Resistin, initially identified as an adipocyte-derived hormone, is associated with obesity, insulin resistance, and diabetes. However, its role in hippocampal neuronal cells remains unclear. This study aimed to investigate the effects of resistin on neuronal hippocampal cell function. Expression of Retn and its receptors (Ror1, Cap1, and Tlr4) was analysed in mouse hippocampal HT-22 cells using RT-qPCR. The effects of resistin (0.1, 1, and 10 ng/ml) on metabolic activity (alamarBlue), proliferation (BrdU), cell cycle distribution and apoptosis (Annexin V/PI flow cytometry) were evaluated. Expression of apoptosis- (Bax, Bcl2, caspases-3, −8, −9, and p53) and proliferation-related markers (cyclins A2, B1, D1, and E1) was assessed using RT-qPCR and Western blotting. Activation of ERK1/2 pathway and the involvement of ERK1/2 and TLR4 signalling in resistin action were examined using pharmacological inhibitors. HT-22 cells expressed resistin and all three investigated receptors. Resistin decreased cellular metabolic activity at 7 h but increased it at 24 h. It stimulated cell proliferation at both time points and altered the cell cycle distribution after 24 h. At a 1 ng/ml, resistin reduced Ccne1 transcript levels and modulated the levels of cyclins and apoptosis-related markers examined. Moreover, resistin decreased the Bax/Bcl2 ratio at both the mRNA and protein levels after 24 h as well as increased ERK1/2 phosphorylation at 5 h. Pharmacological inhibition of ERK1/2 pathway indicated the involvement of ERK1/2 signalling in the resistin-mediated regulation of metabolic activity and proliferation, while TLR4 signalling was involved in the regulation of Casp3 expression and cell proliferation in HT-22 cells. Resistin may act as a novel regulator of hippocampal neuronal cell function.
Bacterial L-asparaginases are key therapeutics for acute lymphoblastic leukemia (ALL), but their clinical efficacy is limited by off-target L-glutaminase co-activity, which contributes to severe side effects. This study aimed to identify highly specific bacterial L-asparaginases with minimal L-glutaminase co-activity. We screened 85,000 prokaryotic genomes using a workflow integrating AlphaFold2 structure prediction, molecular docking, binding-energy estimation, and molecular dynamics simulations. Six top-ranked enzymes were selected for experimental validation. RhAII protein from Acidobacteriota sp. showed high specificity toward L-asparagine (L-Asn), with a Michaelis constant (KM) of 12 ± 2 µM and turnover number (kcat) of 34 ± 2 s⁻¹, and negligible L-glutaminase activity. Molecular dynamics (MD) simulations revealed a relationship between enzyme activity and the conformational dynamics of the flexible gating element (FGE), characterized by residue-level root mean square fluctuation (RMSF), and L-Asn positional fluctuations, evaluated by ligand root mean square deviation (RMSD) relative to the protein. High L-asparaginase activity was associated with optimal FGE dynamics and low L-Asn RMSD, consistent with stable substrate positioning within the active site. In contrast, enzymes with altered FGE dynamics relative to the reference EcAII enzyme from Escherichia coli, such as PoAII from Planctomycetota sp., showed poor L-asparaginase performance (KM 5797 ± 1143 µM; kcat 1.2 ± 0.1 s⁻¹). Genome- and structure-guided screening identified RhAII as a promising antileukemic candidate for further validation in biological models. A key limitation of the computational workflow was the lack of correlation between predicted substrate binding energies and catalytic efficiency, highlighting the importance of active-site dynamics in enzyme kinetics.
Crohn’s disease (CD) is a chronic inflammatory bowel disorder characterized by a relapsing–remitting course and substantial heterogeneity in clinical presentation. This study aimed to assess the comparative efficacy and safety of approved biologic and small-molecule therapies for CD, with particular emphasis on guselkumab and mirikizumab. A systematic review and frequentist network meta-analysis (NMA) was conducted in accordance with PRISMA-NMA, the Cochrane Handbook, and ISPOR guidelines. MEDLINE, EMBASE, and the Cochrane Library were searched from inception to June 2026. Phase 3 randomized controlled trials (RCTs) evaluating adalimumab, guselkumab, infliximab, mirikizumab, risankizumab, vedolizumab, upadacitinib, or ustekinumab in adults with CD were included. A total of 27 RCTs were included. During induction therapy, guselkumab 400 mg achieved the highest P-scores for both clinical response and remission and was associated with higher odds of these outcomes compared with placebo and several active comparators. Mirikizumab was also more effective than placebo but ranked in the middle of the treatment hierarchy. During maintenance therapy, guselkumab 200 mg and 100 mg achieved the highest rankings for clinical response and remission; however, differences between guselkumab and several active comparators were not statistically significant. These comparisons were predominantly informed by indirect evidence and should not be interpreted as establishing definitive clinical superiority. No consistent evidence of major safety differences was observed across interventions; however, heterogeneity and inconsistency in several safety networks limited the certainty of the comparisons. Although guselkumab achieved favourable rankings for serious adverse events and serious infections, few statistically significant differences were observed between active treatments. The results should be interpreted in the context of indirect comparisons and methodological heterogeneity among included studies. Within the limitations of an NMA based predominantly on indirect evidence, guselkumab achieved the highest rankings for several efficacy outcomes during both induction and maintenance therapy. Mirikizumab showed higher odds of response and remission than placebo, although its node was informed by a single eligible phase 3 study. Given differences in study populations and trial designs, particularly in maintenance studies, these findings should be interpreted cautiously and not as evidence of definitive clinical superiority. Biologic therapies are effective in moderate to severe Crohn’s disease, but comparative evidence between approved agents is limited due to a lack of direct head-to-head trials. This network meta-analysis found that guselkumab had high P-score rankings for several induction and maintenance efficacy outcomes. Mirikizumab showed higher odds of response and remission than placebo, while its comparisons with most active treatments were inconclusive. Most active-treatment comparisons were predominantly based on indirect evidence. These findings provide comparative evidence that may help contextualize treatment options for Crohn’s disease, particularly among IL-23-targeted therapies. However, they should be interpreted alongside trial heterogeneity, prior biologic exposure, patient characteristics, clinical guidelines, and the absence of a formal certainty-of-evidence assessment.
The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) is a first-line pharmacological treatment for mood-related illnesses in the adolescent population – in which girls exhibit approximately twice the risk of being diagnosed with such disorders. Despite increasing FLX prescription rates in adolescents, the potential for unexpected long-term side effects remains poorly understood. To address this issue, we evaluated whether juvenile FLX exposure alters baseline responses to anxiety-inducing environments in adulthood. Adolescent female C57BL/6 mice received FLX (20 mg/kg) for 15 consecutive days (postnatal day [PD] 35–49). Three weeks later, once the mice reached adulthood (PD70), separate groups of mice were evaluated on the novelty suppressed feeding test or the elevated plus maze, two behavioral tasks validated for the assessment of anxiety-related responses. We found that adult female mice with adolescent FLX pre-exposure displayed decreases in body weight and exploratory behavior in the elevated plus maze, along with a longer latency to initiate feeding behavior in the novelty suppressed feeding test, without changes in locomotor activity. Our data show that adolescent exposure to FLX results in anxiety-like phenotypes in adulthood, suggesting that early-life SSRI exposure may induce long-term changes in neural circuits regulating affective-related behavior.
Marine ecosystems are a vast, underexplored reservoir of bioactive compounds with unique structural diversity and potent biological activities. Enveloped viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continue to pose significant global health threats, exacerbated by emerging variants, limited therapeutic options beyond vaccines, and challenges such as drug resistance and immune dysregulation. Compounds derived from marine organisms, including lectins (e.g., griffithsin from red algae Griffithsia sp.), sulfated polysaccharides (e.g., iota-carrageenan from red algae Chondrus crispus), polyphenols (e.g., dieckol from brown algae Ecklonia cava), and depsipeptides (e.g., plitidepsin from tunicates), have shown promising antiviral effects in preclinical studies. These molecules primarily act by inhibiting viral entry (via the spike glycoprotein or glycan binding), replication (targeting proteases such as the main protease [Mpro] and the RNA-dependent RNA polymerase [RdRp]), or by modulating host immune responses (e.g., reducing cytokine storms or oxidative stress). In vitro, in vivo, and in silico evidence highlights their potential against SARS-CoV-2 and related enveloped viruses (e.g., HIV, HSV, influenza, HCMV), which share mechanistic similarities, including envelope-mediated fusion and RNA-based replication. This narrative review provides a cohesive overview of selected marine-derived bioactive compounds with reported activity against SARS-CoV-2 and other enveloped viruses. It examines their sources, structural features, mechanisms of action, key activity metrics (e.g., IC₅₀/EC₅₀ values), and translational prospects, and addresses challenges such as scalability, preclinical-to-clinical gaps, and sustainability aligned with the European Blue Economy. By integrating recent findings, this review aims to highlight promising leads and guide future research toward innovative, broad-spectrum antiviral therapies.
