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An analysis on the role of glucagon-like peptide-1 receptor agonists in cognitive and mental health disorders
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are novel drugs approved for diabetes and obesity. They are acknowledged as a major scientific breakthrough. In addition to their metabolic effects, these medications act on other bodily systems involved in the physiopathology of various neurological and psychiatric disorders. Several stakeholders are calling for more research to investigate the repurposing potential of GLP-1RAs in cognitive and mental disorders, while others advocate for a better assessment of their safety profile from a neuropsychiatric perspective. In this Analysis, we searched for relevant literature on the effects of GLP-1RAs across a range of illnesses, gathering and describing the available pre-clinical and mechanistic (278 studies) and clinical (96 studies) evidence for cognitive disorders, substance-use disorders, psychotic disorders, mood and anxiety disorders, eating disorders, and others. By leveraging translational insights from these data, we consider potential implications for clinical practice and propose avenues for further research.
Fasting appetite-related gut hormone responses after weight loss induced by calorie restriction, exercise, or both in people with overweight or obesity: a meta‐analysis
Altered appetite-related gut hormone concentrations may reflect a physiological adaptation facilitating weight regain after weight loss. This review investigates hormonal changes after weight loss achieved through calorie restriction (CR), exercise (EX), or both combined (CREX).
Crosstalk between gut microbiotas and fatty acid metabolism in colorectal cancer
Colorectal cancer (CRC) is the third most common malignancy globally and the second leading cause of cancer-related mortality. Its development is a multifactorial and multistage process influenced by a dynamic interplay between gut microbiota, environmental factors, and fatty acid metabolism. Dysbiosis of intestinal microbiota and abnormalities in microbiota-associated metabolites have been implicated in colorectal carcinogenesis, highlighting the pivotal role of microbial and metabolic interactions. Fatty acid metabolism serves as a critical nexus linking dietary patterns with gut microbial activity, significantly impacting intestinal health. In CRC patients, reduced levels of short-chain fatty acids (SCFAs) and SCFA-producing bacteria have been consistently observed. Supplementation with SCFA-producing probiotics has demonstrated tumor-suppressive effects, while therapeutic strategies aimed at modulating SCFA levels have shown potential in enhancing the efficacy of radiation therapy and immunotherapy in both preclinical and clinical settings. This review explores the intricate relationship between gut microbiota, fatty acid metabolism, and CRC, offering insights into the underlying mechanisms and their potential translational applications. Understanding this interplay could pave the way for novel diagnostic, therapeutic, and preventive strategies in the management of CRC.
Nitroglycerin-responsive gene switch for the on-demand production of therapeutic proteins
Gene therapies and cell therapies require precise, reversible and patient-friendly control over the production of therapeutic proteins. Here we present a fully human nitric-oxide-responsive gene-regulation system for the on-demand and localized release of therapeutic proteins through clinically licensed nitroglycerin patches. Designed for simplicity and robust human compatibility, the system incorporates human mitochondrial aldehyde dehydrogenase for converting nitroglycerin into nitric oxide, which then activates soluble guanylate cyclase to produce cyclic guanosine monophosphate, followed by protein kinase G to amplify the signal and to trigger target gene expression. In a proof-of-concept study, human cells expressing the nitroglycerin-responsive system were encapsulated and implanted subcutaneously in obese mice with type 2 diabetes. Transdermal nitroglycerin patches applied over the implant enabled the controlled and reversible production of glucagon-like peptide-1 throughout the 35-day experimental period, effectively restoring blood glucose levels in these mice without affecting heart rate or blood pressure. The approach may facilitate the development of safe, convenient and responsive implantable devices for the sustained delivery of biopharmaceuticals for the management of chronic diseases.
Relationships of eating behaviors with psychopathology, brain maturation and genetic risk for obesity in an adolescent cohort study
Unhealthy eating, a risk factor for eating disorders (EDs) and obesity, often coexists with emotional and behavioral problems; however, the underlying neurobiological mechanisms are poorly understood. Analyzing data from the longitudinal IMAGEN adolescent cohort, we investigated associations between eating behaviors, genetic predispositions for high body mass index (BMI) using polygenic scores (PGSs), and trajectories (ages 14–23 years) of ED-related psychopathology and brain maturation. Clustering analyses at age 23 years (N = 996) identified 3 eating groups: restrictive, emotional/uncontrolled and healthy eaters. BMI PGS, trajectories of ED symptoms, internalizing and externalizing problems, and brain maturation distinguished these groups. Decreasing volumes and thickness in several brain regions were less pronounced in restrictive and emotional/uncontrolled eaters. Smaller cerebellar volume reductions uniquely mediated the effects of BMI PGS on restrictive eating, whereas smaller volumetric reductions across multiple brain regions mediated the relationship between elevated externalizing problems and emotional/uncontrolled eating, independently of BMI. These findings shed light on distinct contributions of genetic risk, protracted brain maturation and behaviors in ED symptomatology.
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