Carbonic anhydrase IX inhibition as a path to treat neuroblastoma.

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.

Selective Colocalization of GHSR and GLP-1R in a Subset of Hypothalamic Neurons and Their Functional Interaction.

The GH secretagogue receptor (GHSR) and the glucagon-like peptide-1 receptor (GLP-1R) are G protein-coupled receptors with critical, yet opposite, roles in regulating energy balance. Interestingly, these receptors are expressed in overlapping brain regions. However, the extent to which they target the same neurons and engage in molecular crosstalk remains unclear.

Associations between genetic variations in oxytocin pathway genes and hippocampal volume: Insights from the UK Biobank.

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.

Increased ROS levels, antioxidant defense disturbances and bioenergetic disruption induced by thiosulfate administration in the brain of neonatal rats.

Sulfite oxidase deficiencies, either caused by deficiency of the apoenzyme or the molybdenum cofactor, and ethylmalonic encephalopathy are inherited disorders that impact sulfur metabolism. These patients present with severe neurodeterioration accompanied by cerebral cortex and cerebellum abnormalities, and high thiosulfate levels in plasma and tissues, including the brain. We aimed to clarify the mechanisms of such abnormalities, so we assessed the ex vivo effects of thiosulfate administration on energetic status and oxidative stress markers in cortical and cerebellar tissues of newborn rats.

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX.

We designed novel pre-drug compounds that transform into an active form that covalently modifies particular His residue in the active site, a difficult task to achieve, and applied to carbonic anhydrase (CAIX), a transmembrane protein, highly overexpressed in hypoxic solid tumors, important for cancer cell survival and proliferation because it acidifies tumor microenvironment helping invasion and metastases processes. The designed compounds have several functionalities: (1) primary sulfonamide group recognizing carbonic anhydrases (CA), (2) high-affinity moieties specifically recognizing CAIX among all CA isozymes, and (3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high initial affinity and selectivity for the disease target protein followed by complete irreversible inactivation of the protein via covalent modification.

Statin use is associated with higher white matter hyperintensity volumes and lower grey matter volumes.

While statins are routinely prescribed to prevent cardiovascular diseases, their effects on brain alterations remain largely unknown. Very few studies have examined the differences in brain volumes between statin users and non-users, and existing research has yielded inconsistent results. This cross-sectional study aims to investigate the association between statin use at baseline and global and specific brain volumes measured 9 years later in a large population-based sample of middle-aged and older adults.

Perfluorooctanoic acid induces transgenerational modifications in reproduction, metabolism, locomotor activity, and sleep behavior in Drosophila melanogaster and deleterious effects in human cancer cells.

Perfluorooctanoic acid (PFOA) has been widely documented to affect various aspects of health, including development, metabolism and neuronal function in a variety of organisms. Despite numerous reports detailing these effects, a comprehensive mechanistic model remains elusive, especially with regard to the long-term effects of PFOA, as it bioaccumulates in food chains with a long half-life. In this study, we evaluated the impact of PFOA on several critical physiological states of Drosophila melanogaster.

Hidden liver-joint axis: HBV infection causes rheumatoid arthritis via TRAFD1 with imbalance of HBV X protein and trans-ferulic acid.

Liver metabolites are involved in the progression of rheumatoid arthritis (RA), indicating a connection between the liver and joints. However, the impact and mechanism of Hepatitis B virus (HBV), a hepatotropic virus, on RA are still unclear. We investigated the correlation between HBV and RA using Mendelian randomization analysis.

Genomic Validation in the UK Biobank Cohort Suggests a Role of C8B and MFG-E8 in the Pathogenesis of Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a severe facial pain disease of uncertain pathophysiology and unclear genetic background. Although recent research has reported a more important role of genetic factors in TN pathogenesis, few candidate genes have been proposed to date. The present study aimed to identify independent genetic variants in the protein-coding genes associated with TN.

The Concentration of Liver-Expressed Antimicrobial Peptide 2 in Human Milk and Infant Plasma Is Positively Associated with Adiposity and Body Weight in the First Year of Life.

Background: The liver-expressed antimicrobial peptide 2 (LEAP2) is a recently recognized anorectic and glucose-regulating hormone with an unknown role in lactation.

Objectives: The objectives of this study were as follows: 1) to assess LEAP2 presence in human milk and putative associations with infant body weight and adiposity in the first year of life, 2) to evaluate the impact of maternal weight status on LEAP2 concentration, and 3) to explore the relationship between infant plasma LEAP2 concentration and body weight and adiposity.

Methods: This prospective cohort observational study assessed LEAP2 concentration in plasma and milk from lactating women with normal weight (n = 26) or overweight or obesity (OW/OB, n = 26) at 6 mo postpartum and in 6-mo-old infant plasma, examining associations with metabolic and anthropometric variables at 6 mo and 1 y.

Oxytocin pathway gene variation and corticostriatal resting-state functional connectivity.

Genetic variations in single nucleotide polymorphisms (SNPs) within oxytocin pathway genes have been linked to social behavior and neurodevelopmental conditions. However, the neurobiological mechanisms underlying these associations remain elusive. In this study, we investigated the relationship between variations of 10 SNPs in oxytocin pathway genes and resting-state functional connectivity among 55 independent components using a large sample from the UK Biobank (N ≈ 30,000).

Blockade of the lncRNA-PART1-PHB2 axis confers resistance to PARP inhibitor and promotes cellular senescence in ovarian cancer.

PARPi is currently the most important breakthrough in the treatment of ovarian cancer in decades, and it has been integrated into the initial maintenance therapy for ovarian cancer. However, the mechanism leading to PARPi resistance remains unelucidated. Our study aims to screen novel targets to better predict and reverse resistance to PARPi and explore the potential mechanism.

Off-target effects of statins: molecular mechanisms, side effects and the emerging role of kinases.

Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations.

LEAP2 is associated with impulsivity and reward sensitivity depending on the nutritional status and decreases with protein intake in humans.

Aim: Liver-expressed antimicrobial peptide 2 (LEAP2) dynamics in human plasma and its association with feeding behaviour remain poorly understood. Therefore, this study aims: (a) to investigate fasting LEAP2 in participants with normal weight or with overweight or mild obesity (OW/OB); (b) to study the association between fasting LEAP2 and anthropometric and metabolic traits, feeding behaviour, LEAP2 genetic variants and blood cell DNA methylation status; and (c) to ascertain postprandial changes in LEAP2 after high protein intake and the association with feeding behaviour and food intake.

Methods: Anthropometric and behavioural measures, genotyping, methylation profiling, plasma glucose and LEAP2 concentrations were assessed in 327 females and males.

Long-term changes in adiposity markers during and after antidepressant therapy in a community cohort.

Research on antidepressant-related weight changes over more than 12 months is scarce and adjustment for the effects of depressive episodes has rarely been applied. Accordingly, our aim was to assess the associations of the use of any antidepressants, subclasses of antidepressant and specific compounds prior to baseline and during a 5.5-year follow-up with changes in adiposity markers, and the effect of sex on these associations, with adjustment for multiple confounders including the effects of depressive episodes and their severity.

Association of polygenic scores for autism with volumetric MRI phenotypes in cerebellum and brainstem in adults.

Previous research on autism spectrum disorders (ASD) have showed important volumetric alterations in the cerebellum and brainstem. Most of these studies are however limited to case-control studies with small clinical samples and including mainly children or adolescents. Herein, we aimed to explore the association between the cumulative genetic load (polygenic risk score, PRS) for ASD and volumetric alterations in the cerebellum and brainstem, as well as global brain tissue volumes of the brain among adults at the population level.

Depression clinical trials worldwide: a systematic analysis of the ICTRP and comparison with ClinicalTrials.gov.

Major depressive disorder (MDD), commonly known as depression, affects over 300 million people worldwide as of 2018 and presents a wide range of clinical symptoms. The international clinical trials registry platform (ICTRP) introduced by WHO includes aggregated data from ClinicalTrials.gov and 17 other national registers, making it the largest clinical trial platform.

Decoding depression: a comprehensive multi-cohort exploration of blood DNA methylation using machine learning and deep learning approaches.

The causes of depression are complex, and the current diagnosis methods rely solely on psychiatric evaluations with no incorporation of laboratory biomarkers in clinical practices. We investigated the stability of blood DNA methylation depression signatures in six different populations using six public and two domestic cohorts (n = 1942) conducting mega-analysis and meta-analysis of the individual studies. We evaluated 12 machine learning and deep learning strategies for depression classification both in cross-validation (CV) and in hold-out tests using merged data from 8 separate batches, constructing models with both biased and unbiased feature selection.

Advances in development of biomarkers for brain damage and ischemia.

Acquired brain injury is an urgent situation that requires rapid diagnosis and treatment. Magnetic resonance imaging (MRI) and computed tomography (CT) are required for accurate diagnosis. However, these methods are costly and require substantial infrastructure and specialized staff.

Genetic variants of LEAP2 are associated with anthropometric traits and circulating insulin-like growth factor-1 concentration: A UK Biobank study.

Aim: To test the hypothesis that liver-expressed antimicrobial peptide 2 (LEAP2) genetic variants might influence the susceptibility to human obesity.

Methods: Using data from the UK Biobank, we identified independent LEAP2 gene single nucleotide polymorphisms (SNPs) and examined their associations with obesity traits and serum insulin-like growth factor-1 (IGF-1) concentration. These associations were evaluated for both individual SNPs and after combining them into a genetic risk score (GRS) using linear and logistic regression models.

Depression proteomic profiling in adolescents with transcriptome analyses in independent cohorts.

Introduction: Depression is a major global burden with unclear pathophysiology and poor treatment outcomes. Diagnosis of depression continues to rely primarily on behavioral rather than biological methods. Investigating tools that might aid in diagnosing and treating early-onset depression is essential for improving the prognosis of the disease course.