Cognitive impairment refers to the abnormality of the hippocampus， cortex and other parts of the brain， which is manifested by the decline of cognitive abilities such as learning， memory and attention. With the increase in people's work pressure and bad living habits， the incidence of cognitive impairment is getting higher and higher， which seriously affects people's normal life. However， there are adverse reactions such as gastrointestinal reactions and extrapyramidal reactions in Western drug treatment for cognitive impairment. Therefore， the development of a drug with relatively minimal adverse reactions is of great significance. Traditional Chinese medicine （TCM） has the characteristics of "multi-component， multi-pathway and multi-target"， and the incidence of adverse reactions is relatively low. Studies have shown that the pathogenesis of cognitive impairment is closely related to oxidative stress， inflammation， apoptosis， autophagy and other processes of neurons in the cerebral cortex and hippocampus. Phosphatidylinositol 3-kinase （PI3K）-protein kinase B （Akt） signal pathway plays an important role in the transmission of intracellular and intracellular signals， and in the regulation of cellular inflammation， apoptosis， autophagy， etc. TCM monomers， TCM extracts， and TCM compounds exert anti-inflammatory， antioxidant， anti-apoptotic and autophagy regulation effects by regulating the PI3K/Akt signaling pathway to improve cognitive impairment. This review first summarized the composition and regulatory process of the PI3K/Akt signaling pathway， and then discussed the research progress on the improvement of cognitive impairment through the improvement of oxidative stress， inflammation， apoptosis and autophagy of neurons. Finally， the recent research status of the regulation of this signaling pathway by TCM extracts， TCM monomers and TCM compounds to improve cognitive impairment was summarized. This study provides a theoretical basis for the future study of new TCM related to cognitive impairment.

Objective To investigate the protective effect of Lycium barbarum polysaccharide(LBP)on reproductive system damage induced by exposure to high-altitude hypoxic environment in female rats,and to explore the mechanisms involved.Methods After undergoing physiological synchronization,30 female Wistar rats were randomly and evenly assigned to 3 groups,including a plain control(C)group,a high-altitude hypoxia(H)group,and a high-altitude hypoxia+LBP(H-LBP)group.The C group was placed in a region at an altitude of 1500 m above sea level(with an oxygen volume fraction of 18.55％),while the H group and the H-LBP group were placed in a region at an altitude of 4 010 m above sea level(with an oxygen volume fraction of 12.70％).Rats in the H-LBP group were fed with LBP at 75 mg/kg via gastric gavage,while the C and H groups received normal saline once a day for 14 days in a row.Changes in estrous cycles were documented throughout the experiment.At the end of the experiment,the serum levels of reproductive hormones and the levels of oxidative stress in the ovarian and uterine tissues were measured.Morphological changes in the ovarian and uterine tissues were assessed using hematoxylin-eosin(HE)staining.A component-target-pathway network diagram was constructed using network pharmacology methods to analyze the key targets and pathways.Results Compared with the C group,rats in the H group had disrupted estrous cycles and significantly lower serum levels of reproductive hormones(all P＜0.05).In addition,rats in the H group had increased oxidative stress damage and experienced pathological damage in the ovarian and uterine tissues.However,compared with those of the H group,the estrous cycle in the H-LBP group became normalized after the administration of LBP and the serum levels of estradiol(E2),progesterone(P),luteinizing hormone(LH),and anti-Müllerian hormone(AMH)were significantly increased in H-LBP group(all P＜0.05).In the ovarian tissue,the malondialdehyde(MDA)content was significantly reduced,superoxide dismutase(SOD)activity was increased,and the content of reduced glutathione(GSH)was increased.In addition,in the uterine tissue,the MDA content was reduced and SOD activity was increased(all P＜0.05),with LBP significantly improving the pathological damage to the reproductive organs of female rats caused by high-altitude hypoxic environment.Through network pharmacology analysis,we identified 76 potential targets for the protective effect of LBP against high-altitude hypoxia-induced reproductive injury,and the targets were mainly involved in the signaling pathways such as calcium channels,PI3K-Akt,MAPK,and HIF-1.Conclusion LBP can ameliorate high-altitude hypoxia-induced reproductive damage in female rats.The mechanisms involved may be associated with the regulation of PI3K-Akt,MAPK,and HIF-1 pathways.

OBJECTIVES: Hypoxia can alter the oral bioavailability of drugs, including various substrates (drugs) of P-glycoprotein (P-gp), suggesting that hypoxia may affect the function of P-gp in intestinal epithelial cells. Currently, Caco-2 monolayer model is the classic model for studying the function of intestinal epithelial P-gp. This study combines the Caco-2 monolayer model with hypoxia to investigate the effects of hypoxia on the expression and function of P-gp in Caco-2 cells, which helps to elucidate the mechanism of changes in drug transport on intestinal epithelial cells in high-altitude hypoxia environment. METHODS: Normally cultured Caco-2 cells were cultured in 1% oxygen concentration for 24, 48, and 72 h, respectively. After the extraction of the membrane proteins, the levels of P-gp were measured by Western blotting. The hypoxia time, with the most significant change of P-gp expression, was selected as the subsequent study condition. After culturing Caco-2 cells in transwell cells for 21 days and establishing a Caco-2 monolayer model, they were divided into a normoxic control group and a hypoxic group. The normoxic control group was continuously cultured in normal condition for 72 h, while the hypoxic group was incubated for 72 h in 1% oxygen concentration. The integrity and polarability of Caco-2 cells monolayer were evaluated by transepithelial electrical resistance (TEER), apparent permeability (Papp) of lucifer yellow, the activity of alkaline phosphatase (AKP), and microvilli morphology and tight junction structure under transmission electron microscope. Then, the Papp of rhodamine 123 (Rh123), a kind of P-gp specific substrate, was detected and the efflux rate was calculated. The Caco-2 cell monolayer, culturing at plastic flasks, was incubated for 72 h in 1% oxygen concentration, the expression level of P-gp was detected. RESULTS: P-gp was decreased in Caco-2 cells with 1% oxygen concentration, especially the duration of 72 h (P<0.01). In hypoxic group, the TEER of monolayer was more than 400 Ω·cm², the Papp of lucifer yellow was less than 5×10^-7 cm/s, and the ratio of AKP activity between apical side and basal side was greater than 3. The establishment of Caco-2 monolayer model was successful, and hypoxia treatment did not affect the integrity and polarization state of the model. Compared with the normoxic control group, the efflux rate of Rh123 was significantly reduced in Caco-2 cell monolayer of the hypoxic group (P<0.01). Hypoxia reduced the expression of P-gp in Caco-2 cell monolayer (P<0.01). CONCLUSIONS Hypoxia inhibits P-gp function in Caco-2 cells, which may be related to the decreased P-gp level.
Humans ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Caco-2 Cells ; ATP Binding Cassette Transporter, Subfamily B ; Hypoxia ; Oxygen

Objective:Plateau hypoxia exposure causes changes in pharmacokinetic parameters and cerebral-blood distribution of drugs,including many substrates of P-glycoprotein(P-gp).Levetiracetam,a kind of antiepileptic drugs,is a substrate of P-gp.Whether plateau hypoxia exposure changes its pharmacokinetic characteristics and cerebral-blood distribution remains unclear.This study aims to investigate the effects of plateau hypoxia on the pharmacokinetics and cerebra-blood distribution of levetiracetam. Methods:Wistar rats were divided into a low-altitude control group,a high-altitude group,a solvent group,and a P-gp induction group.After 24 h of exposure at altitude of 4 010 m,rats in the high-altitude group were given levetiracetam orally or intravenously.The plasma was respectively collected at 0.083,0.25,0.5,0.83,1.25,2,4,6,8,10,12,and 24 h after oral administration of the drug,while both plasma and brain were respectively collected at 5,45,60,120 and 240 min after intravenous injection.After 3 days administration of dexamethasone,plasma and brain of rats in the P-gp induction group were collected at 120 min after intravenously giving levetiracetam.Plasma and brain concentrations of the drug were determined by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).The expression of P-gp in blood-brain barrier was detected by Western blotting. Results:Compared with the low-altitude control group,the area under the curve(AUC)and mean residence time(MRT)of levetiracetam were respectively decreased by 14.69%(P<0.01)and 15.42%(P<0.01),while the clearance(CL)was increased by 16.67%(P<0.01)in the high-altitude group.The ratio of brain/blood plasma drug concentration was decreased by 22.82%(P<0.05),12.42%(P<0.05),17.40%(P<0.01),and 13.22%(P<0.01)at 5,45,120,and 240 min after injection,respectively.The expression of P-gp on the blood-brain barrier was increased by 86.3%(P<0.05).Compared with the solvent control group,the expression of P-gp on the blood-brain barrier in the P-gp induction group was increased by 56.3%(P<0.05),the ratio of brain/blood plasma drug concentration was decreased by 19.3%(P<0.05). Conclusion:After acute plateau hypoxia exposure,the pharmacokinetic of levetiracetam in rats are altered,and the cerebral-blood distribution of the drug in rats is decreased,which may be related to the up-regulation of P-gp expression on the blood-brain barrier.

Objective To explore the CT findings of mucoepidermoid carcinoma (MEC) of the tracheobronchial tree and improve the diagnostic accuracy. Methods The CT images, histopathological and clinical data in 24 patients with pathologically proved MEC of the tracheobroncbial tree were retrospectively analyzed. Results The clinical symptoms included cough, sputum, fever, wheezing, chest pain and hemoptysis. The patient was proved to be low-grade (n=19) and high-grade (n=5) MEC histopathologically. One lesion was located in trachea, 6 in main bronchus, 12 in lobar bronchus and 5 in segmental, subsegmental and distal bronchus. The tumor presented as no-invasive endotracheobronchial well-defined round-like nodule (n=13, locating in lobar and higher bronchus) and columnar sharp (n=3, locating in main bronchus), or intra-and-extraluminal well-defined round-like nodule or mass (n=6, locating in lobar and lower bronchus) and irregular mass with invasive pattern (n=2, high-grade type). The density of lesion was similar to the muscule and the calcification within lesion was showed in 4 patients on non-enhanced CT. The lesion had marked enhancement in 17 patients on enhanced CT. Obstructive changes were found in 20 patients. Conclusion MEC of the tracheobronchial tree is usually low-grade malignancy and locates in main and lobar bronchus with no-invasive well-defined airway mass, marked enhancement and calcification on CT.