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American Journal of Respiratory Cell... Apr 2024Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to...
Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to alterations of airways and the distal lung. Although clinical studies have shown striking associations between antenatal stress and BPD, little is known about the underlying pathogenetic mechanisms. Whether dysanapsis, the concept of discordant growth of the airways and parenchyma, contributes to late respiratory disease as a result of antenatal stress is unknown. We hypothesized that antenatal endotoxin (ETX) impairs juvenile lung function as a result of altered central airway and distal lung structure, suggesting the presence of dysanapsis in this preclinical BPD model. Fetal rats were exposed to intraamniotic ETX (10 μg) or saline solution (control) 2 days before term. We performed extensive structural and functional evaluation of the proximal airways and distal lung in 2-week-old rats. Distal lung structure was quantified by stereology. Conducting airway diameters were measured using micro-computed tomography. Lung function was assessed during invasive ventilation to quantify baseline mechanics, response to methacholine challenge, and spirometry. ETX-exposed pups exhibited distal lung simplification, decreased alveolar surface area, and decreased parenchyma-airway attachments. ETX-exposed pups exhibited decreased tracheal and second- and third-generation airway diameters. ETX increased respiratory system resistance and decreased lung compliance at baseline. Only Newtonian resistance, specific to large airways, exhibited increased methacholine reactivity in ETX-exposed pups compared with controls. ETX-exposed pups had a decreased ratio of FEV in 0.1 second to FVC and a normal FEV in 0.1 second, paralleling the clinical definition of dysanapsis. Antenatal ETX causes abnormalities of the central airways and distal lung growth, suggesting that dysanapsis contributes to abnormal lung function in juvenile rats.
Topics: Rats; Animals; Female; Pregnancy; Bronchopulmonary Dysplasia; Endotoxins; Methacholine Chloride; X-Ray Microtomography; Rats, Sprague-Dawley; Animals, Newborn; Lung
PubMed: 38207120
DOI: 10.1165/rcmb.2023-0157OC -
Journal of Cardiovascular Pharmacology Apr 2024Chronic stress induces a group of unrecognized cardiovascular impairments, including elevated hemodynamic variables and vascular dysfunction. Moreover, hydrogen sulfide...
Chronic stress induces a group of unrecognized cardiovascular impairments, including elevated hemodynamic variables and vascular dysfunction. Moreover, hydrogen sulfide (H 2 S), a gasotransmitter that regulates the cardiovascular system decreases under chronic stress. Thus, this study assessed the impact of sodium hydrosulfide (NaHS) (H 2 S donor) on chronic restraint stress (CRS)-induced cardiovascular changes. For that purpose, male Wistar rats were restrained for 2 hours a day in a transparent acrylic tube over 8 weeks. Then, body weight, relative adrenal gland weight, serum corticosterone, H 2 S-synthesizing enzymes, endothelial nitric oxide synthetize expression, reactive oxygen species levels, lipid peroxidation, and reduced glutathione-to-oxidized glutathione (GSH 2 :GSSG) ratio were determined in the thoracic aorta. The hemodynamic variables were measured in vivo by the plethysmograph method. The vascular function was evaluated in vitro as vasorelaxant responses induced by carbachol or sodium nitroprusside, and norepinephrine (NE)-mediated vasocontractile responses in the thoracic aorta. CRS increased (1) relative adrenal gland weight; (2) hemodynamic variables; (3) vasoconstrictor responses induced by NE, (4) reactive oxygen species levels, and (5) lipid peroxidation in the thoracic aorta. In addition, CRS decreased (1) body weight; (2) vasorelaxant responses induced by carbachol; (3) GSH content, and (4) GSH 2 :GSSG ratio. Notably, NaHS administration (5.6 mg/kg) restored hemodynamic variables and lipid peroxidation and attenuated the vasoconstrictor responses induced by NE in the thoracic aorta. In addition, NaHS treatment increased relative adrenal gland weight and the GSH 2 :GSSG ratio. Taken together, our results demonstrate that NaHS alleviates CRS-induced hypertension by reducing oxidative stress and restoring vascular function in the thoracic aorta.
Topics: Rats; Animals; Male; Reactive Oxygen Species; Glutathione Disulfide; Carbachol; Rats, Wistar; Hydrogen Sulfide; Oxidative Stress; Vasoconstrictor Agents; Vasodilator Agents; Body Weight; Sulfides
PubMed: 38207007
DOI: 10.1097/FJC.0000000000001538 -
JCI Insight Jan 2024Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of...
Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre:Lin28aloxP/loxP (conditional KO [cKO]) and Nestin-Cre:Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A-cKO mice, as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1+/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomics analysis and IHC validation at 3 days after pilocarpine administration provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a potentially novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis.
Topics: Animals; Nestin; Pilocarpine; Seizures; Status Epilepticus; Hippocampus; Neurogenesis; Epilepsy
PubMed: 38193536
DOI: 10.1172/jci.insight.175627 -
Brain Research Bulletin Feb 2024In temporal lobe epilepsy (TLE), the epileptogenic zones, such as the temporal lobe structure, could generate pathological high-frequency oscillations (pHFOs,...
In temporal lobe epilepsy (TLE), the epileptogenic zones, such as the temporal lobe structure, could generate pathological high-frequency oscillations (pHFOs, 250-500 Hz) before the ictal period. These pHFOs have also been observed during the process of seizures in both TLE patients and animals, exhibiting a critical role as promising biomarkers for TLE seizures. TLE seizures could be modulated via regulating the neural excitability in epileptogenic zones, for that TLE is primarily associated with the excitation-inhibition imbalance. However, whether these kinds of modulations could also impact the pHFOs characteristics during TLE seizures is still unclear. For this purpose, we pharmaco-genetically inhibited the principal cells (PCs) in the mouse CA3 region and tracked the difference in the behavioral and electrophysiological features during LiCl-pilocarpine-induced TLE seizure between the hM4Di+CNO (experimental) mice and mCherry+CNO (control) mice. Delayed latency, decreased averaged duration, and reduced counts of the generalized seizure were observed in the experimental mice. Besides, the electrophysiological characteristics, such as the firing rate of PCs and the count of pHFO, exhibited significant decline in the CA3 and CA1 regions. During TLE seizure, there existed strong phase-coupling between pHFO and PCs spike timing in the control mice, while it was abolished in the experimental mice. In addition, we also found that the counts of pHFO were significantly associated with the behavioral features, indicating the close relationships within them. Collectively, our findings suggested that alterations in pHFO and the retardation of seizures may be attributed to disruptions in neuronal excitability, and the variations of electrophysiological features were related to seizure severity during TLE seizures. These results provide valuable insights into the role of pHFOs in TLE and shed light on the underlying mechanisms involved.
Topics: Humans; Mice; Animals; Epilepsy, Temporal Lobe; Seizures; Temporal Lobe; Pilocarpine; Electroencephalography
PubMed: 38184151
DOI: 10.1016/j.brainresbull.2024.110869 -
BMC Research Notes Jan 2024Silicosis is an irreversible occupational lung disease resulting from crystalline silica inhalation. Previously, we discovered that Western diet (HFWD)-consumption...
OBJECTIVES
Silicosis is an irreversible occupational lung disease resulting from crystalline silica inhalation. Previously, we discovered that Western diet (HFWD)-consumption increases susceptibility to silica-induced pulmonary inflammation and fibrosis. This study investigated the potential of HFWD to alter silica-induced effects on airway epithelial ion transport and smooth muscle reactivity.
METHODS
Six-week-old male F344 rats were fed a HFWD or standard rat chow (STD) and exposed to silica (Min-U-Sil 5, 15 mg/m, 6 h/day, 5 days/week, for 39 d) or filtered air. Experimental endpoints were measured at 0, 4, and 8 weeks post-exposure. Transepithelial potential difference (V), short-circuit current (I) and transepithelial resistance (R) were measured in tracheal segments and ion transport inhibitors [amiloride, Na channel blocker; NPPB; Cl- channel blocker; ouabain, Na, K-pump blocker] identified changes in ion transport pathways. Changes in airway smooth muscle reactivity to methacholine (MCh) were investigated in the isolated perfused trachea preparation.
RESULTS
Silica reduced basal I at 4 weeks and HFWD reduced the I response to amiloride at 0 week compared to air control. HFWD + silica exposure induced changes in ion transport 0 and 4 weeks after treatment compared to silica or HFWD treatments alone. No effects on airway smooth muscle reactivity to MCh were observed.
Topics: Male; Rats; Animals; Amiloride; Silicon Dioxide; Diet, Western; Rats, Inbred F344; Epithelium; Ion Transport; Methacholine Chloride; Muscle, Smooth
PubMed: 38172968
DOI: 10.1186/s13104-023-06672-w -
Neurologia 2024The growth hormone (GH) has been reported as a crucial neuronal survival factor in the hippocampus against insults of diverse nature. Status epilepticus (SE) is a...
INTRODUCTION
The growth hormone (GH) has been reported as a crucial neuronal survival factor in the hippocampus against insults of diverse nature. Status epilepticus (SE) is a prolonged seizure that produces extensive neuronal cell death. The goal of this study was to evaluate the effect of intracerebroventricular administration of GH on seizure severity and SE-induced hippocampal neurodegeneration.
METHODOLOGY
Adult male rats were implanted with a guide cannula in the left ventricle and different amounts of GH (70, 120 or 220ng/3μl) were microinjected for 5 days; artificial cerebrospinal fluid was used as the vehicle. Seizures were induced by the lithium-pilocarpine model (3mEq/kg LiCl and 30mg/kg pilocarpine hydrochloride) one day after the last GH administration. Neuronal injury was assessed by Fluoro-Jade B (F-JB) staining.
RESULTS
Rats injected with 120ng of GH did not had SE after 30mg/kg pilocarpine, they required a higher number of pilocarpine injections to develop SE than the rats pretreated with the vehicle, 70ng or 220ng GH. Prefrontal and parietal cortex EEG recordings confirmed that latency to generalized seizures and SE was also significantly higher in the 120ng group when compared with all the experimental groups. FJ-B positive cells were detected in the hippocampus after SE in all rats, and no significant differences in the number of F-JB cells in the CA1 area and the hilus was observed between experimental groups.
CONCLUSION
Our results indicate that, although GH has an anticonvulsive effect in the lithium-pilocarpine model of SE, it does not exert hippocampal neuroprotection after SE.
Topics: Animals; Male; Rats; Anticonvulsants; Growth Hormone; Lithium; Neuroprotective Agents; Pilocarpine; Seizures; Status Epilepticus
PubMed: 38161069
DOI: 10.1016/j.nrleng.2023.12.003 -
Biomedical Chromatography : BMC Apr 2024Temporal lobe epilepsy (TLE) is a common form of refractory epilepsy in adulthood. The metabolic profile of epileptogenesis is still poorly investigated. Elucidation of... (Review)
Review
Temporal lobe epilepsy (TLE) is a common form of refractory epilepsy in adulthood. The metabolic profile of epileptogenesis is still poorly investigated. Elucidation of such a metabolic profile using animal models of epilepsy could help identify new metabolites and pathways involved in the mechanisms of epileptogenesis process. In this study, we evaluated the metabolic profile during the epileptogenesis periods. Using a pilocarpine model of epilepsy, we analyzed the global metabolic profile of hippocampal extracts by untargeted metabolomics based on ultra-performance liquid chromatography-high-resolution mass spectrometry, at three time points (3 h, 1 week, and 2 weeks) after status epilepticus (SE) induction. We demonstrated that epileptogenesis periods presented different hippocampal metabolic profiles, including alterations of metabolic pathways of amino acids and lipid metabolism. Six putative metabolites (tryptophan, N-acetylornithine, N-acetyl-L-aspartate, glutamine, adenosine, and cholesterol) showed significant different levels during epileptogenesis compared to their respective controls. These putative metabolites could be associated with the imbalance of neurotransmitters, mitochondrial dysfunction, and cell loss observed during both epileptogenesis and epilepsy. With these findings, we provided an overview of hippocampal metabolic profiles during different stages of epileptogenesis that could help investigate pathways and respective metabolites as predictive tools in epilepsy.
Topics: Animals; Epilepsy; Epilepsy, Temporal Lobe; Hippocampus; Metabolome; Pilocarpine
PubMed: 38154955
DOI: 10.1002/bmc.5820 -
Brain and Nerve = Shinkei Kenkyu No... Dec 2023Eserine, well-known as physostigmine, is classified as an alkaloid. It is a cholinesterase inhibitor and appears in Agatha Christie's novel entitled, Crooked House and...
Eserine, well-known as physostigmine, is classified as an alkaloid. It is a cholinesterase inhibitor and appears in Agatha Christie's novel entitled, Crooked House and Curtain: Poirot's Last Case. In clinical medicine, eserine was used as an ophthalmic treatment for glaucoma and considered as a treatment for myasthenia gravis, Alzheimer's disease, and hereditary cerebellar ataxias. Currently, it is used as a treatment for anticholinergic poisoning.
Topics: Humans; Physostigmine; Cholinesterase Inhibitors; Myasthenia Gravis
PubMed: 38097226
DOI: 10.11477/mf.1416202536 -
Advances in Medical Sciences Mar 2024Bronchial hyperresponsiveness (BHR), a hallmark of bronchial asthma, is typically diagnosed through a methacholine inhalation test followed by spirometry, known as the...
PURPOSE
Bronchial hyperresponsiveness (BHR), a hallmark of bronchial asthma, is typically diagnosed through a methacholine inhalation test followed by spirometry, known as the methacholine challenge test (MCT). While spirometry relies on proper patients' cooperation and precise execution of forced breathing maneuvers, we conducted a comparative analysis with the portable nanomaterial-based sensing device, SenseGuard™, to non-intrusively assess tidal breathing parameters.
MATERIALS AND METHODS
In this prospective study, 37 adult participants with suspected asthma underwent sequential spirometry and SenseGuard™ measurements after inhaling increasing methacholine doses.
RESULTS
Among the 37 participants, 18 were MCT responders, 17 were non-responders and 2 were excluded due to uninterpretable data. The MCT responders exhibited a significant lung function difference when comparing the change from baseline to maximum response. This was evident through a notable decrease in forced expiratory volume in 1 s (FEV) levels in spirometry, as well as in prominent changes in tidal breathing parameters as assessed by SenseGuard™, including the expiratory pause time (T) to total breath time (T) ratio, and the expiratory time (T) to T ratio. Notably, the ratios T/T (∗p = 0.02), T/T (∗p = 0.002), and inspiratory time (T) to T (∗p = 0.04) identified MCT responders distinctly, corresponding to spirometry (∗p < 0.0001).
CONCLUSIONS
This study demonstrates that tidal breathing assessment using SenseGuard™ device reliably detects clinically relevant changes of respiratory parameter during the MCT. It effectively distinguishes between responders and non-responders, with strong agreement to conventional spirometry-measured FEV. This technology holds promise for monitoring clinical respiratory changes in bronchial asthma patients pending further studies.
Topics: Humans; Methacholine Chloride; Male; Female; Adult; Bronchial Provocation Tests; Prospective Studies; Spirometry; Middle Aged; Asthma; Tidal Volume; Young Adult; Bronchial Hyperreactivity
PubMed: 38096771
DOI: 10.1016/j.advms.2023.11.001 -
Scientific Reports Dec 2023Transient brain insults including status epilepticus (SE) can initiate a process termed 'epileptogenesis' that results in chronic temporal lobe epilepsy. As a...
Transient brain insults including status epilepticus (SE) can initiate a process termed 'epileptogenesis' that results in chronic temporal lobe epilepsy. As a consequence, the entire tri-synaptic circuit of the hippocampus is fundamentally impaired. A key role in epileptogenesis has been attributed to the CA1 region as the last relay station in the hippocampal circuit and as site of aberrant plasticity, e.g. mediated by acquired channelopathies. The transcriptional profiles of the distinct hippocampal neurons are highly dynamic during epileptogenesis. Here, we aimed to elucidate the early SE-elicited mRNA signature changes and the respective upstream regulatory cascades in CA1. RNA sequencing of CA1 was performed in the mouse pilocarpine-induced SE model at multiple time points ranging from 6 to 72 h after the initial insult. Bioinformatics was used to decipher altered gene expression, signalling cascades and their corresponding cell type profiles. Robust transcriptomic changes were detected at 6 h after SE and at subsequent time points during early epileptogenesis. Major differentially expressed mRNAs encoded primarily immediate early and excitability-related gene products, as well as genes encoding immune signalling factors. Binding sites for the transcription factors Nfkb1, Spi1, Irf8, and two Runx family members, were enriched within promoters of differentially expressed genes related to major inflammatory processes, whereas the transcriptional repressors Suz12, Nfe2l2 and Rest were associated with hyperexcitability and GABA / glutamate receptor activity. CA1 quickly responds to SE by inducing transcription of genes linked to inflammation and excitation stress. Transcription factors mediating this transcriptomic switch represent targets for new highly selected, cell type and time window-specific anti-epileptogenic strategies.
Topics: Mice; Animals; Hippocampus; Status Epilepticus; Epilepsy, Temporal Lobe; Neurons; Pilocarpine; Transcription Factors; Disease Models, Animal
PubMed: 38092829
DOI: 10.1038/s41598-023-49310-y