BACKGROUND: Modafinil is primarily used to treat narcolepsy but is also used as an off-label cognitive enhancer. Functional magnetic resonance imaging studies indicate that modafinil modulates the connectivity of neocortical networks primarily involved in attention and executive functions. However, much less is known about the drug's effects on subcortical structures. Following preliminary findings, we evaluated modafinil's activity on the connectivity of distinct cerebellar regions with the neocortex. We assessed the spatial relationship of these effects with the expression of neurotransmitter receptors/transporters. METHODS: Patterns of resting-state functional magnetic resonance imaging connectivity were estimated in 50 participants from scans acquired pre- and postadministration of a single (100 mg) dose of modafinil (n = 25) or placebo (n = 25). Using specific cerebellar regions as seeds for voxelwise analyses, we examined modafinil's modulation of cerebellar-neocortical connectivity. Next, we conducted a quantitative evaluation of the spatial overlap between the modulation of cerebellar-neocortical connectivity and the expression of neurotransmitter receptors/transporters obtained by publicly available databases. RESULTS: Modafinil increased the connectivity of crus I and vermis IX with prefrontal regions. Crus I connectivity changes were associated with the expression of dopaminergic D2 receptors. The vermis I-II showed enhanced coupling with the dorsal anterior cingulate cortex and matched the expression of histaminergic H3 receptors. The vermis VII-VIII displayed increased connectivity with the visual cortex, an activity associated with dopaminergic and histaminergic neurotransmission. CONCLUSIONS: Our study reveals modafinil's modulatory effects on cerebellar-neocortical connectivity. The modulation mainly involves crus I and the vermis and spatially overlaps the distribution of dopaminergic and histaminergic receptors.

• MeSH
• Adult MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Young Adult MeSH
• Modafinil * pharmacology   administration & dosage   MeSH
• Cerebellum * drug effects   diagnostic imaging   metabolism   MeSH
• Neocortex drug effects   metabolism   diagnostic imaging   MeSH
• Neural Pathways drug effects   metabolism   MeSH
• Wakefulness-Promoting Agents pharmacology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: The progression and recurrence are the fatal prognostic factors in glioma patients. However, the therapeutic role and potential mechanism of TRAF7 in glioma patients remain largely unknown. METHODS: TRAF7 RNA-seq was analysed with the TCGA and CGGA databases between glioma tissues and normal brain tissues. The expression of TRAF7, cellular senescence and cell cycle arrest pathways in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The interaction between TRAF7 and KLF4 was determined by Co-immunoprecipitation (Co-IP) assays. The functions of TRAF7 combined with lomustine in glioma were assessed by both in vitro, in vivo and patient-derived primary and recurrent glioma stem cell (GSC) assays. RESULTS: High TRAF7 expression is closely associated with a higher recurrence rate and poorer overall survival (OS). In vitro, TRAF7 knockdown significantly inhibits glioma cell proliferation, invasion, and migration. RNA-seq analysis revealed that TRAF7 inhibition activates pathways related to cellular senescence and cell cycle arrest. In both in vitro and patient-derived GSC assays, the combination of sh-TRAF7 and lomustine enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest, surpassing the effects of lomustine or TRAF7 inhibition alone. Mechanistically, TRAF7 interacts with KLF4, and a rescue assay demonstrated that KLF4 overexpression could reverse the effects of TRAF7 depletion on proliferation and cellular senescence. In vivo, TRAF7 knockdown combined with lomustine treatment effectively suppressed glioma growth. CONCLUSION: TRAF7 could be used as a predictive biomarker and the potential therapeutic target among National Comprehensive Cancer Network (NCCN) treatment guidelines in the progression and recurrence of glioma. Lomustine, regulating cellular senescence and cell cycle could be the priority choice in glioma patients with high-level TRAF7 expression.

• MeSH
• Gene Knockdown Techniques MeSH
• Glioma * pathology   genetics   drug therapy   metabolism   MeSH
• Kruppel-Like Factor 4 MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * genetics   pathology   MeSH
• Lomustine * pharmacology   therapeutic use   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Brain Neoplasms * pathology   genetics   drug therapy   metabolism   MeSH
• Tumor Necrosis Factor Receptor-Associated Peptides and Proteins * genetics   metabolism   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Cell Proliferation MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Cellular Senescence * drug effects   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Berberine (BBR), a small molecule protoberberine isoquinoline alkaloid, is easy to cross the blood-brain barrier and is a potential drug for neurodegenerative diseases. Here, we explored the role and molecular mechanism of BBR in Alzheimer's disease (AD) progression. Weighted gene co-expression network analysis (WGCNA) was conducted to determine AD pathology-associated gene modules and differentially expressed genes (DEGs) were also identified. GO and KEGG analyses were performed for gene function and signaling pathway annotation. Cell counting kit-8 (CCK8) assay was applied to analyze cell viability. Immunofluorescence (IF) staining assay was conducted to measure the levels of polarization markers. The production of inflammatory cytokines was analyzed by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) were detected using a ROS detection kit and a MMP Detection Kit (JC-1), respectively. AD pathology-associated DEGs were applied for GO function annotation and KEGG enrichment analysis, and the results uncovered that AD pathology was related to immune and inflammation. Lipopolysaccharide (LPS) exposure induced the M1 phenotype of microglia, and BBR suppressed LPS-induced M1 polarization and induced microglia toward M2 polarization. Through co-culture of microglia and neuronal cells, we found that BBR exerted a neuro-protective role by attenuating the injury of LPS-induced HMC3 on SH-SY5Y cells. Mechanically, BBR switched the M1/M2 phenotypes of microglia by activating PI3K-AKT signaling. In summary, BBR protected neuronal cells from activated microglia-mediated neuro-inflammation by switching the M1/M2 polarization in LPS-induced microglia via activating PI3K-AKT signaling. Key words Alzheimer's Disease, Berberine, Microglia polarization, Neuroinflammation, PI3K-AKT signaling.

• MeSH
• Alzheimer Disease * metabolism   drug therapy   pathology   MeSH
• Berberine * pharmacology   therapeutic use   MeSH
• Phosphatidylinositol 3-Kinases * metabolism   MeSH
• Humans MeSH
• Microglia * drug effects   metabolism   MeSH
• Mice MeSH
• Neuroprotective Agents * pharmacology   MeSH
• Cell Polarity drug effects   MeSH
• Proto-Oncogene Proteins c-akt * metabolism   MeSH
• Signal Transduction * drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

We present here the co-expressed protein-protein interactions algorithm. In addition to minimizing correlation-causality imbalance and contextualizing protein-protein interactions to the investigated systems, it combines protein-protein interactions and protein co-expression networks to identify differentially correlated functional modules. To test the algorithm, we processed a set of proteomic profiles from different brain regions of controls and subjects affected by idiopathic Parkinson's disease or carrying a GBA1 mutation. Its robustness was supported by the extraction of functional modules, related to translation and mitochondria, whose involvement in Parkinson's disease pathogenesis is well documented. Furthermore, the selection of hubs and bottlenecks from the weightedprotein-protein interactions networks provided molecular clues consistent with the Parkinson pathophysiology. Of note, like quantification, the algorithm revealed less variations when comparing disease groups than when comparing diseased and controls. However, correlation and quantification results showed low overlap, suggesting the complementarity of these measures. An observation that opens the way to a new investigation strategy that takes into account not only protein expression, but also the level of coordination among proteins that cooperate to perform a given function.

• MeSH
• Algorithms * MeSH
• Glucosylceramidase genetics   metabolism   MeSH
• Humans MeSH
• Protein Interaction Mapping * methods   MeSH
• Protein Interaction Maps MeSH
• Brain metabolism   MeSH
• Parkinson Disease * metabolism   genetics   physiopathology   MeSH
• Proteomics methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

AIM: In 2005-2006, a chikungunya epidemic of unprecedented magnitude hit Reunion Island, which raised a public health concern through the substantial proportions of long-lasting manifestations. To understand the pathophysiology underlying chronic chikungunya (CC), we designed the CHIKGene cohort study and collected blood samples from 133 subjects diagnosed with CC and from 86 control individuals that had recovered within 3 months, 12-to-15 years after exposure. METHODS: We conducted bulk RNAseq analysis on peripheral blood mononuclear cells to find differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) and gene ontologies to uncover top-level enriched terms associated with DEGs, and weighted gene correlation network analysis (WGCNA) to elucidate underlying cellular processes. RESULTS: Among 1549 DEGs, gene expression analysis identified 10 top genes including NR4A2 and TRIM58 (upregulated in CC), IGHG3 and IGHV3-49 (downregulated in CC) linked to immune regulation, OSBP2 (upregulated in CC) and SEMA6B (downregulated in CC) linked to neuronal homeostasis and axon guidance, respectively. GSEA and WGCNA unveiled cellular processes such as "Metabolism of RNA" and "Cell Cycle". CONCLUSIONS: This study uncovers a shift in gene expression of CC subjects. IGHG3 and IGHV3-49 gene shut-offs spotlight the importance of neutralizing antibodies against chikungunya virus in the progression to chronic disease. Human diseases associations highlight connections to rheumatoid arthritis, nervous and cardiac systems. GSEA and WGCNA bounce the hypotheses of a persistent viral reservoir or an increased susceptibility to RNA viral pathogens with new onset infections. Together, our findings might offer potential targets for therapeutic options aimed at alleviating chronic chikungunya.

• MeSH
• Chronic Disease MeSH
• Adult MeSH
• Chikungunya Fever * genetics   epidemiology   virology   MeSH
• Cohort Studies MeSH
• Leukocytes, Mononuclear MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Gene Expression Profiling MeSH
• Transcriptome * MeSH
• Chikungunya virus MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Reunion MeSH

Expression of CD2, CD25 and/or CD30 in extracutaneous mast cells (MC) is a minor diagnostic criterion for systemic mastocytosis (SM) in the classification of the World Health Organization and International Consensus Classification. So far, it remains unknown whether expression of these antigens on MC is of prognostic significance in SM. We performed a retrospective multi-center study of patients with SM using the data set of the registry of the European Competence Network on Mastocytosis, including 5034 patients with various MC disorders. The percentage of CD2-, CD25+ and/or CD30+ MC was considerably lower in patients with indolent SM compared to patients with advanced SM, including aggressive SM and MC leukemia. Whereas CD25 and CD30 expression in MC could not be associated with prognosis, we found that lack of CD2 expression in MC is associated with a significantly reduced overall survival (OS) in patients with SM (p < 0.0001). Lack of CD2 was also associated with the presence of extramedullary involvement affecting the spleen, liver, and/or lymph nodes (odds ratio 2.63 compared to SM with CD2+ MC). Together, lack of CD2 expression in MC is a prognostic marker and indicator of reduced OS and extramedullary disease expansion in patients with SM.

• MeSH
• Ki-1 Antigen * metabolism   MeSH
• CD2 Antigens * metabolism   MeSH
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Mast Cells * metabolism   pathology   immunology   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Prognosis MeSH
• Interleukin-2 Receptor alpha Subunit * metabolism   MeSH
• Registries * MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Mastocytosis, Systemic * metabolism   pathology   mortality   diagnosis   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Europe MeSH

Autism spectrum disorder (ASD) is a neurodevelopmental disorder accompanied by narrow interests, difficulties in communication and social interaction, and repetitive behavior. In addition, ASD is frequently associated with eating and feeding problems. Although the symptoms of ASD are more likely to be observed in boys, the prevalence of eating disorders is more common in females. The ingestive behavior is regulated by the integrative system of the brain, which involves both homeostatic and hedonic neural circuits. Sex differences in the physiology of food intake depend on sex hormones regulating the expression of the ASD-associated Shank genes. Shank3 mutation leads to ASD-like traits and Shank3B -/- mice have been established as an animal model to study the neurobiology of ASD. Therefore, the long-lasting neuronal activity in the central neural circuit related to the homeostatic and hedonic regulation of food intake was evaluated in both sexes of Shank3B mice, followed by the evaluation of the food intake and preference. In the Shank3B +/+ genotype, well-preserved relationships in the tonic activity within the homeostatic neural network together with the relationships between ingestion and hedonic preference were observed in males but were reduced in females. These interrelations were partially or completely lost in the mice with the Shank3B -/- genotype. A decreased hedonic preference for the sweet taste but increased total food intake was found in the Shank3B -/- mice. In the Shank3B -/- group, there were altered sex differences related to the amount of tonic cell activity in the hedonic and homeostatic neural networks, together with altered sex differences in sweet and sweet-fat solution intake. Furthermore, the Shank3B -/- females exhibited an increased intake and preference for cheese compared to the Shank3B +/+ ones. The obtained data indicate altered functional crosstalk between the central homeostatic and hedonic neural circuits involved in the regulation of food intake in ASD.

• MeSH
• Homeostasis * physiology   MeSH
• Microfilament Proteins * genetics   metabolism   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Sex Characteristics * MeSH
• Autism Spectrum Disorder * genetics   metabolism   MeSH
• Food Preferences physiology   MeSH
• Eating * physiology   genetics   MeSH
• Nerve Tissue Proteins * genetics   MeSH
• Proto-Oncogene Proteins c-fos metabolism   biosynthesis   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by the accumulation of fat in the liver in the absence of excessive alcohol consumption or a secondary cause of hepatic steatosis. The prevalence of NAFLD is increasing worldwide and its management has become a public health concern. Animal models are traditionally used to elucidate disease mechanisms and identify potential drug targets; however, their translational aspects in human diseases have not been fully established. This study aimed to clarify the utility of animal models for translational research by assessing their relevance to human diseases using gene expression analysis. Weighted gene co-expression network analysis of liver tissues from Western diet (WD)-induced NAFLD mice was performed to identify the modules associated with disease progression. Moreover, the similarity of the gene co-expression network across species was evaluated using module preservation analysis. Nineteen disease-associated modules were identified. The brown module was positively associated with disease severity, and functional analyses indicated that it may be involved in inflammatory responses in immune cells. Moreover, the gene co-expression network of the brown module was highly preserved in human NAFLD liver gene expression datasets. These results indicate that WD-induced NAFLD mice have similar gene co-expression networks (especially genes associated with inflammatory responses) to humans and are thought to be a useful experimental tool for preclinical research on NAFLD. Keywords: Nonalcoholic fatty liver disease (NAFLD), Weighted gene co-expression network analysis (WGCNA), Western diet (WD).

• MeSH
• Liver metabolism   pathology   MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Mice, Inbred C57BL * MeSH
• Mice MeSH
• Non-alcoholic Fatty Liver Disease * genetics   metabolism   etiology   pathology   MeSH
• Gene Expression Profiling methods   MeSH
• Transcriptome * MeSH
• Diet, Western * adverse effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O2) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s-1 and 15 cm·s-1. In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation.NEW & NOTEWORTHY Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration.

• MeSH
• Hippocampus * metabolism   MeSH
• Hypoxia metabolism   physiopathology   MeSH
• rho-Associated Kinases * metabolism   genetics   MeSH
• Rats MeSH
• Spinal Cord metabolism   physiology   MeSH
• Cerebral Cortex metabolism   physiology   MeSH
• Neuronal Plasticity physiology   MeSH
• Rats, Wistar * MeSH
• rho GTP-Binding Proteins MeSH
• rhoA GTP-Binding Protein metabolism   MeSH
• Signal Transduction * physiology   MeSH
• High-Intensity Interval Training * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: Parasite-mediated selection is considered one of the potential mechanisms contributing to the coexistence of asexual-sexual complexes. Gibel carp (Carassius gibelio), an invasive fish species in Europe, often forms populations composed of gynogenetic and sexual specimens. METHODS: The experimental infection was induced in gynogenetic and sexual gibel carp using eye-fluke Diplostomum pseudospathaceum (Trematoda), and the transcriptome profile of the spleen as a major immune organ in fish was analyzed to reveal the differentially expressed immunity-associated genes related to D. pseudospathaceum infection differing between gynogenetic and sexual gibel carp. RESULTS: High parasite infection was found in gynogenetic fish when compared to genetically diverse sexuals. Although metacercariae of D. pseudospathaceum are situated in an immune-privileged organ, our results show that eye trematodes may induce a host immune response. We found differential gene expression induced by eye-fluke infection, with various impacts on gynogenetic and sexual hosts, documenting for the majority of DEGs upregulation in sexuals, and downregulation in asexuals. Differences in gene regulation between gynogenetic and sexual gibel carp were evidenced in many immunity-associated genes. GO analyses revealed the importance of genes assigned to the GO terms: immune function, the Notch signaling pathway, MAP kinase tyrosine/threonine/phosphatase activity, and chemokine receptor activity. KEGG analyses revealed the importance of the genes involved in 12 immunity-associated pathways - specifically, FoxO signaling, adipocytokine signaling, TGF-beta signaling, apoptosis, Notch signaling, C-type lectin receptor signaling, efferocytosis, intestinal immune network for IgA production, insulin signaling, virion - human immunodeficiency virus, Toll-like receptor signaling, and phosphatidylinositol signaling system. DISCUSSION: Our study indicates the limited potential of asexual fish to cope with higher parasite infection (likely a loss of capacity to induce an effective immune response) and highlights the important role of molecular mechanisms associated with immunity for the coexistence of gynogenetic and sexual gibel carp, potentially contributing to its invasiveness.

• MeSH
• Trematode Infections * veterinary   immunology   parasitology   MeSH
• Host-Parasite Interactions immunology   MeSH
• Carps parasitology   immunology   genetics   MeSH
• Fish Diseases * immunology   parasitology   MeSH
• Gene Expression Regulation MeSH
• Reproduction immunology   MeSH
• Gene Expression Profiling MeSH
• Transcriptome MeSH
• Trematoda * physiology   MeSH
• Introduced Species * MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH