Crude oil contamination has been shown to impair reproduction in aquatic animals through carcinogenic and genotoxic properties. Here, we assessed the endocrine-disrupting function of crude oil on male reproductive system based on testicular histology, sex steroid hormones, and fertility endpoints in adult male goldfish (Carassius auratus), which were exposed to 0.02- to 2-mg/L crude oil for 21 days (Experiment #1) or to 5- to 250-mg/L crude oil for 9 days (Experiment #2). The crude oil contained 0.22-mg/L nickel (Ni), 1.10-mg/L vanadium (V), and 12.87-mg/L polycyclic aromatic hydrocarbons (PAHs). Twenty-four hours after adding crude oil, the sum of PAHs ranged from 0.30 to 2.28 μg/L in the aquaria containing 0.02- and 250-mg/L crude oil, respectively. Water analyses for heavy metals in Experiment #2 showed high concentrations (mg/L) of Ni (0.07-0-09) and V (0.10-0.21). For both experiments, exposure to crude oil did not impact gonadosomatic index; however, testes showed histopathological defects including hyperplasia or hypertrophy of Sertoli cells, depletion of the Leydig cells, necrosis of germ cells, and fibrosis of lobular wall. In Experiment #1, sperm production and motility, testosterone (T), and 17β-estradiol (E2) were not significantly different among treatments. In Experiment #2, the number of spermiating males decreased by ~50% following exposure to 250-mg/L crude oil. Sperm production, motility kinematics, T, and the T/E2 ratio significantly decreased in males exposed to ≥ 50-mg/L crude oil; however, E2 remained unchanged. Results show crude oil-induced imbalance of sex steroid hormones disrupts spermatogenesis resulting in diminished sperm production and motility.
- MeSH
- Water Pollutants, Chemical * toxicity MeSH
- Endocrine Disruptors * toxicity MeSH
- Goldfish * physiology MeSH
- Sperm Motility * drug effects MeSH
- Gonadal Steroid Hormones * metabolism blood MeSH
- Petroleum * toxicity MeSH
- Reproduction drug effects MeSH
- Spermatozoa * drug effects pathology MeSH
- Testis * drug effects pathology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
OBJECTIVE: Transgenic mice with fluorescent protein (FP) reporters take full advantage of new in vivo imaging technologies. Therefore, we generated a TRPC5- and a TRPA1-reporter mouse based on FP C-terminal fusion, providing us with better alternatives for studying the physiology, interaction and coeffectors of these two TRP channels at the cellular and tissue level. METHODS: We generated transgenic constructs of the murine TRPC5- and TRPA1-gene with a 3*GGGGS linker and C-terminal fusion to mCherry and mTagBFP, respectively. We microinjected zygotes to generate reporter mice. Reporter mice were examined for visible fluorescence in trigeminal ganglia with two-photon microscopy, immunohistochemistry and calcium imaging. RESULTS: Both TRPC5-mCherry and TRPA1-mTagBFP knock-in mouse models were successful at the DNA and RNA level. However, at the protein level, TRPC5 resulted in no mCherry fluorescence. In contrast, sensory neurons derived from the TRPA1-reporter mice exhibited visible mTag-BFP fluorescence, although TRPA1 had apparently lost its ion channel function. CONCLUSIONS: Creating transgenic mice with a TRP channel tagged at the C-terminus with a FP requires detailed investigation of the structural and functional consequences in a given cellular context and fine-tuning the design of specific constructs for a given TRP channel subtype. Different degrees of functional impairment of TRPA1 and TRPC5 constructs suggest a specific importance of the distal C-terminus for the regulation of these two channels in trigeminal neurons.
- MeSH
- Red Fluorescent Protein MeSH
- Trigeminal Ganglion metabolism MeSH
- Gene Knock-In Techniques * MeSH
- TRPC Cation Channels * genetics metabolism MeSH
- TRPA1 Cation Channel * genetics metabolism MeSH
- Luminescent Proteins * genetics metabolism MeSH
- Mice, Transgenic * MeSH
- Mice MeSH
- Recombinant Fusion Proteins metabolism genetics MeSH
- Calcium metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction. When applied topically to human stratum corneum sheets, SPC and GS increased water loss, decreased electrical impedance, and slightly disordered lipid chains. In lipid models containing isolated human stratum corneum ceramides, reducing ceramides by ≥ 30% significantly increased permeability to four markers, likely due to loss of long-periodicity phase (LPP) lamellae and phase separation within the lipid matrix, as revealed by X-ray diffraction and infrared spectroscopy. However, when the missing ceramides were replaced by lysosphingolipids and FFAs, no further increase in permeability was observed. Conversely, these molecules partially mitigated the negative effects of ceramide deficiency, particularly with 5%-10% SPC, which reduced permeability even compared to control with "healthy" lipid composition. These findings suggest that while ceramide deficiency is a key factor in skin barrier dysfunction, the presence of lysosphingolipids and FFAs does not aggravate lipid structural or functional damage, but may provide partial compensation, raising further questions about the behavior of lyso(sphingo)lipids in rigid multilamellar lipid environments, such as the stratum corneum, that warrant further investigation.
- MeSH
- Models, Biological MeSH
- Ceramides * metabolism MeSH
- Phosphorylcholine analogs & derivatives MeSH
- Skin * metabolism MeSH
- Fatty Acids, Nonesterified metabolism MeSH
- Humans MeSH
- Lysophospholipids metabolism MeSH
- Permeability drug effects MeSH
- Sphingosine analogs & derivatives metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Although neuromelanin-sensitive magnetic resonance imaging (NM-MRI) has been used to evaluate early neurodegeneration in Parkinson's disease, studies concentrating on the locus coeruleus (LC) in pre-dementia stages of dementia with Lewy bodies (DLB) are lacking. OBJECTIVES: The aims were to evaluate NM-MRI signal changes in the LC in patients with mild cognitive impairment with Lewy bodies (MCI-LB) compared to healthy controls (HC) and to identify the cognitive correlates of the changes. We also aimed to test the hypothesis of a caudal-rostral α-synuclein pathology spread using NM-MRI of the different LC subparts. METHODS: A total of 38 MCI-LB patients and 59 HCs underwent clinical and cognitive testing and NM-MRI of the LC. We calculated the contrast ratio of NM-MRI signal (LC-CR) in the whole LC as well as in its caudal, middle, and rostral MRI slices, and we compared the LC-CR values between the MCI-LB and HC groups. Linear regression analyses were performed to assess the relationship between the LC-CR and cognitive outcomes. RESULTS: The MCI-LB group exhibited a significant reduction in the right LC-CR compared to HCs (P = 0.021). The right LC-CR decrease was associated with impaired visuospatial memory in the MCI-LB group. Only the caudal part of the LC exhibited significant LC-CR decreases in MCI-LB patients compared to HCs on both sides (P < 0.0001). CONCLUSIONS: This is the first study that focuses on LC-CRs in MCI-LB patients and analyzes the LC subparts, offering new insights into the LC integrity alterations in the initial stages of DLB and their clinical correlates. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- MeSH
- alpha-Synuclein metabolism MeSH
- Lewy Body Disease * diagnostic imaging pathology MeSH
- Cognitive Dysfunction * diagnostic imaging pathology physiopathology etiology MeSH
- Middle Aged MeSH
- Humans MeSH
- Locus Coeruleus * diagnostic imaging pathology MeSH
- Magnetic Resonance Imaging * MeSH
- Neuropsychological Tests MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
OBJECTIVES: Decision-analytic models assessing the value of emerging Alzheimer's disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. METHODS: A benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. RESULTS: Nine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating - sum of boxes, clinical dementia rating - global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from -US$66 897 to US$11 896. CONCLUSIONS: Trial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.
- MeSH
- Alzheimer Disease * economics drug therapy MeSH
- Cost-Benefit Analysis * MeSH
- Models, Economic MeSH
- Cognitive Dysfunction * economics MeSH
- Quality-Adjusted Life Years MeSH
- Humans MeSH
- Decision Support Techniques MeSH
- Disease Progression MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
Alexander disease (AxD) is a rare and severe neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP). While the exact disease mechanism remains unknown, previous studies suggest that mutant GFAP influences many cellular processes, including cytoskeleton stability, mechanosensing, metabolism, and proteasome function. While most studies have primarily focused on GFAP-expressing astrocytes, GFAP is also expressed by radial glia and neural progenitor cells, prompting questions about the impact of GFAP mutations on central nervous system (CNS) development. In this study, we observed impaired differentiation of astrocytes and neurons in co-cultures of astrocytes and neurons, as well as in neural organoids, both generated from AxD patient-derived induced pluripotent stem (iPS) cells with a GFAPR239C mutation. Leveraging single-cell RNA sequencing (scRNA-seq), we identified distinct cell populations and transcriptomic differences between the mutant GFAP cultures and a corrected isogenic control. These findings were supported by results obtained with immunocytochemistry and proteomics. In co-cultures, the GFAPR239C mutation resulted in an increased abundance of immature cells, while in unguided neural organoids and cortical organoids, we observed altered lineage commitment and reduced abundance of astrocytes. Gene expression analysis revealed increased stress susceptibility, cytoskeletal abnormalities, and altered extracellular matrix and cell-cell communication patterns in the AxD cultures, which also exhibited higher cell death after stress. Overall, our results point to altered cell differentiation in AxD patient-derived iPS-cell models, opening new avenues for AxD research.
- MeSH
- Alexander Disease * genetics pathology metabolism MeSH
- Astrocytes * metabolism pathology MeSH
- Cell Differentiation * physiology MeSH
- Glial Fibrillary Acidic Protein * metabolism genetics MeSH
- Induced Pluripotent Stem Cells * metabolism MeSH
- Coculture Techniques MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Mutation MeSH
- Neural Stem Cells metabolism MeSH
- Neurons metabolism pathology MeSH
- Organoids metabolism pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: A number of recent studies have shown that the intestinal microbiome, part of the brain-gut axis, is implicated in the pathophysiology of multiple sclerosis. An essential part of this axis, is the intestinal barrier and gastrointestinal disorders with intestinal barrier dysregulation appear to be linked to CNS demyelination, and hence involved in the etiopathogenesis of multiple sclerosis (MS). OBJECTIVE: The aim of this study was to evaluate the integrity of the intestinal barrier in patients with clinically definite multiple sclerosis (CDMS) and clinically isolated syndrome (CIS) using two serum biomarkers, claudin-3 (CLDN3), a component of tight epithelial junctions, and intestinal fatty acid binding protein (I-FABP), a cytosolic protein in enterocytes. METHODS: Serum levels of CLDN3 in 37 MS patients and 22 controls, and serum levels of I-FABP in 46 MS patients and 51 controls were measured using commercial ELISA kits. Complete laboratory tests excluded the presence of gluten-related disorders in all subjects. Thirty MS patients received either disease-modifying drugs (DMD), immunosuppression (IS) or corticosteroid treatment. RESULTS: CLDN3 levels were only significantly higher in the MS patients treated with DMD or IS compared to the control group (P=0.006). There were no differences in I-FABP serum levels between the groups. Serum CLDN3 levels did not correlate with serum I-FABP levels in CDMS, in CIS patients or controls. CONCLUSIONS: In multiple sclerosis patients, the intestinal epithelium may be impaired with increased permeability, but without significant enterocyte damage characterized by intracellular protein leakage. Based on our data, CLDN3 serum levels appear to assess intestinal dysfunction in MS patients but mainly in treated ones.
- MeSH
- Biomarkers * blood MeSH
- Claudin-3 * metabolism MeSH
- Adult MeSH
- Intestinal Barrier Function MeSH
- Middle Aged MeSH
- Humans MeSH
- Permeability * MeSH
- Fatty Acid-Binding Proteins * blood MeSH
- Multiple Sclerosis * physiopathology metabolism blood MeSH
- Intestinal Mucosa metabolism MeSH
- Case-Control Studies MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND AND PURPOSE: Cognitive impairment (CI) in multiple sclerosis (MS) is associated with bidirectional changes in resting-state centrality measures. However, practicable functional magnetic resonance imaging (fMRI) biomarkers of CI are still lacking. The aim of this study was to assess the graph-theory-based degree rank order disruption index (kD) and its association with cognitive processing speed as a marker of CI in patients with MS (PwMS) in a secondary cross-sectional fMRI analysis. METHODS: Differentiation between PwMS and healthy controls (HCs) using kD and its correlation with CI (Symbol Digit Modalities Test) was compared to established imaging biomarkers (regional degree, volumetry, diffusion-weighted imaging, lesion mapping). Additional associations were assessed for fatigue (Fatigue Scale for Motor and Cognitive Functions), gait and global disability. RESULTS: Analysis in 56 PwMS and 58 HCs (35/27 women, median age 45.1/40.5 years) showed lower kD in PwMS than in HCs (median -0.30/-0.06, interquartile range 0.55/0.54; p = 0.009, Mann-Whitney U test), yielding acceptable yet non-superior differentiation (area under curve 0.64). kD and degree in medial prefrontal cortex (MPFC) correlated with CI (kD/MPFC Spearman's ρ = 0.32/-0.45, p = 0.019/0.001, n = 55). kD also explained fatigue (ρ = -0.34, p = 0.010, n = 56) but neither gait nor disability. CONCLUSIONS: kD is a potential biomarker of CI and fatigue warranting further validation.
- MeSH
- Adult MeSH
- Cognitive Dysfunction etiology physiopathology diagnostic imaging MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging * MeSH
- Cross-Sectional Studies MeSH
- Multiple Sclerosis * complications diagnostic imaging physiopathology MeSH
- Processing Speed MeSH
- Fatigue * physiopathology etiology diagnostic imaging MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Alzheimerova choroba je nejčastější příčinou demence a včasná diagnostika je klíčová pro zahájení léčby. Porucha čichu, zejména schopnost identifikace pachů, byla opakovaně identifikována jako raný příznak neurodegenerativních změn a může pomoci při časné detekci Alzheimerovy choroby. Psychofyzické testy čichu, jako je Sniffin’ Sticks, (SST) University of Pennsylvania Smell Identification Test (UPSIT), či test parfémovaných fixů (OMT), jsou spolehlivými nástroji pro hodnocení čichových funkcí a mají potenciál doplnit tradiční neuropsychologické testy. Kombinace čichových a kognitivních testů významně zvyšuje přesnost predikce nástupu demence.
Koutná V, Štěpánek L, Trajerová R, Janout V, Janoutová J. Olfactory impairment as a biomarker in early diagnosis of Alzheimer’s disease in primary care Alzheimer’s disease is the most common cause of dementia and early diagnosis is key to initiating treatment. Olfactory dysfunction, particularly the ability to discriminate odors, has been repeatedly identified as an early sign of neurodegenerative changes and may aid in the early detection of Alzheimer’s disease. Psychophysical olfactory tests such as the Sniffin’ Sticks (SST), University of Pennsylvania Smell Identification Test (UPSIT) or the Odorized Marker Test (OMT) are reliable tools for assessing olfactory function and have potential to complement traditional neuropsychological tests. The combination of olfactory and cognitive tests significantly increases the accuracy of predicting the onset of dementia.
Neural networks are responsible for processing sensory stimuli and driving the synaptic activity required for brain function and behavior. This computational capacity is expensive and requires a steady supply of energy and building blocks to operate. Importantly, the neural networks are composed of different cell populations, whose metabolic profiles differ between each other, thus endowing them with different metabolic capacities, such as, for example, the ability to synthesize specific metabolic precursors or variable proficiency to manage their metabolic waste. These marked differences likely prompted the emergence of diverse intercellular metabolic interactions, in which the shuttling and cycling of specific metabolites between brain cells allows the separation of workload and efficient control of energy demand and supply within the central nervous system. Nevertheless, our knowledge about brain bioenergetics and the specific metabolic adaptations of neural cells still warrants further studies. In this review, originated from the Fourth International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Schmerlenbach, Germany (2022), we describe and discuss the specific metabolic profiles of brain cells, the intercellular metabolic exchanges between these cells, and how these bioenergetic activities shape synaptic function and behavior. Furthermore, we discuss the potential role of faulty brain metabolic activity in the etiology and progression of Alzheimer's disease, Parkinson disease, and Amyotrophic lateral sclerosis. We foresee that a deeper understanding of neural networks metabolism will provide crucial insights into how higher-order brain functions emerge and reveal the roots of neuropathological conditions whose hallmarks include impaired brain metabolic function.
- MeSH
- Energy Metabolism * physiology MeSH
- Humans MeSH
- Metabolic Networks and Pathways * physiology MeSH
- Brain * metabolism MeSH
- Nerve Net * metabolism MeSH
- Neurons * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
