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Scientific Reports Jun 2024Human health is becoming concerned about exposure to endocrine disrupting chemicals (EDCs) emanating from plastic, such as phthalates, which are industrially employed as...
Human health is becoming concerned about exposure to endocrine disrupting chemicals (EDCs) emanating from plastic, such as phthalates, which are industrially employed as plasticizers in the manufacturing of plastic products. Due to some toxicity concerns, di(2-ethylhexyl) phthalate (DEHP) was replaced by diisononyl phthalate (DiNP). Recent data, however, highlights the potential of DiNP to interfere with the endocrine system and influence allergic responses. Asthma affects brain function through hypoxia, systemic inflammation, oxidative stress, and sleep disturbances and its effective management is crucial for maintaining respiratory and brain health. Therefore, in DiNP-induced asthmatic mice, this study investigated possible crosstalk between the lungs and the brain inducing perturbations in neural mitochondrial antioxidant status, inflammation biomarkers, energy metabolizing enzymes, and apoptotic indicators. To achieve this, twelve (n = 12, 20-30 g) male BALB/c mice were divided into two (2) experimental groups, each with five (6) mice. Mice in group II were subjected to 50 mg/kg body weight (BW) DiNP (Intraperitoneal and intranasal), while group I served as the control group for 24 days. The effects of DiNP on neural energy metabolizing enzymes (Hexokinase, Aldolase, NADase, Lactate dehydrogenase, Complex I, II, II & IV), biomarkers of inflammation (Nitric oxide, Myeloperoxidase), oxidative stress (malondialdehyde), antioxidants (catalase, glutathione-S-transferase, and reduced glutathione), oncogenic and apoptotic factors (p53, K-ras, Bcl, etc.), and brain histopathology were investigated. DiNP-induced asthmatic mice have significantly (p < 0.05) altered neural energy metabolizing capacities due to disruption of activities of enzymes of glycolytic and oxidative phosphorylation. Other responses include significant inflammation, oxidative distress, decreased antioxidant status, altered oncogenic-apoptotic factors level and neural degeneration (as shown in hematoxylin and eosin-stained brain sections) relative to control. Current findings suggest that neural histoarchitecture, energy metabolizing potentials, inflammation, oncogenic and apoptotic factors, and mitochondrial antioxidant status may be impaired and altered in DiNP-induced asthmatic mice suggesting a pivotal crosstalk between the two intricate organs (lungs and brain).
Topics: Animals; Apoptosis; Asthma; Oxidative Stress; Mitochondria; Mice; Male; Mice, Inbred BALB C; Lung; Phthalic Acids; Cell Respiration; Signal Transduction; Brain
PubMed: 38926453
DOI: 10.1038/s41598-024-65356-y -
Scientific Reports Jun 2024The incidence and clinical distribution of intracranial haemorrhage (ICH) in neonates at risk of cerebral hypoxia-ischaemia have not been reported in specific studies....
The incidence and clinical distribution of intracranial haemorrhage (ICH) in neonates at risk of cerebral hypoxia-ischaemia have not been reported in specific studies. Based on conventional magnetic resonance imaging (MRI) versus susceptibility weighted imaging (SWI), this study aimed to analyse the occurrence of asymptomatic ICH in newborns with or without risk of cerebral hypoxia-ischaemia and to accumulate objective data for clinical evaluations of high-risk neonates and corresponding response strategies. 317 newborns were included. MRI revealed that the overall incidence of ICH was 59.31%. The most common subtype was intracranial extracerebral haemorrhage (ICECH) which included subarachnoid haemorrhage (SAH) and subdural haemorrhage (SDH). ICECH accounted for 92.02% of ICH. The positive detection rate of ICECH by SWI was significantly higher than that by T1WI. The incidence of total ICH, ICECH and SAH was greater among children who were delivered vaginally than among those who underwent caesarean delivery. Asymptomatic neonatal ICH may be a common complication of the neonatal birth process, and SWI may improve the detection rate. Transvaginal delivery and a weight greater than 2500 g were associated with a high incidence of ICECH in neonates. The impact of neonatal cerebral hypoxia-ischaemia risk factors on the occurrence of asymptomatic ICH may be negligible.
Topics: Humans; Infant, Newborn; Female; Magnetic Resonance Imaging; Incidence; Male; Intracranial Hemorrhages; Hypoxia-Ischemia, Brain; Risk Factors
PubMed: 38926428
DOI: 10.1038/s41598-024-62473-6 -
Nature Communications Jun 2024Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples,...
Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.
Topics: Humans; RNA Editing; Adenosine; Adenosine Deaminase; Brain; Inosine; RNA-Binding Proteins; Autopsy; Prefrontal Cortex; Postmortem Changes; Male
PubMed: 38926387
DOI: 10.1038/s41467-024-49268-z -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2024To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore its mechanisms via the...
OBJECTIVES
To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore its mechanisms via the PI3K/AKT signaling pathway, aiming to provide a basis for the clinical application of melatonin.
METHODS
Seven-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group, an HIBD group, and a melatonin group (=9 each). The neonatal rat HIBD model was established using the classic Rice-Vannucci method. Neuronal morphology in the neonatal rat cerebral cortex was observed with hematoxylin-eosin staining and Nissl staining. Autophagy-related protein levels of microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 were detected by immunofluorescence staining and Western blot analysis. Phosphorylated phosphoinositide 3-kinase (p-PI3K) and phosphorylated protein kinase B (p-AKT) protein expression levels were measured by immunohistochemistry and Western blot. The correlation between autophagy and the PI3K pathway in the melatonin group and the HIBD group was analyzed using Pearson correlation analysis.
RESULTS
Twenty-four hours post-modeling, neurons in the sham operation group displayed normal size and orderly arrangement. In contrast, neurons in the HIBD group showed swelling and disorderly arrangement, while those in the melatonin group had relatively normal morphology and more orderly arrangement. Nissl bodies were normal in the sham operation group but distorted in the HIBD group; however, they remained relatively intact in the melatonin group. The average fluorescence intensity of LC3 and Beclin-1 was higher in the HIBD group compared to the sham operation group, but was reduced in the melatonin group compared to the HIBD group (<0.05). The number of p-PI3K and p-AKT cells decreased in the HIBD group compared to the sham operation group but increased in the melatonin group compared to the HIBD group (<0.05). LC3 and Beclin-1 protein expression levels were higher, and p-PI3K and p-AKT levels were lower in the HIBD group compared to the sham operation group (<0.05); however, in the melatonin group, LC3 and Beclin-1 levels decreased, and p-PI3K and p-AKT increased compared to the HIBD group (<0.05). The correlation analysis results showed that the difference of the mean fluorescence intensity of LC3 and Beclin-1 protein in the injured cerebral cortex between the melatonin and HIBD groups was negatively correlated with the difference of the number of p-PI3K and p-AKT cells between the two groups (<0.05).
CONCLUSIONS
Melatonin can inhibit excessive autophagy in cortical neurons of neonatal rats with HIBD, thereby alleviating HIBD. This mechanism is associated with the PI3K/AKT pathway.
Topics: Animals; Melatonin; Hypoxia-Ischemia, Brain; Rats, Sprague-Dawley; Rats; Proto-Oncogene Proteins c-akt; Animals, Newborn; Cerebral Cortex; Autophagy; Phosphatidylinositol 3-Kinases; Neurons; Signal Transduction; Male; Female
PubMed: 38926381
DOI: 10.7499/j.issn.1008-8830.2312053 -
Cell Death Discovery Jun 2024Head and neck squamous cell carcinomas (HNSCCs) are amongst the most aggressive, complex, and heterogeneous malignancies. The standard of care treatments for HNC... (Review)
Review
Head and neck squamous cell carcinomas (HNSCCs) are amongst the most aggressive, complex, and heterogeneous malignancies. The standard of care treatments for HNC patients include surgery, radiotherapy, chemotherapy, or their combination. However, around 50% do not benefit while suffering severe toxic side effects, costing the individuals and society. Decades have been spent to improve HNSCC treatment outcomes with only limited success. Much of the research in HNSCC treatment has focused on understanding the genetics of the HNSCC malignant cells, but it has become clear that tumour microenvironment (TME) plays an important role in the progression as well as treatment response in HNSCC. Understanding the crosstalk between cancer cells and TME is crucial for inhibiting progression and treatment resistance. Cancer-associated fibroblasts (CAFs), the predominant component of stroma in HNSCC, serve as the primary source of extra-cellular matrix (ECM) and various pro-tumoral composites in TME. The activation of CAFs in HNSCC is primarily driven by cancer cell-secreted molecules, which in turn induce phenotypic changes, elevated secretive status, and altered ECM production profile. Concurrently, CAFs play a pivotal role in modulating the cell cycle, stemness, epithelial-mesenchymal transition (EMT), and resistance to targeted and chemoradiotherapy in HNSCC cells. This modulation occurs through interactions with secreted molecules or direct contact with the ECM or CAF. Co-culture and 3D models of tumour cells and other TME cell types allows to mimic the HNSCC tumour milieu and enable modulating tumour hypoxia and reprograming cancer stem cells (CSC). This review aims to provide an update on the development of HNSCC tumour models comprising CAFs to obtain better understanding of the interaction between CAFs and tumour cells, and for providing preclinical testing platforms of current and combination with emerging therapeutics.
PubMed: 38926351
DOI: 10.1038/s41420-024-02053-9 -
Redox Biology Jun 2024Pulmonary vascular remodeling and inflammation play an important role in the hypoxic-induced lung diseases. Our previous investigations showed that peptide from yak milk...
Pulmonary vascular remodeling and inflammation play an important role in the hypoxic-induced lung diseases. Our previous investigations showed that peptide from yak milk residues could alleviate inflammation. In this study, our results suggest that peptide (LV) from yak milk residues peptide had protective effect of lung in the animal models of hypoxic-induced lung injury. LV Gavage could improve pulmonary vascular remodeling in the lung tissues of hypoxic mice. A comprehensive analysis of metabolomics and transcriptomics revealed that 5-KETE, 8,9-EET, and 6-keto-prostaglandin F1a might be potential targets to prevent lung injury in the hypoxic mice. These metabolites can be regulated by MAPK/VEGF and inflammatory pathways. Our data indicated that LV treatment could inhibit apoptosis and inflammation via Nrf2/NF-κB/MAPK/PHD-2 pathway and protected hypoxic-induced lung epithelial cells injury. Taken together, our results suggest that LV provides a novel therapeutic clue for the prevention of hypoxia-induced lung injury and inflammation-related lung diseases.
PubMed: 38925040
DOI: 10.1016/j.redox.2024.103252 -
ELife Jun 2024During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid...
During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB.
Topics: Dendritic Cells; Glycolysis; Monocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mycobacterium tuberculosis; Cell Movement; Animals; Tuberculosis; Mice; Toll-Like Receptor 2; Mice, Inbred C57BL; Female
PubMed: 38922679
DOI: 10.7554/eLife.89319 -
Toxins May 2024A major pathogenic factor is the cholesterol-dependent cytolysin pneumolysin, binding membrane cholesterol and producing permanent lytic or transient pores. During...
A major pathogenic factor is the cholesterol-dependent cytolysin pneumolysin, binding membrane cholesterol and producing permanent lytic or transient pores. During brain infections, vascular damage with variable ischemia occurs. The role of ischemia on pneumolysin's pore-forming capacity remains unknown. In acute brain slice cultures and primary cultured glia, we studied acute toxin lysis (via propidium iodide staining and LDH release) and transient pore formation (by analyzing increases in the intracellular calcium). We analyzed normal peripheral tissue glucose conditions (80 mg%), normal brain glucose levels (20 mg%), and brain hypoglycemic conditions (3 mg%), in combinations either with normoxia (8% oxygen) or hypoxia (2% oxygen). At 80 mg% glucose, hypoxia enhanced cytolysis via pneumolysin. At 20 mg% glucose, hypoxia did not affect cell lysis, but impaired calcium restoration after non-lytic pore formation. Only at 3 mg% glucose, during normoxia, did pneumolysin produce stronger lysis. In hypoglycemic (3 mg% glucose) conditions, pneumolysin caused a milder calcium increase, but restoration was missing. Microglia bound more pneumolysin than astrocytes and demonstrated generally stronger calcium elevation. Thus, our work demonstrated that the toxin pore-forming capacity in cells continuously diminishes when oxygen is reduced, overlapping with a continuously reduced ability of cells to maintain homeostasis of the calcium influx once oxygen and glucose are reduced.
Topics: Streptolysins; Glucose; Animals; Bacterial Proteins; Oxygen; Cholesterol; Streptococcus pneumoniae; Brain; Calcium; Cells, Cultured; Neuroglia
PubMed: 38922127
DOI: 10.3390/toxins16060232 -
Journal of Functional Morphology and... May 2024Hypoxia increases inspiratory muscle work and consequently contributes to a reduction in exercise performance. We evaluate the effects of inspiratory muscle warm-up...
Hypoxia increases inspiratory muscle work and consequently contributes to a reduction in exercise performance. We evaluate the effects of inspiratory muscle warm-up (IMW) on a 10 km cycling time trial in normoxia (NOR) and hypoxia (HYP). Eight cyclists performed four time trial sessions, two in HYP (FiO: 0.145) and two in NOR (FiO: 0.209), of which one was with IMW (set at 40% of maximal inspiratory pressure-MIP) and the other was with the placebo effect (PLA: set at 15% MIP). Time trials were unchanged by IMW (NOR: 893.8 ± 31.5 vs. NOR: 925.5 ± 51.0 s; HYP: 976.8 ± 34.2 vs. HYP: 1008.3 ± 56.0 s; > 0.05), while ventilation was higher in HYP (107.7 ± 18.3) than HYP (100.1 ± 18.9 L.min; ≤ 0.05), and SpO was lower (HYP: 73 ± 6 vs. HYP: 76 ± 6%; ≤ 0.05). A post-exercise-induced reduction in inspiratory strength was correlated with exercise elapsed time during IMW sessions (HYP: r = -0.79; ≤ 0.05; NOR: r = -0.70; ≤ 0.05). IMW did not improve the 10 km time trial performance under normoxia and hypoxia.
PubMed: 38921633
DOI: 10.3390/jfmk9020097 -
Insects Jun 2024The skin beetle is regularly found beyond North America where it originated. The larvae cause considerable concern in museums, as they damage hides or furs in addition...
The skin beetle is regularly found beyond North America where it originated. The larvae cause considerable concern in museums, as they damage hides or furs in addition to being a special source of damage to collections of dried plants in herbaria or collections of insects and other zoological specimens. arrived in Europe in the mid-20th century and was associated mostly with stored food products, but over time, it has become recognised as a museum pest. Although it is still uncommon and may only be observed in a small fraction of museums, when the insect is found in large numbers, it can cause problems. Catches from blunder traps in Austrian museums and from an online database in the UK were used to track changing concern over the insect. As a single female beetle can continue to reproduce because the species is parthenogenetic, its presence can persist over long periods of time. Although small populations in museums are typically found in the adult form, the larval forms are more common where a site is infested by high numbers, perhaps because the larvae and adults must range more widely for food. Although can be controlled using pesticides, it is also possible to kill the larvae within infested materials through freezing or anoxia.
PubMed: 38921120
DOI: 10.3390/insects15060405