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Background: The cytosolic 5'-nucleotidase II (NT5C2) enzyme has been implicated in both psychiatric disorders and metabolic traits, but whether these associations reflect a shared biological basis remains unclear. Here we combined cross-species approaches to investigate how reduced NT5C2 function shapes behavior.

Results: In Drosophila melanogaster, neuronal knockdown of the ortholog dNT5B increased activity around light-dark transitions, reduced sleep fragmentation, and selectively suppressed food intake under satiated conditions. Moreover, analysis of mouse phenotyping data revealed that whole-body Nt5c2 knockout alters locomotor activity, sensorimotor gating, and anxiety-related behaviors. Finally, human variant-trait associations showed reproducible enrichment in both metabolic domains, including body composition and BMI, and neuro-psychiatric outcomes such as schizophrenia, smoking, and anxiety.

Conclusions: Together, these phenotypic findings indicate that NT5C2 is a conserved neuro-metabolic regulator, linking energy-related pathways to specific behavioral dimensions that may underlie its pleiotropic impact on psychiatric and metabolic risk.

Omega-3 polyunsaturated fatty acids (PUFAs) are essential for brain development and function, affecting inflammation, neurotransmission, and neuroplasticity. These nutrients are associated with benefits in managing stress, sleep disorders, anxiety, and mild cognitive impairment. This study investigated the effects of chronic exposure to varying omega-3 PUFA levels, from gestation to adulthood, on behavioral and molecular aspects related to memory, anxiety, and depression in male mice. Dams received one of three diets: Control (soybean oil, 7 %), omega-3 Deficient (sunflower oil, 7 %), or omega-3 Enriched (4.2 % cod liver oil +2.8 % soybean oil). After weaning, the offspring continued on their respective diets until adulthood. The omega-3 Deficient diet led to increased locomotor activity, anxiety-like behavior, and a trend toward greater immobility time in the tail suspension test. It also upregulated the expression of Avp and its receptor Avpr1b within the hypothalamic-pituitary axis, suggesting a potential mechanistic link between omega-3 deficiency and mood disorders. In contrast, the Enriched group exhibited reduced locomotor activity and anxiolytic-like behavior in the elevated plus maze. At the molecular level, the Deficient diet downregulated Grin1, while the Enriched diet upregulated Creb1 in the hippocampus, providing insight into how omega-3 PUFAs influence cognitive processes. Chronic insufficient omega-3 consumption throughout development and adulthood may negatively affect anxiety-and depression-related responses, while high omega-3 intake may play a protective role in anxiety regulation. These findings deepen our understanding of the role of omega-3 PUFAs in affective and cognitive regulation, highlighting the significance of balanced intake to support mental health.

The unprecedented outbreak of the COVID-19 pandemic has altered the course of many lives, resulting in multiple health and social challenges. Due to the speed at which this pandemic spread, various public health 'lockdown' measures were introduced to mitigate its spread. The outcome of adherence to these measures has revealed the possible influence on individuals' varying cognitive abilities. Accordingly, this study aimed to explore the predictive relationships between lockdown responses and COVID-19 restrictions, memory recall performance, and associated emotional responses while examining the sociodemographic influences of age and sex. Participants were drawn from a secondary dataset of an international online survey study of 1634 individuals aged 18-75 years across 49 countries. Participants' demographic questionnaires, free memory recall, and hospital anxiety and depression scale scores were used to collect the data for analysis. Four-way MANOVA and hierarchical multiple regression were utilised to explore the mean differences and predict relationships between the study variables. Significant differences were found in memory recall performance and anxiety and depression scores across lockdown groups (the comply, sufferer, and defiant). Regression analysis indicated that age and gender were predictive markers of lockdown responses and anxiety (R² = 0.14, F_4,1625 = 66.15, p < .001, f² = 0.17), while age was the only predictor of lockdown responses and depression association (b = -0.78, t(1625) = -4.35, p < .001). Lockdown compliance was associated with better free recall (M = 8.51, SD = 6.38, p < .001; η² = 0.01), lockdown suffering was associated with greater anxiety (M = 9.97, SD = 4.36, p < .001; η² = 0.06), and lockdown deviance was associated with greater depression (M = 7.90, SD = 3.12, p < .001; η² = 0.05). The current study provides valuable information on the mechanisms of cognitive interpretations and emotional arousal in individuals' social isolation responses to recent life stress and potential severe pandemics. This may support the need for robust interventions aimed at improving people's psychological appraisals associated with anxiety in preparation for any new potential waves or future pandemics.

Hunger enhances the consumption of rewarding foods, but the neurobiological basis of this adaptation remains unclear. We hypothesize that agouti-related protein (AgRP) neurons in the hypothalamic arcuate nucleus (ARH) promote the consumption of rewarding stimuli under calorie restriction, independent of caloric content. To test this, we study mice fed 40% of their average daily intake and exposed daily to the non-caloric sweetener saccharin before feeding. We show that calorie-restricted (CR) mice increase saccharin intake before each restricted feeding event and that this response requires ARH integrity. CR mice exhibit activation of AgRP neurons and their brain targets without significant changes in AgRP fiber density. Furthermore, satiated mice increase saccharin intake following chemogenetic activation of AgRP neurons, whereas CR mice with selective chemogenetic inhibition of AgRP neurons show reduced saccharin intake. Thus, we conclude that AgRP neuron activation enhances the consumption of a purely rewarding stimulus in CR mice. These findings contribute to our understanding of how the brain shapes food choices under conditions of energy deficit and could be important for managing food consumption during dieting or in eating disorders.

The role of oxytocin-related genes in social-cognitive function has been previously established, but structural brain mechanisms underlying this link remain poorly understood. Utilizing a substantial dataset from the UK Biobank (N ≈ 30,000), this research determined associations between variations in ten single nucleotide polymorphisms (SNPs) within three oxytocin pathway genes (i.e., the oxytocin/neurophysin I prepropetide gene, the cluster of differentiation 38 glycoprotein gene, the oxytocin receptor gene) and whole-brain gray matter volume. Carriers of the AA or AG genotypes of the oxytocin receptor gene rs237851 SNP exhibited significantly larger hippocampal volume than carriers of the GG genotype. These results support the link between variations in the oxytocin receptor gene and hippocampal structure, with possible impact on social-cognitive function such as social recognition memory.

Background and Purpose

Tumour hypoxia frequently presents a major challenge in the treatment of neuroblastoma (NBL). The neuroblastoma cells produce carbonic anhydrase IX (CA IX), an enzyme crucial for the survival of cancer cells in low-oxygen environments.

Experimental Approach

We designed and synthesised a novel high-affinity inhibitor of CA IX. The highest to-date. The affinities were determined for all human catalytically active CA isozymes showing significant selectivity for CA IX over other isozymes. The inhibitor effect on neuroblastoma cancer cell growth was determined in vitro and in vivo via a mice xenograft model.

Key Results

The novel designed inhibitor effectively mitigated the acidification induced by CA IX and reduced spheroid growth under hypoxic conditions in the SK-N-AS cell line. It also diminished the secretion of pro-tumour chemokines IL-8 (CXCL2) and CCL2. When we combined this novel CA IX inhibitor with a compound that inhibits the chemokine receptor CCR2 protein activity, we observed a reduction in mouse tumour growth. The combined treatment also prompted tumours to exhibit adaptive resistance by producing higher levels of vascular endothelial growth factor receptors (VEGFR) and other compensatory signals.

Conclusions and Implications

This research underscores the pivotal role of CA IX in cancer and the potential of a novel CA IX inhibitor-based combination intervention therapy for neuroblastoma treatment.

Background: The specific and non-specific toxicities of cryoprotective agents (CPAs) for semen or spermatozoa cryopreservation/vitrification (SC/SV) remain challenges to the success of assisted reproductive technologies.

Objective: We searched for and integrated the physicochemical and toxicological characteristics of small-molecule CPAs as well as curated the information of all extenders reported for carnivores to provide a foundation for new research avenues and computational cryobiology.

Methods: The PubMed database was systematically searched for CPAs reported in SC/SV of carnivores from 1964 to 2024. The physicochemical features, ADMET parameters, toxicity classes, optimized structures, biological activities, thermodynamic equilibrium constants, and kinetic parameters were curated and assessed computationally.

Results: Sixty-two relevant papers pertaining to CPAs used in SC/SV were found, and 11 CPAs were selected. Among the properties of CPAs, the molecular weight range (59–758 g/mol), melting point (−60°C to 236°C), XlogP3 (−4.5 to 12.9), topological polar surface area (TPSA; 20–160 Ų), Caco2 permeability (−0.62 to 1.55 log(Papp) in 10^–6 cm/s), volume of distribution (−1.04 to 0.19 log L/kg), unbound fraction of a CPA in plasma (0.198–0.895), and Tetrahymena pyriformis toxicity (log µg/L; −2.230 to 0.285) are reported here. Glutathione, dimethyl formamide, methyl formamide, and dimethyl sulfoxide were used as the P-glycoprotein substrates. Ethylene glycol, dimethyl sulfoxide, dimethyl formamide, methyl formamide, glycerol, and soybean lecithin showed Caco2 permeabilities in this order, whereas fructose, glutathione, glutamine, glucose, and citric acid were not Caco2-permeable. The CPAs were distributed in various compartments and could alter the physiological properties of both seminal plasma and spermatozoa. Low volume distributions of all CPAs except glucose indicate high water solubility or high protein binding because higher amounts of the CPAs remain in the seminal plasma.

Conclusion: ADMET information of the CPAs and extenders in the bipartite compartments of seminal plasma and intracellular spaces of spermatozoa are very important for systematic definition and integration because the nature of the extenders and seminal plasma could alter the physiology of cryopreserved spermatozoa.

After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet 3-cells, significant research has recently demonstrated that 3-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D.<br /> Significance Statement: This research delves into the underlying causes of T1D and identifies critical mechanisms governing 3-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting 3-cells, (3) compounds that act simultaneously on both immune cell and 3-cell pathways, and (4) combinations of compounds simultaneously targeting immune and 3-cell pathways.<br /> (c) 2025 The Authors. Published by Elsevier Inc. on behalf of American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Endometrial carcinoma (EC) is one of the leading causes of mortality in women. Metabolic disorders, such as abnormal fatty acid metabolism (FAM), are considered to be indicators of tumorigenesis. However, to the best of our knowledge, the relationship between EC and FAM remains unclear. The process of FAM is associated with the function of immune cells, thus samples from The Cancer Genome Atlas were grouped according to immune infiltration levels. Subsequently, prognostic gene signatures were constructed based on selected FAM-associated genes. The signature effect was validated, and enrichment analyses were conducted based on sample classification. Nomograms were used to predict survival, merging clinical data and the gene signature. Samples were divided into high- and low-risk groups based on the gene signature. The survival status, clinical characteristics, enrichment analysis and immune infiltration were significantly different between high- and low-risk groups. According to the nomogram, low microsatellite instability-high as well as a high tumor mutation burden can be observed in the low-nomo-score group. Immune checkpoint inhibitor-associated genes were differentially expressed between groups and 35 sensitive compounds were identified. Comprehensive bioinformatics analysis in EC revealed potential roles of FAM in tumorigenesis, the tumor microenvironment and prognosis, suggesting that FAM-associated signatures are promising biomarkers for EC. These findings may improve the understanding of FAM in EC and pave the way for a more accurate assessment of prognosis and immunotherapy outcomes.

G protein-coupled receptors (GPCRs) form one of the largest drug target families, reflecting their involvement in numerous pathophysiological processes. In this Review, we analyse drug discovery trends for the GPCR superfamily, covering compounds, targets and indications that have reached regulatory approval or that are being investigated in clinical trials. We find that there are 516 approved drugs targeting GPCRs, making up 36% of all approved drugs. These drugs act on 121 GPCR targets, one-third of all non-sensory GPCRs. Furthermore, 337 agents targeting 133 GPCRs, including 30 novel targets, are being investigated in clinical trials. Notably, 165 of these agents are approved drugs being tested for additional indications and novel agents are increasingly allosteric modulators and biologics. Remarkably, diabetes and obesity drugs targeting GPCRs had sales of nearly US $30 billion in 2023 and the numbers of clinical trials for GPCR modulators in the metabolic diseases, oncology and immunology areas are increasing strongly. Finally, we highlight the potential of untapped target-disease associations and pathway-biased signalling. Overall, this Review provides an up-to-date reference for the drugged and potentially druggable GPCRome to inform future GPCR drug discovery and development.