Table of Content

Volume 28 Issue 12
26 December 2023

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Mechanism of Pingxiao capsule promoting breast cancer apoptosis through AKT1/β-catenin signal based on network pharmacology

CHEN Hongxiao, LIU Su, JIN Le, ZHANG Huihui, ZHANG Lei, CHEN Zhaolin

2023, 28(12):  1321-1330.  doi:10.12092/j.issn.1009-2501.2023.12.001

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AIM: To explore the potential mechanism of action of Pingxiao capsule in the treatment of breast cancer. METHODS: TCMSP, TCM-ID, GeneCards and other databases were used to screen the related targets of Pingxiao capsule and breast cancer. Cytoscape software builds drug-target-disease networks. R software was used for GO and KEGG analysis. Autodock Vina and Pymol software were used for molecular docking and visualization of Pingxiao capsule active ingredients and core targets. Core targets were analyzed by R software survival package, and genes closely related to overall survival time were screened out. Cell viability was detected by CCK-8 method. Flow cytometry was used to detect cell apoptosis. The protein expression levels of p-AKT1, β-catenin and cyclinD1 were detected by Western blot. RESULTS: A total of 194 drug targets were screened, 1612 disease targets were identified, 127 intersection targets were identified by Venn diagram, and 20 core targets were TB53, AKT1, TNF, CASP3, etc. GO analysis was mainly related to oxidative stress response, cell regulation of chemical reaction and other biological activities. KEGG analysis was mainly related to PI3K-AKT signaling pathway, TNF signaling pathway, IL-17 signaling pathway and other pathways. Molecular docking results showed that the active constituents were well combined with the core targets AKT1, MAPK1 and RELA. Cell experiments showed that quercetin (40, 80, 120 μmol/L) promoted apoptosis of breast cancer cells. Western blot analysis showed that the protein expressions of p-AKT1, β-catenin and cyclinD1 decreased with different concentrations of quercetin treated for 48h. CONCLUSION: Network pharmacology and cell experiments confirmed that Pingxiao capsule may exert its anti-breast cancer effect by regulating AKT1/β-catenin signaling pathway. 

Emodin reduces the injury of glomerular mesangial cells in lupus nephritis by targeting forkhead protein K2 through miR-96-5p

SHI Shanhong, LIN Weiyuan, ZHANG Jiequn, ZHENG Yanling

2023, 28(12):  1331-1338.  doi:10.12092/j.issn.1009-2501.2023.12.002

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AIM: To investigate the injury of emodin (EMO) in reduce of glomerular mesangial cells (MCs) in lupus nephritis by targeting forkhead protein K2 (FOXK2) through miR-96-5p. METHODS: The contents of 24 h urine protein, serum urea nitrogen (BUN) and serum creatinine (Scr) in MRL/faslpr mice (lupus nephritis group) and MRL/MPJ mice (control group) were detected. MCs were separated, purified and divided into: MCs group (MCs without any treatment), L-EMO group (MCs treated with 10 μmol/L Emodin), M-EMO group (MCs treated with 25 μmol/L Emodin), H-EMO group (MCs treated with 50 μmol/L Emodin), H-EMO+miR-96-5p-NC group (MCs treated with 50 μmol/L Emodin and transfected with miR-96-5p-NC), and H-EMO+miR-96-5p-minic group (MCs treated with 50 μmol/L Emodin and transfected with miR-96-5p-minic). Double luciferase report experiment was used to verify the targeting relationship between miR-96-5p and FOXK2. The real-time quantitative fluorescent polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-96-5p. Western blot was used to detect the expression of FOXK2 and apoptosis related proteins. The enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory factors in MCs. cell count kit 8 (CCK-8) was used to determine the activity of MCs. Annexin-V FITC/PI double staining was used to detect apoptosis of MCs. RESULTS: Compared with the control group, 24 h urinary protein content, serum BUN and Scr levels in the lupus nephritis group were significantly increased (P<0.05). Compared with the MCs group, the miR-96-5p expression, interleukin1β (IL-1β), interleukin6 (IL-6), tumor necrosis factor-α (TNF-α), A450 value and B-lymphoblastoma-2 (Bcl-2) protein in the L-EMO group, M-EMO group and H-EMO group were significantly decreased (P<0.05), the FOXK2 level, cell apoptosis rate, Bcl-2 related X gene (Bax), aspartate specific cysteine proteinase-3 (cleaved Caspase-3) protein levels were significantly increased, respectively (P<0.05), the effect of Emodin was dose-dependent. Compared with the H-EMO group and H-EMO+miR-96-5p-NC group, H-EMO+miR-96-5p-minic group obviously increased the miR-96-5p expression, inflammatory factor levels, A450 value and Bcl-2 protein level (P<0.05), and obviously decreased FOXK2 level and cell apoptosis rate (P<0.05). CONCLUSION: EMO can reduce the injury of lupus nephritis MCs by down-regulating miR-96-5p and then up-regulating FOXK2.

Hederagenin improves psoriasis skin lesions by inhibiting macrophage mincle-mediated inflammation

HE Xinyu, ZHONG Xia, LIU Peng, TAN Ruizhi

2023, 28(12):  1339-1346.  doi:10.12092/j.issn.1009-2501.2023.12.003

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AIM: To observe the effects and mechanisms of hederagenin (HDG) in improving psoriasis skin lesions and inflammation in mice. METHODS: A mouse model of psoriasis was established by depilation of the back and continuous application of imiquimod for 7 days in C57 mice. After modeling, HDG was administered orally (low dose: 25 mg·kg-1·d-1 and high dose: 50 mg·kg-1·d-1) 1 hour later, and a positive control group was treated with dexamethasone. After 7 days of drug intervention, pathological, immunohistochemical, immunofluorescence, ELISA, real-time quantitative PCR, and Western blot analyses were performed on the skin lesions of each group of mice. RESULTS: Compared with the model group, the HDG intervention group showed varying degrees of improvement in skin pathological damage and inflammatory cell infiltration. Real-time PCR and ELISA results of skin tissue suspension confirmed that the mRNA and protein levels of inflammatory factors IL-1β, IL-6, and TNF-α in mouse skin were reduced in the HDG intervention group compared to the model group, indicating a significant anti-inflammatory effect of HDG. Immunohistochemical and Western blot results showed that compared with the normal group, the protein expression of Mincle in the skin of the model group mice was significantly increased, which was significantly down-regulated after HDG intervention. Immunofluorescence confirmed the co-localization of Mincle expression and macrophage marker F4/80 in the skin of the model group. Western blot analysis revealed that HDG not only down-regulated the protein level of Mincle in the treatment group but also reduced the protein phosphorylation levels of downstream signaling molecules Syk and NF-κB. CONCLUSION: Hederagenin intervention can significantly inhibit pathological damage and macrophage-related inflammation in psoriasis, and its potential molecular mechanism may be related to the down-regulation of the Mincle/Syk/NF-κB signaling pathway.

Inhibitory and clearance effect of azithromycin combined with levofloxacin on biofilm of different ST types of Klebsiella pneumoniae

CAO Ruonan, LI Xiaoning, RUAN Xinran, LIU Shihui, CHEN Jingxuan, XU Hao, SHEN Jilu, ZHU Guoping

2023, 28(12):  1347-1356.  doi:10.12092/j.issn.1009-2501.2023.12.004

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AIM: Given the biofilm formation ability of different ST-type Klebsiella pneumoniae, our study was aimed at exploring the inhibitory and clearance of azithromycin combined with levofloxacin on the biofilm of Klebsiella pneumoniae of different ST-types and providing a new strategy for the prevention of biofilm formation in the treatment of post-infectious Klebsiella pneumoniae. METHODS: 9 strains of Klebsiella pneumoniae from all susceptibility groups, 19 strains of Klebsiella pneumoniae producing extended-spectrum β-lactamases (ESBLs), and 37 strains of Carbapenem-resistant Klebsiella pneumoniae (CRKP) were randomly collected from the samples of patients hospitalized in the First Affiliated Hospital of Wannan Medical College from August 2019 to November 2021. The isolates were identified using VITEK MS IVD KB V3.2 and VITEK 2-Compact 60. Multilocus sequence typing (MLST) was performed to analyze the homology of each strain; crystal violet staining was used for semi-quantitative detection of biofilm to compare the differences in biofilm formation ability between different ST-type Klebsiella pneumoniae. Different ST-type strains were selected, and the partial inhibitory concentration index (FICI) was calculated by micro broth dilution method to judge the combination effect and select the optimal combination concentration; crystalline violet staining method was used to investigate the inhibition and clearance effect of azithromycin combined with levofloxacin on the biofilm of different ST-type Klebsiella pneumoniae; laser scanning confocal fluorescence microscopy was used to observe the structural changes of the biofilm of Klebsiella pneumoniae before and after the effect of the antibacterial drugs. RESULTS: MLST typing results showed that the sensitive group of Klebsiella pneumoniae strains had 8 sequences such as ST86, ST727, etc., the ESBLs group strains belonged to 14 sequence types such as ST15, ST37, ST11, etc., of which ST15 accounted for 26.32% (5/19). The CRKP group strains belonged to 9 sequence types such as ST11, ST15, ST656, etc., of which ST11 accounted for 48.65% (18/37), ST15 accounted for 27.03% (10/37); ST15 (ESBLs), ST11 (CRKP), ST15 (CRKP) type Klebsiella pneumoniae biofilms all reached maturity on the 5th day, the ST15 (ESBLs) group had a stronger ability to produce material to be membranous than the ST15 (CRKP) group. The ST11 (CRKP) group had a stronger ability to produce material to be membranous than the ST15 (CRKP) group (P<0.01); the results of azithromycin combined with levofloxacin drug sensitivity showed that it had an additive effect on different ST-type Klebsiella pneumoniae bacteria; in the inhibition of biofilm formation and clearance test, the 2×MIC azithromycin group and the combined concentration group had a stronger inhibition of biofilm formation of different ST-type Klebsiella pneumoniae bacteria, and the inhibitory ability of the combined group was better than that of the single-drug group, and the highest inhibition rate could reach 89.93%; the clearance effects were all combined drug group>azithromycin>levofloxacin, and the highest clearance rate was 44.79%. CONCLUSION: There are differences in biofilm formation ability between different ST-type Klebsiella pneumoniae, and azithromycin combined with levofloxacin has a better inhibitory effect on different ST-type Klebsiella pneumoniae biofilm, conbined application can be used in the treatment of biofilm infections early stage. 

Central mechanism of curcumin on the paraventricular hypothalamic nucleus of high salt induced hypertension rats

MENG Tingting, GAO Hongli, GAO Yifan, ZHANG Qinglan, YU Xiaojing

2023, 28(12):  1357-1364.  doi:10.12092/j.issn.1009-2501.2023.12.005

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AIM: To assess the effect of curcumin in hypothalamic paraventricular nucleus (PVN) and mean arterial pressure so as to explore the central mechanism of hypertension. METHODS: Sixty Sprague-Dawley rats which body weights between 170 and 190 grams fed with a normal salt (0.3% NaCl) or a high salt (8% NaCl) diet for 6 weeks. Meanwhile half of each team received curcumin administration or vehicle by intragastric administration. Mean Arterial pressure was measured noninvasively via tail-cuff instrument and their recording system. The PVN tissue samPles were collected and stored at ?80 °C for later analyses. We performed the following experimental procedures: Western blot analysis, immunofluorescence, immunofluorescence and statistical analysis. RESULTS：The average arterial blood Pressure of rats in the high-salt diet group was significantly reduced after 6 weeks of curcumin intervention. The levels of NOX2, NOX4, TLR4, MyD88, IL-6, IL-1β, MCP-1 and ROS in the long-term high-salt diet grouP were significantly higher after curcumin intervention. CONCLUSION:Curcumin can improve blood pressure in hypertensive rats induced by long-term high salt, the mechanism may be related to the imProvement of oxidative stress and inflammatory cytokines in the paraventricular nucleus of the hypothalamus.

Study on bioequivalence evaluation of dexamethasone acetate tablets in Chinese healthy volunteers

XIAO Lei, XU Yuanyuan, HUANG Xiaoqing, ZHANG Wen, CAO Yang, XIE Jing, ZHOU Huan, HUANG Shunwang

2023, 28(12):  1365-1371.  doi:10.12092/j.issn.1009-2501.2023.12.006

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AIM: To assess the bioequivalence of oral dexamethasone acetate tablets between the test and reference formulations in healthy adult Chinese subjects on an empty stomach and after meals. METHODS: A randomized, open, single-dose, two-cycle double crossover bioequivalence study was followed. Twenty-four healthy subjects were included in the fasting group, and 32 healthy subjects were included in the postprandial group, taking 2 tablets (0.75 mg/tablet) of the test formulation (T) or 3 tablets (0.50 mg/tablet) of the reference formulation (R) per cycle for two cycles. The concentrations of dexamethasone acetate in human plasma were determined using liquid chromatography-mass spectrometry, and the pharmacokinetic parameters were calculated according to the non-atrial model using WinNonlin 8.0 software.The bioequivalence of both the test formulation and the reference formulation was evaluated. RESULTS: The pharmacokinetic parameters after oral administration of dexamethasone acetate tablets in a fasted state in subjects with the reference formulation are as follows: Tmax 1.13 (0.50, 4.00) and 1.00 (0.50,5.00) h, AUC0-t (72.25±21.55) and (69.23±17.76) ng·mL-1·h, Cmax (14.53±4.51) and (14.52±3.68) ng/mL, AUC0-∞ (74.63±23.01) and (71.32±19.12) ng·mL-1·h. The pharmacokinetic parameters after oral administration of dexamethasone acetate tablets in the postprandial state in subjects were as follows: Tmax 2.00 (1.00,4.50) and 1.50 (1.00, 4.50)h, AUC0-t (81.57±21.28) and (76.06±13.63) ng·mL-1·h, Cmax (12.14±3.21) and (11.93±2.78) ng/mL, and AUC0-∞ (85.12±23.92) and (78.95±14.99) ng·mL-1·h. The 90% confidence intervals for the geometric mean ratios of the main pharmacokinetic parameters of the test formulation of dexamethasone acetate to the reference formulation ranged from 80.00% to 125.00% under both fasting and postprandial conditions. CONCLUSION: Under fasting and postprandial conditions, the test formulation of dexamethasone acetate tablets was bioequivalent to the reference formulation of dexamethasone acetate tablets.

Effects of remimazolam tosilate combined with remifentanil anesthesia on hemodynamics, serum IL-1β, CXCL8 levels in elderly patients undergoing spinal surgery

DONG Li, ZHOU Feng

2023, 28(12):  1372-1377.  doi:10.12092/j.issn.1009-2501.2023.12.007

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AIM: To investigate the anesthetic effect of remimazolam tosilate combined with remifentanil in elderly patients undergoing spinal surgery, and its impacts on hemodynamics, serum interleukin-1β (IL-1β) and C-X-C motif chemokine ligand 8 (CXCL8) level. METHODS: A total of 88 elderly patients who underwent spinal surgery in our hospital from May 2022 to May 2023 were randomly separated into an experimental group and a control group. The control group was given remifentanil, and the experimental group was anesthetized with remimazolam tosilate on the basis of the control group. The anesthesia effect, hemodynamic indicators, serum IL-1β and CXCL8 levels, and complication rate were compared between two groups. RESULTS: After different anesthesia regimens, the recovery time of spontaneous respiration, extubation time, and recovery time of the two groups were compared, and the experimental group were obviously shorter than the control group (P<0.05); compared with pre administration (T0), the fluctuation ranges of hemodynamic indexes, including heart rate (HR) and mean arterial pressure (MAP), in the experimental group after 1 min (T1), 5 min (T2) , 10 min (T3) and after extubation (T4) of administration were obviously lower than those in the control group (P<0.05). After surgery, the levels of IL-1β and CXCL8 in the serum of the two groups obviously increased (P<0.05), but the experimental group showed a obvious decrease compared to the control group (P<0.05); there was no significant difference in the incidence of complications between the two groups (P>0.05). CONCLUSION: The combined anesthesia of remimazolam tosilate and remifentanil has an ideal effect and high clinical application value for elderly patients undergoing spinal surgery.

Research progress on the treatment of Alzheimer's disease based on the target of mammalian target of rapamycin

WANG Zhun, SUN Yuying, HUANG Hanchang

2023, 28(12):  1378-1390.  doi:10.12092/j.issn.1009-2501.2023.12.008

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Mammalian target of rapamycin (mTOR) regulates cell survival, proliferation, and metabolism. Alzheimer's disease (AD) is a common neurodegenerative disease with a complex pathogenesis and is closely related to aging. Studies have found that the pathological development of AD is often accompanied by changes in mTOR activity, but the role of mTOR in the pathogenesis of AD is not clear. In this paper, the complex of mTOR and its signaling pathways are first introduced, focusing on the effects of mTOR signaling pathways on synaptic plasticity and memory function, autophagy, β-amyloid-β (Aβ), Tau protein and brain insulin resistance and other AD pathological features, secondly, the regulatory effects of mTOR signaling pathways in anti-aging and life prolongation are described, and finally the application of mTOR inhibitors in AD pathological research is introduced to provide new ideas for delaying and improving AD.

Molecular mechanism of high altitude hypoxia induced intestinal homeostasis imbalance and research progress of traditional Chinese medicine

KANG Qian, XIU Minghui, ZHANG Xueyan, YANG Dan, WANG Shuwei, HE Jianzheng, GONG Hongxia, CAO Wangjie, SU Yun

2023, 28(12):  1391-1402.  doi:10.12092/j.issn.1009-2501.2023.12.009

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Hypoxia is one of the factors restricting the survival of people at high altitudes, which can cause various symptoms such as vomiting, diarrhea, palpitations, shortness of breath and acute coma. About 80% of patients with acute mountain sickness have at least one symptom of a gastrointestinal distress (e.g., anorexia, nausea, diarrhea, vomiting, etc.). The pathological characteristics, pathogenesis and drug treatment of intestinal injury caused by high-altitude hypoxia were studied, which is conducive to the diagnosis and treatment of plateau gastrointestinal diseases. Therefore, by summarized relevant literature and systematically expounds the related researches on intestinal damage caused by high altitude hypoxia. We summarized the changes of intestinal morphology, intestinal cells, intestinal flora and other intestinal homeostasis caused by high altitude hypoxia, the mechanism of intestinal inflammation and oxidative damage, and the treatment of traditional Chinese medicine, which provide reference and information for reference for scientific research workers and clinicians.

Research progress in sodium calcium exchanger and heart failure with preserved ejection fraction

CHEN Feng, HUANG Yuting, WANG Xiao, FAN Guanwei

2023, 28(12):  1403-1408.  doi:10.12092/j.issn.1009-2501.2023.12.010

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Sodium calcium exchanger (NCX) is encoded by the SCL8 family genes and belongs to the cation/Ca2+ exchanger superfamily. It is a widely distributed cation transporter protein on membrane structures, controlling the outflow and inflow of cellular calcium, and playing a key role in maintaining stable intracellular calcium concentration and normal cardiac function; Heart failure with preserved ejection fraction is characterized by high morbidity, high hospitalization rate and high mortality, and there is no ideal treatment method at present. In HFpEF, overexpression of NCX reverse mode leads to impaired diastolic function of the heart, and calcium transient in myocardial cells varies depending on the etiology of HFpEF. At present, various specific inhibitors targeting NCX can specifically inhibit calcium influx, improve diastolic dysfunction of HFpEF, and improve the survival rate of HFpEF models. Actively developing compounds targeting NCX inhibition is an important scientific challenge.

Research progress on the role of melatonin in the treatment of ischemia-reperfusion injury

JIN Xuelei, LU Yapeng, DI Xuerui, ZHENG Qihui, SHI Yisa

2023, 28(12):  1409-1414.  doi:10.12092/j.issn.1009-2501.2023.12.011

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Ischemia-reperfusion (I/R) is a complex hemodynamic process that can cause tissue damage through oxidative stress, mitochondrial dysfunction, and inflammatory reactions. It is an important factor leading to poor prognosis in patients, and the exploration of effective prevention and treatment measures is of significant clinical significance.As an endogenous hormone with strong antioxidant and anti-inflammatory properties, Melatonin plays an important role in reducing cell death and improving tissue I/R injury. Therefore, this article reviews the relationship between Melatonin and organ I/R injury in order to provide a theoretical basis for the clinical application of melatonin to alleviate organ I/R injury.

Research progress of JAK/STAT signaling pathway in the intervention of diabetic microvascular complications

LI Tao, YANG Lixia, GAO Bo, LI Qin, SONG Shuang

2023, 28(12):  1415-1421.  doi:10.12092/j.issn.1009-2501.2023.12.012

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Diabetic microvascular complications are the main reason for the high mortality of diabetic patients. There is still a great shortage of existing therapeutic drugs, so there is an urgent need for more effective new drugs. Janus kinase/signal transducer and activator of transcription (JAK/STAT) is involved in the progression of diabetic microvascular complications, which can be improved by regulating this pathway. Therefore, this article reviews the progress of JAK/STAT in diabetic microvascular complications (diabetic kidney disease, diabetic retinopathy, diabetic peripheral neuropathy), and summarizes the potential drugs that intervene JAK/stat to improve diabetic microvascular complications in recent years from three aspects of therapeutic drugs, preclinical drugs, and traditional Chinese medicine, in order to provide ideas for drug development and treatment of diabetic microvascular complications.

Research progress on new antiplatelet therapeutic targets for the treatment of acute coronary syndrome

LIU Qiang, REN Yanqin

2023, 28(12):  1422-1428.  doi:10.12092/j.issn.1009-2501.2023.12.013

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Acute coronary syndrome (ACS) is a cardiac acute ischemic syndrome caused by the rupture or erosion of unstable atherosclerotic plaques within the coronary artery, leading to thrombus formation. Antiplatelet therapy is a key strategy in treating ACS, and although some success has been achieved, there are still limitations, such as thrombus recurrence and bleeding side effects, which limit the long-term use of drugs. Future antiplatelet therapies may achieve more effective or safer treatment methods by targeting novel targets involved in platelet function. This article focuses on potential target inhibitors, including GPVI, protease-activated receptor (PAR)-4, GPIb, 5-hydroxytryptamine receptor subtype 2A (5-HT2A), protein disulfide isomerase, P-selectin, and phosphatidylinositol 3-kinase β inhibitors.

Pharmacologic effects and clinical evaluation of Tenapanor, a new drug for hyperphosphatemia

HOU Wenping, XU Lei, SU Changhai

2023, 28(12):  1429-1435.  doi:10.12092/j.issn.1009-2501.2023.12.014

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Tenapanor is a novel phosphorus-lowering drug, which mainly inhibits sodium/hydrogen exchange protein 3 (NHE3), and also reduces intestinal phosphorus absorption by down-regulating the expression of sodium phosphate co-transporter protein (NAPI).Tenapanor is mainly used for the treatment of hyperphosphatemia in patients with end-stage renal disease-hemodialysis (ESRD-HD). Diarrhea is the most common adverse reaction to this product. This article reviews Tenapanor by performing a literature search on its pharmacological effects, pharmacokinetic properties, clinical evaluation, safety, drug interactions and dosage.

Paraventricular thalamic nucleus nerve pathways involved in general anesthesia wakefulness and sleep wakefulness

GU Yunfei, CHEN Suheng, YU Kaihua, BAO Zhenxing, LI Yulan

2023, 28(12):  1436-1440.  doi:10.12092/j.issn.1009-2501.2023.12.015

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The paraventricular thalamic nucleus (PVT) is a key nucleus involved in wakefulness. PVT plays an important role in normal sleep-wake regulation, but its role may vary during anesthesia depending on the stage of anesthesia. This article will review the role of PVT in sleep and anesthesia based on its wakefulness function neural pathways.