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Journal of the Endocrine Society Oct 2022Gestational diabetes mellitus (GDM) results in an increased risk of pre- and postpartum health complications for both mother and child. Metabolomics analysis can... (Review)
Review
Gestational diabetes mellitus (GDM) results in an increased risk of pre- and postpartum health complications for both mother and child. Metabolomics analysis can potentially identify predictive biomarkers and provide insight into metabolic alterations associated with GDM pathogenesis and progression, but few metabolomics studies investigate alterations observed across the first and third trimester. We hypothesize that metabolites altered in first-trimester GDM that remain altered in late pregnancy may best inform interventions. Metabolomic studies comparing plasma and serum metabolite alterations in GDM vs non-GDM pregnancies were retrieved by searching PubMed, Medline, and CINAHL Plus databases. The present scoping review summarizes the metabolites found to be consistently altered throughout the course of GDM and proposes mechanisms that explain how these metabolic perturbations relate to GDM development and progression. Metabolites involved in fatty acid metabolism, reductive carboxylation, branched-chain amino acid metabolism, cell membrane lipid metabolism, purine degradation, and the gut microbiome were found to be altered throughout GDM pregnancies, with many of these pathways showing mechanistic links to insulin resistance, inflammation, and impaired cell signaling. Future studies are required to investigate if normalization of these perturbed pathways can be the targets of interventions.
PubMed: 36320628
DOI: 10.1210/jendso/bvac134 -
Oncogene Jul 2022The consistency of the associations between gastric mucosal microbiome and gastric cancer across studies remained unexamined. We aimed to identify universal microbial... (Meta-Analysis)
Meta-Analysis
The consistency of the associations between gastric mucosal microbiome and gastric cancer across studies remained unexamined. We aimed to identify universal microbial signatures in gastric carcinogenesis through a meta-analysis of gastric microbiome from multiple studies. Compositional and ecological profiles of gastric microbes across stages of gastric carcinogenesis were significantly altered. Meta-analysis revealed that opportunistic pathobionts Fusobacterium, Parvimonas, Veillonella, Prevotella and Peptostreptococcus were enriched in GC, while commensals Bifidobacterium, Bacillus and Blautia were depleted in comparison to SG. The co-occurring correlation strengths of GC-enriched bacteria were increased along disease progression while those of GC-depleted bacteria were decreased. Eight bacterial taxa, including Veillonella, Dialister, Granulicatella, Herbaspirillum, Comamonas, Chryseobacterium, Shewanella and Helicobacter, were newly identified by this study as universal biomarkers for robustly discriminating GC from SG, with an area under the curve (AUC) of 0.85. Moreover, H. pylori-positive samples exhibited reduced microbial diversity, altered microbiota community and weaker interactions among gastric microbes. Our meta-analysis demonstrated comprehensive and generalizable gastric mucosa microbial features associated with histological stages of gastric carcinogenesis, including GC associated bacteria, diagnostic biomarkers, bacterial network alteration and H. pylori influence.
Topics: Carcinogenesis; Dysbiosis; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Microbiota; Stomach; Stomach Neoplasms
PubMed: 35680985
DOI: 10.1038/s41388-022-02377-9 -
BioRxiv : the Preprint Server For... May 2023Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently...
Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently in chemotherapy-treated breast cancer and leukemic cells in vitro and in vivo. Consistently, m6A increases on RNA from chemo-treated cells, and is needed for chemosurvival. This is regulated by eIF2α phosphorylation and mTOR inhibition upon therapy treatment. METTL3 mRNA purification reveals that eIF3 promotes METTL3 translation that is reduced by mutating a 5'UTR m6A-motif or depleting METTL3. METTL3 increase is transient after therapy treatment, as metabolic enzymes that control methylation and thus m6A levels on METTL3 RNA, are altered over time after therapy. Increased METTL3 reduces proliferation and anti-viral immune response genes, and enhances invasion genes, which promote tumor survival. Consistently, overriding phospho-eIF2α prevents METTL3 elevation, and reduces chemosurvival and immune-cell migration. These data reveal that therapy-induced stress signals transiently upregulate METTL3 translation, to alter gene expression for tumor survival.
PubMed: 37292633
DOI: 10.1101/2023.05.19.540602 -
Frontiers in Molecular Neuroscience 2022Autism spectrum disorder (ASD) is a neurodevelopmental disorder mainly characterized by social-communication impairments, repetitive behaviors and altered sensory... (Review)
Review
Autism spectrum disorder (ASD) is a neurodevelopmental disorder mainly characterized by social-communication impairments, repetitive behaviors and altered sensory perception. Auditory hypersensitivity is the most common sensory-perceptual abnormality in ASD, however, its underlying neurobiological mechanisms remain elusive. Consistently with reports in ASD patients, animal models for ASD present sensory-perception alterations, including auditory processing impairments. Here we review the current knowledge regarding auditory dysfunction in rodent models of ASD, exploring both shared and distinct features among them, mechanistic and molecular underpinnings, and potential therapeutic approaches. Overall, auditory dysfunction in ASD models seems to arise from impaired central processing. Depending on the model, impairments may arise at different steps along the auditory pathway, from auditory brainstem up to the auditory cortex. Common defects found across models encompass atypical tonotopicity in different regions of the auditory pathway, temporal and spectral processing impairments and histological differences. Imbalance between excitation and inhibition (E/I imbalance) is one of the most well-supported mechanisms explaining the auditory phenotype in the ASD models studied so far and seems to be linked to alterations in GABAergic signaling. Such E/I imbalance may have a large impact on the development of the auditory pathway, influencing the establishment of connections responsible for normal sound processing.
PubMed: 35493332
DOI: 10.3389/fnmol.2022.845155 -
Redox Biology Feb 2023Glyoxalase 2 is the second enzyme of the glyoxalase system, catalyzing the detoxification of methylglyoxal to d-lactate via SD-Lactoylglutathione. Recent in vitro...
Glyoxalase 2 is the second enzyme of the glyoxalase system, catalyzing the detoxification of methylglyoxal to d-lactate via SD-Lactoylglutathione. Recent in vitro studies have suggested Glo2 as a regulator of glycolysis, but if Glo2 regulates glucose homeostasis and related organ specific functions in vivo has not yet been evaluated. Therefore, a CRISPR-Cas9 knockout of glo2 in zebrafish was created and analyzed. Consistent with its function in methylglyoxal detoxification, SD-Lactoylglutathione, but not methylglyoxal accumulated in glo2 larvae, without altering the glutathione metabolism or affecting longevity. Adult glo2 livers displayed a reduced hexose concentration and a reduced postprandial P70-S6 kinase activation, but upstream postprandial AKT phosphorylation remained unchanged. In contrast, glo2 skeletal muscle remained metabolically intact, possibly compensating for the dysfunctional liver through increased glucose uptake and glycolytic activity. glo2 zebrafish maintained euglycemia and showed no damage of the retinal vasculature, kidney, liver and skeletal muscle. In conclusion, the data identified Glo2 as a regulator of cellular energy metabolism in liver and skeletal muscle, but the redox state and reactive metabolite accumulation were not affected by the loss of Glo2.
Topics: Animals; Zebrafish; Lactoylglutathione Lyase; Pyruvaldehyde; Lactic Acid; Glucose; Thiolester Hydrolases
PubMed: 36535130
DOI: 10.1016/j.redox.2022.102576 -
Experimental & Molecular Medicine Jan 2023Hepatocellular carcinoma (HCC) pathogenesis is associated with alterations in splicing machinery components (spliceosome and splicing factors) and aberrant expression of...
Hepatocellular carcinoma (HCC) pathogenesis is associated with alterations in splicing machinery components (spliceosome and splicing factors) and aberrant expression of oncogenic splice variants. We aimed to analyze the expression and potential role of the spliceosome component PRPF8 (pre-mRNA processing factor 8) in HCC. PRPF8 expression (mRNA/protein) was analyzed in a retrospective cohort of HCC patients (n = 172 HCC and nontumor tissues) and validated in two in silico cohorts (TCGA and CPTAC). PRPF8 expression was silenced in liver cancer cell lines and in xenograft tumors to understand the functional and mechanistic consequences. In silico RNAseq and CLIPseq data were also analyzed. Our results indicate that PRPF8 is overexpressed in HCC and associated with increased tumor aggressiveness (patient survival, etc.), expression of HCC-related splice variants, and modulation of critical genes implicated in cancer-related pathways. PRPF8 silencing ameliorated aggressiveness in vitro and decreased tumor growth in vivo. Analysis of in silico CLIPseq data in HepG2 cells demonstrated that PRPF8 binds preferentially to exons of protein-coding genes, and RNAseq analysis showed that PRPF8 silencing alters splicing events in multiple genes. Integrated and in vitro analyses revealed that PRPF8 silencing modulates fibronectin (FN1) splicing, promoting the exclusion of exon 40.2, which is paramount for binding to integrins. Consistent with this finding, PRPF8 silencing reduced FAK/AKT phosphorylation and blunted stress fiber formation. Indeed, HepG2 and Hep3B cells exhibited a lower invasive capacity in membranes treated with conditioned medium from PRPF8-silenced cells compared to medium from scramble-treated cells. This study demonstrates that PRPF8 is overexpressed and associated with aggressiveness in HCC and plays important roles in hepatocarcinogenesis by altering FN1 splicing, FAK/AKT activation and stress fiber formation.
Topics: Humans; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Fibronectins; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Proto-Oncogene Proteins c-akt; Retrospective Studies; RNA-Binding Proteins
PubMed: 36609600
DOI: 10.1038/s12276-022-00917-7 -
NeuroImage. Clinical 2023The hypothalamus is an important neuroendocrine hub for the control of appetite and satiety. In animal studies it has been established that hypothalamic lesioning or...
The hypothalamus is an important neuroendocrine hub for the control of appetite and satiety. In animal studies it has been established that hypothalamic lesioning or stimulation causes alteration to feeding behaviour and consequently body mass, and exposure to high calorie diets induces hypothalamic inflammation. These findings suggest that alterations in hypothalamic structure and function are both a cause and a consequence of changes to food intake. However, there is limited in vivo human data relating the hypothalamus to obesity or eating disorders, in part due to technical problems relating to its small size. Here, we used a novel automated segmentation algorithm to exploratorily investigate the relationship between hypothalamic volume, normalised to intracranial volume, and body mass index (BMI). The analysis was applied across four independent datasets comprising of young adults (total n = 1,351 participants) spanning a range of BMIs (13.3 - 47.8 kg/m). We compared underweight (including individuals with anorexia nervosa), healthy weight, overweight and obese individuals in a series of complementary analyses. We report that overall hypothalamic volume is significantly larger in overweight and obese groups of young adults. This was also observed for a number of hypothalamic sub-regions. In the largest dataset (the HCP-Young Adult dataset (n = 1111)) there was a significant relationship between hypothalamic volume and BMI. We suggest that our findings of a positive relationship between hypothalamic volume and BMI is potentially consistent with hypothalamic inflammation as seen in animal models in response to high fat diet, although more research is needed to establish a causal relationship. Overall, we present novel, in vivo findings that link elevated BMI to altered hypothalamic structure. This has important implications for study of the neural mechanisms of obesity in humans.
Topics: Animals; Young Adult; Humans; Body Mass Index; Overweight; Obesity; Inflammation; Hypothalamus
PubMed: 37558541
DOI: 10.1016/j.nicl.2023.103478 -
Neuroscience and Biobehavioral Reviews Nov 2022Clinical empathy refers to the ability of healthcare providers (HP) to recognize and understand what patients feel. While neuroimaging investigations have identified a... (Meta-Analysis)
Meta-Analysis Review
Clinical empathy refers to the ability of healthcare providers (HP) to recognize and understand what patients feel. While neuroimaging investigations have identified a neural network of empathy, activation consistency of brain regions and their specific functions in clinical empathy remains unclear. Herein, we conducted meta-analyses of dispositional assessments using random-effects models and functional neuroimaging using Seed-based d Mapping with Permutation of Subject Images to ascertain the shared neural processes consistently identified as relevant to clinical empathy. The dispositional meta-analysis (n = 15) revealed that HP exhibited higher scores on empathic concern and perspective taking. The HP neuroimaging meta-analysis (n = 11) identified consistent activation of the anterior mid-cingulate cortex, anterior insula, and ventrolateral prefrontal cortex (vlPFC) while HP vs. controls comparison (n = 9) did not yield robust alterations. The vlPFC mediated positive and negative functional connectivity of the insula. We revisited the framework of emotion regulation in clinical empathy. The empathetic agent flexibly shifts between affective regulatory strategies to meet contextual demands, with vlPFC figuring as the key region where this neural mechanism takes place.
Topics: Humans; Empathy; Magnetic Resonance Imaging; Functional Neuroimaging; Emotions; Brain; Neuroimaging; Brain Mapping
PubMed: 36116577
DOI: 10.1016/j.neubiorev.2022.104874 -
Epilepsia Open Mar 2021Drug-resistant epileptic patients make up approximately one-third of the global epilepsy population. The pathophysiology of drug resistance has not been fully... (Review)
Review
Drug-resistant epileptic patients make up approximately one-third of the global epilepsy population. The pathophysiology of drug resistance has not been fully elucidated; however, current evidence suggests intestinal dysbiosis, as a possible etiopathogenic factor. Ketogenic diet, whose effect is considered to be mediated by alteration of gut microbiota synthesis, has long been administered in patients with medically refractory seizures, with positive outcomes. In this review, we present data derived from clinical studies regarding alterations of gut microbiome profile in drug-resistant epileptic patients. We further attempt to describe the mechanisms through which the gut microbiome modification methods (including ketogenic diet, pre- or probiotic administration) improve drug-resistant epilepsy, by reporting findings from preclinical and clinical studies. A comprehensive search of the published literature on the PubMed, Embase, and Web of science databases was performed. Overall, the role of gut microbiome in drug-resistant epilepsy is an area which shows promise for the development of targeted therapeutic interventions. More research is required to confirm the results from preliminary studies, as well as safety and effectiveness of altering gut bacterial composition, through the above-mentioned methods.
Topics: Diet, Ketogenic; Drug Resistant Epilepsy; Dysbiosis; Gastrointestinal Microbiome; Humans; Probiotics
PubMed: 33681645
DOI: 10.1002/epi4.12461 -
MBio Feb 2021CsrA is a posttranscriptional global regulator in Although CsrA is critical for survival within the mammalian host, the regulatory targets of CsrA remain mostly...
CsrA is a posttranscriptional global regulator in Although CsrA is critical for survival within the mammalian host, the regulatory targets of CsrA remain mostly unknown. To identify pathways controlled by CsrA, RNA-seq transcriptome analysis was carried out by comparing the wild type and the mutant grown to early exponential, mid-exponential, and stationary phases of growth. This enabled us to identify the global effects of CsrA-mediated regulation throughout the growth cycle. We found that CsrA regulates 22% of the transcriptome, with significant regulation within the gene ontology (GO) processes that involve amino acid transport and metabolism, central carbon metabolism, lipid metabolism, iron uptake, and flagellum-dependent motility. Through CsrA-RNA coimmunoprecipitation experiments, we found that CsrA binds to multiple mRNAs that encode regulatory proteins. These include transcripts encoding the major sigma factors RpoS and RpoE, which may explain how CsrA regulation affects such a large proportion of the transcriptome. Other direct targets include , encoding a central regulator in flagellar gene expression, and , encoding the virulence gene transcription factor AphA. We found that CsrA binds to the mRNA both and , and CsrA significantly increases AphA protein synthesis. The increase in AphA was due to increased translation, not transcription, in the presence of CsrA, consistent with CsrA binding to the transcript and enhancing its translation. CsrA is required for the virulence of and this study illustrates the central role of CsrA in virulence gene regulation., a Gram-negative bacterium, is a natural inhabitant of the aqueous environment. However, once ingested, this bacterium can colonize the human host and cause the disease cholera. In order to successfully transition between its aqueous habitat and the human host, the bacterium must sense changes in its environment and rapidly alter gene expression. Global regulators, including CsrA, play an integral role in altering the expression of a large number of genes to promote adaptation and survival, which is required for intestinal colonization. We used transcriptomics and a directed CsrA-RNA coimmunoprecipitation to characterize the CsrA regulon and found that CsrA alters the expression of more than 800 transcripts in Processes regulated by CsrA include motility, the rugose phenotype, and virulence pathways. CsrA directly binds to the transcript and positively regulates the production of the virulence regulator AphA. Thus, CsrA regulates multiple processes that have been linked to pathogenesis.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; RNA-Binding Proteins; Regulon; Trans-Activators; Transcriptome; Vibrio cholerae; Virulence
PubMed: 33531387
DOI: 10.1128/mBio.03380-20