Full article

Background: Emotional dysregulation (ED) is a transdiagnostic feature of multiple adolescent psychiatric disorders and a predictor of functional impairment and self-harming behaviors. Despite its clinical relevance, pharmacological treatments targeting ED in youth remain underexplored. This retrospective study investigated the clinical effectiveness and tolerability of adjunctive lithium therapy in adolescents with severe ED, independent of specific diagnostic categories. Methods: A total of 35 inpatients (13–17 years) with significant ED were divided into two groups based on pharmacological treatment: lithium add-on therapy (Li group, n = 17) and standard therapy without lithium (Control group, n = 18). Clinical severity (CGI-S) and global functioning (C-GAS) were assessed at baseline (T0), 6 months (T1), and 12 months (T2). A mixed-design ANOVA was performed to assess group × time interactions. Adverse events and treatment adherence were also examined. Results: At T1, the Li group showed a significantly greater reduction in symptom severity (CGI-S) compared to the Control group (p = 0.029). Global functioning (C-GAS) improved over time in both groups (p < 0.001), with no significant interaction effects. Adverse effects, primarily metabolic and endocrine, were more frequent in the Li group but did not reduce adherence. Conclusions: Adjunctive lithium therapy may reduce symptom severity in adolescents with severe ED without negatively affecting treatment tolerability or adherence. These findings support the potential utility of lithium in complex adolescent cases and warrant further prospective research. Full article

Alzheimer’s disease (AD), the most prevalent form of neurodegenerative dementia, is characterized by progressive cognitive decline and neuronal loss. Despite advances in pharmacological treatments, current therapies remain limited in efficacy and often induce adverse effects. Increasing evidence highlights oxidative stress, mitochondrial dysfunction, and disrupted neurotrophic signaling as key contributors to AD pathogenesis. Pulsed electromagnetic fields (PEMFs) are emerging as a non-invasive, multifactorial approach with promising biological effects. In this study, we investigated the neuroprotective potential of PEMFs in NGF-differentiated PC12 cells exposed to hydrogen peroxide (H₂O₂) or amyloid-β peptide (Aβ), both of which model pathological features of AD. PEMF treatment significantly counteracted H₂O₂- and Aβ-induced cytotoxicity by restoring cell viability, reducing reactive oxygen species production, and improving catalase activity. Furthermore, PEMFs preserved the mitochondrial membrane potential and decreased caspase-3 activation and chromatin condensation. Mechanistically, PEMFs inhibited ERK phosphorylation and enhanced cAMP levels, CREB phosphorylation, and BDNF expression, pathways known to support neuronal survival and plasticity. In conclusion, these findings suggest that PEMFs modulate multiple stress response systems, promoting neuroprotection under oxidative and amyloidogenic conditions. Full article