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In Vivo (Athens, Greece) 2024This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver...
BACKGROUND/AIM
This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice.
MATERIALS AND METHODS
Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks.
RESULTS
Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006.
CONCLUSION
TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host.
Topics: Animals; Gastrointestinal Microbiome; Tocotrienols; Mice; Homeostasis; Obesity; Male; Dietary Supplements; Bone and Bones; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Diet, High-Fat; Bixaceae; Mice, Obese; Plant Extracts; Glucose; Mice, Inbred C57BL; Insulin Resistance; Blood Glucose; Disease Models, Animal; Liver; Biomarkers; Carotenoids
PubMed: 38936927
DOI: 10.21873/invivo.13606 -
Neuroscience and Biobehavioral Reviews Jun 2024The prenatal and neonatal periods are two of the most important developmental stages of the human brain. It is therefore crucial to understand normal brain development... (Review)
Review
The prenatal and neonatal periods are two of the most important developmental stages of the human brain. It is therefore crucial to understand normal brain development and how early connections are established during these periods, in order to advance the state of knowledge on altered brain development and eventually identify early brain markers of neurodevelopmental disorders and diseases. In this systematic review (Prospero ID: CRD42024511365), we compiled resting state functional magnetic resonance imaging (fMRI) studies in healthy fetuses and neonates, in order to outline the main characteristics of typical development of the functional brain connectivity during the prenatal and neonatal periods. A systematic search of five databases identified a total of 12 573 articles. Of those, 28 articles met pre-established selection criteria based determined by the authors after surveying and compiling the major limitations reported within the literature. Inclusion criteria were: (1) resting state studies; (2) presentation of original results; (3) use of fMRI with minimum one Tesla; (4) a population ranging from 20 weeks of GA to term birth (around 37-42 weeks of PMA); (5) singleton pregnancy with normal development (absence of any complications known to alter brain development). Exclusion criteria were: (1) preterm studies; (2) post-mortem studies; (3) clinical or pathological studies; (4) twin studies; (5) papers with a sole focus on methodology (i.e. focused on tool and analysis development); (6) volumetric studies; (7) activation map studies; (8) cortical analysis studies; (9) conference papers. A risk of bias assessment was also done to evaluate each article's methodological rigor. 1877 participants were included across all the reviewed articles. Results consistently revealed a developmental gradient of increasing functional brain connectivity from posterior to anterior regions and from proximal-to-distal regions. A decrease in local small-world organization shortly after birth was also observed; small-world characteristics were present in fetuses and newborns, but appeared weaker in the latter group. Also, the posterior-to-anterior gradient could be associated with earlier development of the sensorimotor networks in the posterior regions while more complex higher-order networks (e.g. attention-related) mature later in the anterior regions. The main limitations of this systematic review stem from the inherent limitations of functional imaging in fetuses, mainly: unevenly distributed populations and limited sample sizes; fetal movements in the womb and other imaging obstacles; and a large voxel resolution when imaging a small brain. Another limitation specific to this review is the relatively small number of included articles compared to very a large search result, which may have led to relevant articles having been overlooked.
PubMed: 38936564
DOI: 10.1016/j.neubiorev.2024.105778 -
Environmental Research Jun 2024Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects....
BACKGROUND
Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans.
OBJECTIVE
To investigate associations between PFAS concentrations and miRNA levels in children.
METHODS
Data from two distinct cohorts were utilized: 176 participants (average age 16.6 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs.
RESULTS
Plasma PFAS concentrations were associated with alterations in 476 miRNAs in the Teen-LABs study and 13 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis.
CONCLUSION
Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.
PubMed: 38936497
DOI: 10.1016/j.envres.2024.119496 -
ACS Nano Jun 2024Nanoplastics (NPs), as emerging contaminants, have been shown to cause testicular disorders in mammals. However, whether paternal inheritance effects on offspring health...
Nanoplastics (NPs), as emerging contaminants, have been shown to cause testicular disorders in mammals. However, whether paternal inheritance effects on offspring health are involved in NP-induced reproductive toxicity remains unclear. In this study, we developed a mouse model where male mice were administered 200 nm polyethylene nanoparticles (PE-NPs) at a concentration of 2 mg/L through daily gavage for 35 days to evaluate the intergenerational effects of PE-NPs in an exclusive male-lineage transmission paradigm. We observed that paternal exposure to PE-NPs significantly affected growth phenotypes and sex hormone levels and induced histological damage in the testicular tissue of both F and F generations. In addition, consistent changes in sperm count, motility, abnormalities, and gene expression related to endoplasmic reticulum stress, sex hormone synthesis, and spermatogenesis were observed across paternal generations. The upregulation of microRNA (miR)-1983 and the downregulation of miR-122-5p, miR-5100, and miR-6240 were observed in both F and F mice, which may have been influenced by reproductive signaling pathways, as indicated by the RNA sequencing of testis tissues and quantitative real-time polymerase chain reaction findings. Furthermore, alterations in the gut microbiota and subsequent Spearman correlation analysis revealed that an increased abundance of and and a decreased abundance of were positively associated with spermatogenic dysfunction. These findings were validated in a fecal microbiota transplantation trial. Our results demonstrate that changes in miRNAs and the gut microbiota caused by paternal exposure to PE-NPs mediated intergenerational effects, providing deeper insights into mechanisms underlying the impact of paternal inheritance.
PubMed: 38935618
DOI: 10.1021/acsnano.4c06298 -
Current Opinion in HIV and AIDS Jun 2024To report recent evidence on associations between human microbiome, particularly airway and gut, and pulmonary comorbidities in people with HIV (PWH). Furthermore, we...
PURPOSE OF REVIEW
To report recent evidence on associations between human microbiome, particularly airway and gut, and pulmonary comorbidities in people with HIV (PWH). Furthermore, we explore how changes in the microbiome may contribute to pulmonary immune dysregulation and higher rates of pulmonary comorbidities among PWH. Finally, we propose future directions in the field.
RECENT FINDINGS
Increased risk of pulmonary comorbidities and rapid lung function decline have been reported in even well treated PWH. Altered microbiota profiles have been reported in PWH with pulmonary comorbidities and rapid lung function decline as compared to those without. The most consistent data have been the association between HIV-related pulmonary comorbidities, lung and oral microbiota dysbiosis, which has been also associated with distinct respiratory mucosal inflammatory profiles and short-term mortality. However, a possible causal link remains to be elucidated.
SUMMARY
Associations between the lung and oral microbiome, HIV-associated pulmonary comorbidities and rapid lung function decline have been reported in recent studies. Yet the underlying mechanism underpinning the observed associations is largely unknown and substantial knowledge gaps remain. Future research is warranted to unveil the role and mechanism of human microbiome from different anatomical compartments in relation to pulmonary comorbidities in PWH.
PubMed: 38935049
DOI: 10.1097/COH.0000000000000871 -
Schizophrenia Bulletin Jun 2024N-Methyl-d-aspartate receptor (NMDA-R) hypofunctioning has been hypothesized to be involved in circuit dysfunctions in schizophrenia (ScZ). Yet, it remains to be...
Effects of N-Methyl-d-Aspartate Receptor Antagonists on Gamma-Band Activity During Auditory Stimulation Compared With Electro/Magneto-encephalographic Data in Schizophrenia and Early-Stage Psychosis: A Systematic Review and Perspective.
BACKGROUND AND HYPOTHESIS
N-Methyl-d-aspartate receptor (NMDA-R) hypofunctioning has been hypothesized to be involved in circuit dysfunctions in schizophrenia (ScZ). Yet, it remains to be determined whether the physiological changes observed following NMDA-R antagonist administration are consistent with auditory gamma-band activity in ScZ which is dependent on NMDA-R activity.
STUDY DESIGN
This systematic review investigated the effects of NMDA-R antagonists on auditory gamma-band activity in preclinical (n = 15) and human (n = 3) studies and compared these data to electro/magneto-encephalographic measurements in ScZ patients (n = 37) and 9 studies in early-stage psychosis. The following gamma-band parameters were examined: (1) evoked spectral power, (2) intertrial phase coherence (ITPC), (3) induced spectral power, and (4) baseline power.
STUDY RESULTS
Animal and human pharmacological data reported a reduction, especially for evoked gamma-band power and ITPC, as well as an increase and biphasic effects of gamma-band activity following NMDA-R antagonist administration. In addition, NMDA-R antagonists increased baseline gamma-band activity in preclinical studies. Reductions in ITPC and evoked gamma-band power were broadly compatible with findings observed in ScZ and early-stage psychosis patients where the majority of studies observed decreased gamma-band spectral power and ITPC. In regard to baseline gamma-band power, there were inconsistent findings. Finally, a publication bias was observed in studies investigating auditory gamma-band activity in ScZ patients.
CONCLUSIONS
Our systematic review indicates that NMDA-R antagonists may partially recreate reductions in gamma-band spectral power and ITPC during auditory stimulation in ScZ. These findings are discussed in the context of current theories involving alteration in E/I balance and the role of NMDA hypofunction in the pathophysiology of ScZ.
PubMed: 38934800
DOI: 10.1093/schbul/sbae090 -
The American Journal of Surgical... Jun 2024GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene...
A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1-altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1- amplified Versus GLI1-rearranged Tumors.
GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-altered mesenchymal neoplasms to date, including 23 GLI1-amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-amplified tumors. GLI1-amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-altered mesenchymal tumors.
PubMed: 38934567
DOI: 10.1097/PAS.0000000000002272 -
Journal of Experimental Zoology. Part... Jun 2024Slow and sustainable intermittent swimming has recently been described in several Centrarchid fishes, such as bluegill and largemouth bass. This swimming behavior...
Slow and sustainable intermittent swimming has recently been described in several Centrarchid fishes, such as bluegill and largemouth bass. This swimming behavior involves short periods of body-caudal fin undulation alternating with variable periods of coasting. This aerobic muscle powered swimming appears to reduce energetic costs for slow, sustainable swimming, with fish employing a "fixed-gear" or constant tailbeat frequency and modulating swimming speed by altering the length of the coasting period. We asked if this swimming behavior was found in other fish species by examining volitional swimming by brook trout in a static swimming tank. Further, we employed muscle mechanics experiments to explore how intermittent swimming affects muscle power output in comparison to steady swimming behavior. Brook trout regularly employ an intermittent swimming form when allowed to swim volitionally, and consistently showed a tailbeat frequency of ~2 Hz. Coasting duration had a significant, inverse relationship to swimming speed. Across a range of slow, sustainable swimming speeds, tailbeat frequency increased modestly with speed. The duration of periods of coasting decreased significantly with increasing speed. Workloop experiments suggest that intermittent swimming reduces fatigue, allowing fish to maintain high power output for longer compared to continuous activity. This study expands the list of species that employ intermittent swimming, suggesting this behavior is a general feature of fishes.
PubMed: 38934396
DOI: 10.1002/jez.2844 -
Frontiers in Genetics 2024The single nucleotide polymorphism (SNP) rs4644 at codon 64 of galectin-3 (gal-3, gene name: ), specifying the variant proline (P64) to histidine (H64), is known to...
INTRODUCTION
The single nucleotide polymorphism (SNP) rs4644 at codon 64 of galectin-3 (gal-3, gene name: ), specifying the variant proline (P64) to histidine (H64), is known to affect the protein's functions and has been associated with the risk of several types of cancer, including differentiated thyroid carcinoma (DTC).
MATERIALS AND METHODS
To deepen our understanding of the biological effects of this SNP, we analyzed the proteome of two isogenic cell lines (NC-P64 vs. NA-H64) derived from the immortalized non-malignant thyrocyte cell line Nthy-Ori, generated through the CRISPR-Cas9 technique to differ by rs4644 genotype. We compared the proteome of these cells to detect differentially expressed proteins and studied their proteome in relation to their transcriptome.
RESULTS
Firstly, we found, consistently with previous studies, that gal-3-H64 could be detected as a monomer, homodimer, and heterodimer composed of one cleaved and one uncleaved monomer, whereas gal-3-P64 could be found only as a monomer or uncleaved homodimer. Moreover, results indicate that rs4644 influences the expression of several proteins, predominantly upregulated in NA-H64 cells. Overall, the differential protein expression could be attributed to the altered mRNA expression, suggesting that rs4644 shapes the function of gal-3 as a transcriptional co-regulator. However, this SNP also appeared to affect post-transcriptional regulatory mechanisms for proteins whose expression was oppositely regulated compared to mRNA expression. It is conceivable that the rs4644-dependent activities of gal-3 could be ascribed to the different modalities of self-dimerization.
CONCLUSION
Our study provided further evidence that rs4644 could affect the gal-3 functions through several routes, which could be at the base of differential susceptibility to diseases, as reported in case-control association studies.
PubMed: 38933925
DOI: 10.3389/fgene.2024.1380495 -
Frontiers in Neuroscience 2024Sensorineural hearing loss (SNHL) is the most common form of sensory deprivation and is often unrecognized by patients, inducing not only auditory but also nonauditory...
PURPOSE
Sensorineural hearing loss (SNHL) is the most common form of sensory deprivation and is often unrecognized by patients, inducing not only auditory but also nonauditory symptoms. Data-driven classifier modeling with the combination of neural static and dynamic imaging features could be effectively used to classify SNHL individuals and healthy controls (HCs).
METHODS
We conducted hearing evaluation, neurological scale tests and resting-state MRI on 110 SNHL patients and 106 HCs. A total of 1,267 static and dynamic imaging characteristics were extracted from MRI data, and three methods of feature selection were computed, including the Spearman rank correlation test, least absolute shrinkage and selection operator (LASSO) and t test as well as LASSO. Linear, polynomial, radial basis functional kernel (RBF) and sigmoid support vector machine (SVM) models were chosen as the classifiers with fivefold cross-validation. The receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity and accuracy were calculated for each model.
RESULTS
SNHL subjects had higher hearing thresholds in each frequency, as well as worse performance in cognitive and emotional evaluations, than HCs. After comparison, the selected brain regions using LASSO based on static and dynamic features were consistent with the between-group analysis, including auditory and nonauditory areas. The subsequent AUCs of the four SVM models (linear, polynomial, RBF and sigmoid) were as follows: 0.8075, 0.7340, 0.8462 and 0.8562. The RBF and sigmoid SVM had relatively higher accuracy, sensitivity and specificity.
CONCLUSION
Our research raised attention to static and dynamic alterations underlying hearing deprivation. Machine learning-based models may provide several useful biomarkers for the classification and diagnosis of SNHL.
PubMed: 38933814
DOI: 10.3389/fnins.2024.1402039