ABSTRACT
Cerebral hypoxia often brings irreversible damage to the central nervous system, which seriously endangers human health. It is of great significance to further explore the mechanism of hypoxia-associated brain injury. As a programmed cell death, ferroptosis mainly manifests as cell death caused by excessive accumulation of iron-dependent lipid peroxides. It is associated with abnormal glutathione metabolism, lipid peroxidation and iron metabolism, and is involved in the occurrence and development of various diseases. Studies have found that ferroptosis plays an important role in hypoxia-associated brain injury. This review summarizes the mechanism of ferroptosis, and describes its research progress in cerebral ischemia reperfusion injury, neonatal hypoxic-ischemic brain damage, obstructive sleep apnea-induced brain injury and high-altitude hypoxic brain injury.
Subject(s)
Brain Injuries , Ferroptosis , Hypoxia-Ischemia, Brain , Reperfusion Injury , Humans , Infant, Newborn , Apoptosis , IronABSTRACT
The drug transporter play a key role in the absorption of drugs. Investigation of the changes of drug transporters in response to hypoxia will provide insight into the mechanism of drug absorption. In this study we investigated the mRNA and protein expression of the transporter P-gp after acute hypoxia, and evaluated the effects of P-gp changes on absorption of levofloxacin in the intestine. The relative expression of m RNA and protein were reduced by 50.80% and 71.30%(P < 0.05). In the single-pass intestinal perfusion model, the intestinal wall permeability was increased by 56.16%, 226.00%, 77.74% and 141.00% in the time intervals at 30-60 min, 60-90 min, 90-120 min and 120-150 min although P-gp expression was decreased(P < 0.05). These results suggest that hypoxia may decrease the expression of P-gp in the intestine to reduce the excretion of levofloxacin and increase the absorption.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Hypoxia/metabolism , Intestine, Small/metabolism , Levofloxacin/metabolism , Animals , Biological Transport , Intestinal Absorption , Perfusion , Permeability , RatsABSTRACT
BACKGROUND AND PURPOSE: Our previous studies have demonstrated adenosine triphosphate-sensitive potassium channel (KATP channel) openers could protect against inflammatory response in brain disease, but little is known about the mechanisms involved in KATP channel openers inhibiting neuroinflammation. METHODS AND RESULTS: In the present study, we found that oxygen-glucose deprivation (OGD) resulted in BV-2 cells activation, significantly increased tumor necrosis factor-alpha and interleukin-1beta (IL-1ß) levels, accompanied by downregulating Kir6.1 subunit. Pretreatment with nicorandil, a KATP channel opener, could attenuate OGD-induced BV-2 cells activation and inhibit pro-inflammatory factors release. Further study demonstrated that OGD activated Toll-like receptor-4 (TLR4) signaling pathway and NOD-like receptor pyrin domain containing three inflammasome, thereby increased IL-1ß production. Pretreatment with nicorandil could reverse the two pathways involved in IL-1ß production. CONCLUSIONS: Our findings reveal that KATP channel openers could protect against OGD-induced neuroinflammation via inhibiting inflammasome activation and TLR4 signal transduction.
Subject(s)
Gene Expression Regulation/drug effects , Inflammation/metabolism , Nicorandil/pharmacology , Signal Transduction/drug effects , Toll-Like Receptors/metabolism , Vitamin B Complex/pharmacology , Animals , Carrier Proteins/metabolism , Caspase 1/metabolism , Cell Line, Transformed , Enzyme-Linked Immunosorbent Assay , Glucose/deficiency , Hypoxia/complications , I-kappa B Kinase/metabolism , Inflammation/etiology , Interleukin-1beta/metabolism , KATP Channels/metabolism , L-Lactate Dehydrogenase/metabolism , Mice , NLR Family, Pyrin Domain-Containing 3 Protein , Phosphorylation/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Asthma is the most common chronic childhood illness today. However, little attention is paid for the impacts of chronic asthma-induced hypoxia on cognitive function in children. The present study used immature mice to establish ovalbumin-induced chronic asthma model, and found that chronic asthma impaired learning and memory ability in Morris Water Maze test. Further study revealed that chronic asthma destroyed synaptic structure, impaired long-term potentiation (LTP) maintaining in the CA1 region of mouse hippocampal slices. We found that intermittent hypoxia during chronic asthma resulted in down-regulation of c-fos, Arc and neurogenesis, which was responsible for the impairment of learning and memory in immature mice. Moreover, our results showed that budesonide treatment alone was inadequate for attenuating chronic asthma-induced cognitive impairment. Therefore, our findings indicate that chronic asthma might result in cognitive dysfunction in children, and more attention should be paid for chronic asthma-induced brain damage in the clinical therapy.
Subject(s)
Asthma/complications , Cognition Disorders/etiology , Developmental Disabilities/etiology , Animals , Animals, Newborn , Asthma/blood , Asthma/chemically induced , Asthma/drug therapy , Bronchodilator Agents/therapeutic use , Budesonide/therapeutic use , Chronic Disease , Cognition Disorders/prevention & control , Cytoskeletal Proteins/metabolism , Developmental Disabilities/prevention & control , Disease Models, Animal , Female , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/physiology , Hippocampus/drug effects , Hippocampus/physiopathology , Hippocampus/ultrastructure , In Vitro Techniques , Ki-67 Antigen/metabolism , Lung/pathology , Lung/ultrastructure , Maze Learning/drug effects , Mice , Mice, Inbred BALB C , Nerve Tissue Proteins/metabolism , Ovalbumin/adverse effects , Pneumonia/drug therapy , Pneumonia/etiology , Time Factors , Vascular Endothelial Growth Factor A/bloodABSTRACT
Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1ß, iNOS, COX(2) and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzoates/pharmacology , Brain Ischemia/metabolism , Bridged-Ring Compounds/pharmacology , Glucosides/pharmacology , Inflammation/metabolism , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Astrocytes/drug effects , Astrocytes/metabolism , Benzoates/administration & dosage , Brain/drug effects , Brain/metabolism , Brain/pathology , Brain Ischemia/drug therapy , Bridged-Ring Compounds/administration & dosage , Cerebral Infarction/drug therapy , Cerebral Infarction/metabolism , Cerebral Infarction/pathology , Cyclooxygenase 2/metabolism , Cytochromes c/genetics , Cytochromes c/metabolism , Disease Models, Animal , Gene Expression Regulation/drug effects , Glucosides/administration & dosage , Hippocampus/drug effects , Inflammation/drug therapy , Interleukin-1beta/blood , Interleukin-1beta/genetics , Lipoxygenase/metabolism , Male , Microglia/drug effects , Microglia/metabolism , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Monoterpenes , NF-kappa B/antagonists & inhibitors , Neurons/drug effects , Neurons/metabolism , Nitric Oxide Synthase Type II/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/genetics , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolismABSTRACT
OBJECTIVE: To investigate the effects of cis-combretastatin-A1 phosphate (cis-CA1P) on tumor cell proliferation, and its effects on the blood vessel formations. METHODS: MTT and IC50 values were used to assess the inhibitory effects of cis-CA1P on tumor cell proliferation. Chicken embryo chorioallantoic membrane and thoracic aorta annulations isolated from rats were used to investigate the effects of cis-CAIP on the blood vessel formation. RESULTS: Cis-CA1P concentration-dependently inhibited the proliferations of several cancer cell lines, including human gastric carcinoma cell line MGC-803, human leukemic monocyte lymphoma cell line U937, human melanoma cell line A375, human colon cancer cell line HCT116, human breast carcinoma cell line MDA-MB-231, and human leukemia cell line K562. Cis-CAIP significantly decreased the formation of blood vessels in chicken embryo chorioallantoic membrane and in thoracic aorta annulations. CONCLUSION: Cis-CA1P inhibits cancer cell proliferation and prevents blood vessel formation.
