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Current Issues in Molecular Biology Jun 2024Semaglutide (SEM), a glucagon-like peptide-1 receptor agonist, has garnered increasing interest for its potential therapeutic effects in neurodegenerative disorders such... (Review)
Review
Semaglutide (SEM), a glucagon-like peptide-1 receptor agonist, has garnered increasing interest for its potential therapeutic effects in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). This review provides a comprehensive description of SEM's mechanism of action and its effects in preclinical studies of these debilitating conditions. In animal models of AD, SEM has proved beneficial effects on multiple pathological hallmarks of the disease. SEM administration has been associated with reductions in amyloid-beta plaque deposition and mitigation of neuroinflammation. Moreover, SEM treatment has been shown to ameliorate behavioral deficits related to anxiety and social interaction. SEM-treated animals exhibit improvements in spatial learning and memory retention tasks, as evidenced by enhanced performance in maze navigation tests and novel object recognition assays. Similarly, in animal models of PD, SEM has demonstrated promising neuroprotective effects through various mechanisms. These include modulation of neuroinflammation, enhancement of mitochondrial function, and promotion of neurogenesis. Additionally, SEM has been shown to improve motor function and ameliorate dopaminergic neuronal loss, offering the potential for disease-modifying treatment strategies. Overall, the accumulating evidence from preclinical studies suggests that SEM holds promise as a novel therapeutic approach for AD and PD. Further research is warranted to elucidate the underlying mechanisms of SEM's neuroprotective effects and to translate these findings into clinical applications for the treatment of these devastating neurodegenerative disorders.
PubMed: 38921025
DOI: 10.3390/cimb46060354 -
Behavioral Sciences (Basel, Switzerland) Jun 2024(1) Background: Previous studies have identified discrepancies in improvements in executive functioning in typically developing children when comparing closed- and... (Review)
Review
Effects of Practicing Closed- vs. Open-Skill Exercises on Executive Functions in Individuals with Attention Deficit Hyperactivity Disorder (ADHD)-A Meta-Analysis and Systematic Review.
(1) Background: Previous studies have identified discrepancies in improvements in executive functioning in typically developing children when comparing closed- and open-skill exercise interventions. However, there is limited research on executive functioning in attention deficit hyperactivity disorder (ADHD). This study aims to conduct a systematic review and meta-analysis to explore the impact of closed- and open-skill exercises on ADHD populations. (2) Methods: The PRISMA guidelines for systematic reviews were followed to search seven databases to evaluate and analyze studies published from 2013 to 2023. Prospero: CRD42023460452. (3) Results: A meta-analysis of 578 subjects with ADHD in 11 RCTs (Randomized control trial) and 3 NRS (Non-randomized studies) revealed that closed-skill exercise significantly improved executive function subdomains, including inhibitory control (standardized mean differences (SMD) = -1.00), cognitive flexibility (SMD = -1.33), and working memory (SMD = -0.85). Furthermore, open-skill exercise was found to have a positive effect on inhibitory control (SMD = -1.98) and cognitive flexibility (SMD = -0.97) in ADHD patients. Both types of exercise interventions demonstrated an improvement in executive function compared to controls, with open-skill exercises exhibiting superior effects (Q = 6.26). (4) Conclusions: The review recommends a 12-week intervention cycle with exercise at least twice a week of moderate or higher intensity as suitable for ADHD individuals. This review also encourages individuals with ADHD to engage in exercises involving multiple motor skill types.
PubMed: 38920831
DOI: 10.3390/bs14060499 -
Behavioral Sciences (Basel, Switzerland) May 2024Associations and families demand the need to raise awareness of the implications in the cognitive and behavioral development of children with Fetal Alcohol Spectrum...
Associations and families demand the need to raise awareness of the implications in the cognitive and behavioral development of children with Fetal Alcohol Spectrum Disorder (FASD) that affect their learning and school participation. This study aims to generate a profile of executive and behavioral functioning in children and adolescents diagnosed with FASD. A probabilistic sampling by clusters (associations for individuals with FASD) is applied. The sample is composed of 66 families from three associations. The BRIEF-2 and SENA tests were administered to assess executive and behavioral functioning domains. Data analysis found that the executive and behavioral functioning profile of individuals with FASD varies with age, with greater impairment in middle and late adolescence. Likewise, the domain of executive functioning most affected in any of the developmental stages is working memory. Finally, cognitive impairment in the executive functioning domains has a direct impact on the social and adaptive functioning of people with FASD.
PubMed: 38920763
DOI: 10.3390/bs14060431 -
Epigenomes Jun 2024The development of the nervous system is regulated by numerous intracellular molecules and cellular signals that interact temporally and spatially with the extracellular... (Review)
Review
The development of the nervous system is regulated by numerous intracellular molecules and cellular signals that interact temporally and spatially with the extracellular microenvironment. The three major cell types in the brain, i.e., neurons and two types of glial cells (astrocytes and oligodendrocytes), are generated from common multipotent neural stem cells (NSCs) throughout life. However, NSCs do not have this multipotentiality from the beginning. During cortical development, NSCs sequentially obtain abilities to differentiate into neurons and glial cells in response to combinations of spatiotemporally modulated cell-intrinsic epigenetic alterations and extrinsic factors. After the completion of brain development, a limited population of NSCs remains in the adult brain and continues to produce neurons (adult neurogenesis), thus contributing to learning and memory. Many biological aspects of brain development and adult neurogenesis are regulated by epigenetic changes via behavioral control of NSCs. Epigenetic dysregulation has also been implicated in the pathogenesis of various brain diseases. Here, we present recent advances in the epigenetic regulation of NSC behavior and its dysregulation in brain disorders.
PubMed: 38920623
DOI: 10.3390/epigenomes8020022 -
Diseases (Basel, Switzerland) Jun 2024Multiple sclerosis (MS) is a chronic, progressive neurological disorder that significantly impacts quality of life and functionality. Ocrelizumab, a monoclonal antibody...
Impact of Ocrelizumab on Disease Progression, Memory Improvement, and Quality of Life in Patients with Relapsing-Remitting Multiple Sclerosis: A Longitudinal MRI and Clinical Criteria Analysis.
Multiple sclerosis (MS) is a chronic, progressive neurological disorder that significantly impacts quality of life and functionality. Ocrelizumab, a monoclonal antibody targeting CD20-positive B cells, has emerged as a treatment for relapsing-remitting MS (RRMS). This study aimed to assess the impact of ocrelizumab on disease progression and quality of life over a longitudinal course, utilizing clinical criteria and magnetic resonance imaging (MRI) analyses. Conducted at the Neurology Department of Pius Brinzeu Clinical Emergency Hospital in Western Romania from 2020 to 2023, this observational study enrolled 93 patients with RRMS who commenced ocrelizumab therapy. The study employed the Expanded Disability Status Scale (EDSS) and MRI to evaluate disease progression, while quality of life was assessed using the World Health Organisation Quality of Life (WHOQOL) questionnaire, Beck Depression Index (BDI), and MOCA scales. Significant improvements were observed post-treatment. EDSS scores decreased from 4.61 to 4.08 ( = 0.038), indicating reduced disability. MRI analyses showed a substantial decrease in expansive lesions (from 67.74% to 26.88%, < 0.001) and an increase in stationary lesions (from 32.26% to 73.12%, < 0.001). Quality of life improvements were notable in the physical (from 58.42 to 64.84, = 0.005) and environmental domains (from 63.21 to 68.44, = 0.033). Cognitive functions, assessed via Montreal Cognitive Assessment (MOCA), showed a significant total score increase from 20.38 to 22.30 ( < 0.001). Subgroup analysis revealed more pronounced effects in females and younger patients, with a significant reduction in depressive symptoms measured by BDI scores (from 14.35 to 11.62, = 0.003). Ocrelizumab significantly reduced disease activity and disability in RRMS patients, as demonstrated by improvements in EDSS scores and MRI findings. Quality of life and cognitive functions also showed considerable enhancements. These findings support ocrelizumab's efficacy in not only managing MS symptoms but also improving overall patient well-being.
PubMed: 38920559
DOI: 10.3390/diseases12060127 -
Frontiers in Immunology 2024Sleep disorders (SD) are known to have a profound impact on human health and quality of life although their exact pathogenic mechanisms remain poorly understood.
BACKGROUND
Sleep disorders (SD) are known to have a profound impact on human health and quality of life although their exact pathogenic mechanisms remain poorly understood.
METHODS
The study first accessed SD datasets from the GEO and identified DEGs. These DEGs were then subjected to gene set enrichment analysis. Several advanced techniques, including the RF, SVM-RFE, PPI networks, and LASSO methodologies, were utilized to identify hub genes closely associated with SD. Additionally, the ssGSEA approach was employed to analyze immune cell infiltration and functional gene set scores in SD. DEGs were also scrutinized in relation to miRNA, and the DGIdb database was used to explore potential pharmacological treatments for SD. Furthermore, in an SD murine model, the expression levels of these hub genes were confirmed through RT-qPCR and Western Blot analyses.
RESULTS
The findings of the study indicate that DEGs are significantly enriched in functions and pathways related to immune cell activity, stress response, and neural system regulation. The analysis of immunoinfiltration demonstrated a marked elevation in the levels of Activated CD4+ T cells and CD8+ T cells in the SD cohort, accompanied by a notable rise in Central memory CD4 T cells, Central memory CD8 T cells, and Natural killer T cells. Using machine learning algorithms, the study also identified hub genes closely associated with SD, including IPO9, RAP2A, DDX17, MBNL2, PIK3AP1, and ZNF385A. Based on these genes, an SD diagnostic model was constructed and its efficacy validated across multiple datasets. In the SD murine model, the mRNA and protein expressions of these 6 hub genes were found to be consistent with the results of the bioinformatics analysis.
CONCLUSION
In conclusion, this study identified 6 genes closely linked to SD, which may play pivotal roles in neural system development, the immune microenvironment, and inflammatory responses. Additionally, the key gene-based SD diagnostic model constructed in this study, validated on multiple datasets showed a high degree of reliability and accuracy, predicting its wide potential for clinical applications. However, limited by the range of data sources and sample size, this may affect the generalizability of the results.
Topics: Computational Biology; Animals; Humans; Mice; Sleep Wake Disorders; Gene Regulatory Networks; Gene Expression Profiling; Protein Interaction Maps; Disease Models, Animal; MicroRNAs; Databases, Genetic; Mice, Inbred C57BL; Transcriptome
PubMed: 38919616
DOI: 10.3389/fimmu.2024.1381765 -
PloS One 2024Early life adversity (ELA) increases the likelihood of later-life neuropsychiatric disorders and cognitive dysfunction. Importantly, ELA, neuropsychiatric disorders, and...
Early life adversity (ELA) increases the likelihood of later-life neuropsychiatric disorders and cognitive dysfunction. Importantly, ELA, neuropsychiatric disorders, and cognitive deficits all involve aberrant immune signaling. Microglia are the primary neuroimmune cells and regulate brain development. Microglia are particularly sensitive to early life insults, which can program their responses to future challenges. ELA in the form of maternal separation (MS) in rats alters later-life microglial morphology and the inflammatory profile of the prefrontal cortex, a region important for cognition. However, the role of microglial responses during MS in the development of later cognition is not known. Therefore, here we aimed to determine whether the presence of microglia during MS mediates long-term impacts on adult working memory. Clodronate liposomes were used to transiently deplete microglia from the brain, while empty liposomes were used as a control. We hypothesized that if microglia mediate the long-term impacts of ELA on working memory in adulthood, then depleting microglia during MS would prevent these deficits. Importantly, microglial function shifts throughout the neonatal period, so an exploratory investigation assessed whether depletion during the early versus late neonatal period had different effects on adult working memory. Surprisingly, empty liposome treatment during the early, but not late, postnatal period induced microglial activity changes that compounded with MS to impair working memory in females. In contrast, microglial depletion later in infancy impaired later life working memory in females, suggesting that microglial function during late infancy plays an important role in the development of cognitive function. Together, these findings suggest that microglia shift their sensitivity to early life insults across development. Our findings also highlight the potential for MS to impact some developmental processes only when compounded with additional neuroimmune challenges in a sex-dependent manner.
Topics: Animals; Microglia; Female; Maternal Deprivation; Rats; Male; Cognition; Memory, Short-Term; Animals, Newborn; Prefrontal Cortex; Rats, Sprague-Dawley; Age Factors
PubMed: 38917075
DOI: 10.1371/journal.pone.0306022 -
JAMA Network Open Jun 2024The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD.
OBJECTIVE
To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT.
DESIGN, SETTING, AND PARTICIPANTS
This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians.
EXPOSURES
Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks.
MAIN OUTCOMES AND MEASURES
Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses.
RESULTS
Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment.
CONCLUSIONS AND RELEVANCE
In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.
Topics: Humans; Ketamine; Electroconvulsive Therapy; Female; Male; Middle Aged; Depressive Disorder, Treatment-Resistant; Adult; Aged; Treatment Outcome
PubMed: 38916891
DOI: 10.1001/jamanetworkopen.2024.17786 -
BioRxiv : the Preprint Server For... Jun 2024has been linked to both obesity and major depressive disorder (MDD). Our lab identified a protein-coding variant in the 2 transmembrane (TM) helix of in rats, and...
OBJECTIVE
has been linked to both obesity and major depressive disorder (MDD). Our lab identified a protein-coding variant in the 2 transmembrane (TM) helix of in rats, and similar obesity variants have been identified in humans. The current study investigates the role of a TM variant in adiposity and behavior.
METHODS
We used CRISPR-SpCas9 to mutate the TM domain of in WKY rats (Adcy3 ). We also created a heterozygous knockout rat in the same strain (Adcy3 ). Wild-type (WT), Adcy3 , and Adcy3 rats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, and memory.
RESULTS
Adcy3 and Adcy3 rats weighed more than WT rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. Adcy3 males displayed increased passive coping and decreased memory while Adcy3 females displayed increased anxiety-like behavior.
CONCLUSIONS
These studies show that the ADCY3 TM domain plays a role in protein function, that may contribute to the relationship between obesity and MDD, and that sex influences the relationships between , metabolism, and behavior.
STUDY IMPORTANCE QUESTIONS
has been linked to both obesity and depression in humans, with protein-coding variants in the transmembrane domain leading to increased obesity. Yet the underlying mechanisms are unknown, and it is unknown if the same variants can cause both obesity and depression. Rodent knockout models show increased adiposity and altered emotional behaviors, but no rodent models have assessed the role of protein-coding variants in Very few studies have assessed sex differences. This is the first study to assess the role of a protein-coding variant in the transmembrane domain of , showing increases in both obesity and emotion-like behaviors in a rat model. We observed striking sex differences, where male and female rats had different factors driving their adiposity and different patterns of altered behavior. Understanding the role of in obesity and MDD may lead to improved treatments for both diseases. Improving our understanding of the sex differences caused by the same mutation emphasizes the importance of studying both sexes and paves the way for personalized medicine approaches.
PubMed: 38916175
DOI: 10.1101/2024.06.16.598846 -
Frontiers in Cardiovascular Medicine 2024Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be...
BACKGROUND
Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management.
METHODS
Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases ( = 12) were analyzed by Nanostring and compared to healthy heart muscle ( = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients ( = 4 baseline and = 8 during irAE) in comparison to patients without toxicity under ICI-therapy ( = 4 baseline and = 7 during ICI-therapy) using flow cytometry.
RESULTS
A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis.
CONCLUSION
Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.
PubMed: 38915743
DOI: 10.3389/fcvm.2024.1408586