ObjectiveTo explore the mechanism of Hei Xiaoyaosan in improving the cognitive function in Alzheimer's disease （AD） from cell apoptosis mediated by the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/nuclear factor kappa B （NF-κB） signaling pathway. MethodsFour-month-old SD male rats were randomly assigned into a blank group， a sham group， a model group， a donepezil hydrochloride （0.45 mg·kg^-1） group， and high-， medium-， and low-dose （15.30， 7.65， and 3.82 g·kg^-1， respectively） Hei Xiaoyaosan groups， with 10 rats in each group. The sham group received bilateral hippocampal injection of 1 μL normal saline， while the other groups received bilateral hippocampal injection of 1 μL beta-amyloid 1-42 （Aβ_1-42） solution for the modeling of AD. Rats were administrated with corresponding agents once a day for 42 consecutive days. The Morris water maze test was carried out to assess the learning and memory abilities of rats. Hematoxylin-eosin staining was employed to observe pathological changes in the hippocampus of rats. Enzyme-linked immunosorbent assay was employed to measure the levels of cysteinyl aspartate-specific proteinase-3 （Caspase-3）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. Western blot was employed to determine the protein levels of PI3K， Akt， and NF-κB. A cell model of AD was established by co-culturing Aβ_1-42 and PC12 cells in vitro. Cell viability and apoptosis were detected by the cell-counting kit 8 （CCK-8） assay and flow cytometry （FC）， respectively. ResultsAnimal experiments showed that compared with the blank group， the model group had a prolonged escape latency （P<0.01）， a reduced number of crossing platforms （P<0.01）， disarrangement and a reduced number of hippocampal neurons， up-regulated expression of Bax and Caspase-3， down-regulated expression of Bcl-2 （P<0.01）， decreased p-PI3K/PI3K and p-Akt/Akt levels， and an increased p-NF-κB/NF-κB level （P<0.01）. Compared with the model group， donepezil hydrochloride and high- and medium-dose Hei Xiaoyaosan shortened the escape latency and increased the number of crossing platforms （P<0.05， P<0.01）， improved the arrangement and increased the number of hippocampal neurons， down-regulated the expression levels of Bax and Caspase-3， up-reguated the expression level of Bcl-2 （P<0.05， P<0.01）， increased the p-PI3K/PI3K and p-Akt/Akt levels （P<0.05， P<0.01）， and reduced the p-NF-κB/NF-κB level （P<0.05， P<0.01）. Cell experiments showed that compared with the blank group， the model group exhibited an increased apoptosis rate （P<0.01）. Compared with the model group， the serum containing Hei Xiaoyaosan at various doses improved the cell viability （P<0.01）， and the serum containing Hei Xiaoyaosan at the high dose decreased the cell apoptosis （P<0.01）. ConclusionHei Xiaoyaosan may improve the learning and memory abilities of AD model rats by regulating cell apoptosis， while increasing the vitality and reducing the apoptosis rate of AD model cells via the PI3K/Akt/NF-κB signaling pathway.

Objective To investigate the mechanism by which angiopoietin-like protein 8(ANGPTL8)regulates vascular smooth muscle cell(VSMCs)apoptosis.Methods An in vitro abdominal aortic aneurysm cell model was established by stimulating human VSMCs(HUSMCs)with angiotensin Ⅱ(AngⅡ).Stable ANGPTL8 knockdown and over-expression VSMC cell strains were generated using lentiviral transfection.TUNEL staining was used to de-tect apoptosis.Western blot analysis was performed to measure the protein expression of ANGPTL8,caspase9,caspase3,Bcl-2,Bax,p53,and PUMA,while RT-qPCR was used to assess mRNA expression of ANGPTL8,Bcl-2 and Bax.Results AngⅡ significantly induced ANGPTL8 expression in HVSMCs in a time-and dose-de-pendent manner(P＜0.05).ANGPTL8 knockdown significantly reduced the expression of apoptosis-related proteins caspase9,caspase3,and Bax,while increased the expression of the anti-apoptotic protein Bcl-2(P＜0.05).Con-versely,ANGPTL8 over-expression markedly induced HVSMCs apoptosis,which was significantly suppressed by treatment with the p53 pathway inhibitor pifithrin-α(PFT-α).Conclusions ANGPTL8 may promote VSMC apop-tosis by activation of p53 signaling pathway.

ObjectiveTo explore the effect and mechanism of Hei Xiaoyaosan in regulating the tumor necrosis factor receptor superfamily member 6 （Fas）/Fas ligand （FasL）/cysteine protease-8 （Caspase-8）/cysteine protease-3 （Caspase-3） signaling pathway to intervene in neuronal apoptosis and prevent Alzheimer's disease （AD）. MethodNinety SPF-grade SD male rats of 4 months old were selected and randomly grouped as follows： 10 rats in the blank group， 10 rats in the sham group （bilateral hippocampus injected with 1 μL normal saline）， and 70 rats in the modeling group ［bilater hippocampus injected with 1 μL amyloid-beta protein 1-42 （Aβ_1-42） solution for the modeling of AD］. Fifty successfully modeled rats were selected and randomly assigned into model， donepezil hydrochloride （0.45 mg·kg^-1）， and high-， medium-， and low-dose （15.30， 7.65， 3.82 g·kg^-1） Hei Xiaoyaosan groups. Rats were administrated with corresponding agents by gavage once a day for 42 days. Terminal-deoxynucleoitidyl transferase-mediated nick end labeling （TUNEL） was employed to observe the apoptosis of neurons in the cortex and hippocampus， and immunohistochemistry （IHC） was used to detect the expression of B-cell lymphoma-2 （Bcl-2） and Bcl-2-associated X protein （Bax） in the hippocampus. Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） was employed to determine the mRNA levels of Fas， FasL， and Fas-associated protein with death domain （Fadd）. Western blot was used to determine the protein levels of Fas， FasL， Fadd， Caspase-3， cleved Caspase-3， Caspase-8， and cleved Caspase-8. ResultCompared with the blank group and sham group， the model group showed increased apoptosis rate in the cortex and hippocampus （P<0.01）， elevated Bax level （P<0.01）， lowered Bcl-2 level （P<0.01）， up-regulated mRNA levels of Fas， FasL， and Fadd in the hippocampus （P<0.01）， and up-regulated protein levels of Fas， FasL， Fadd， cleaved Caspase-3， and cleaved Caspase-8 （P<0.01）. Compared with the model group， donepezil hydrochloride and Hei Xiaoyaosan at high and medium doses decreased the apoptosis rate in the cortex and hippocampus （P<0.05， P<0.01）， lowered the Bax level （P<0.01）， elevated the Bcl-2 level （P<0.01）， and down-regulated the mRNA levels of Fas， FasL， and Fadd and the protein levels of Fas， FasL， Fadd， cleaved Caspase-3， and cleaved Caspase-8 （P<0.05， P<0.01） in the hippocampus. Low-dose Hei Xiaoyaosan decreased the apoptosis rate in the cortex and hippocampus （P<0.05， P<0.01）， lowered the Bcl-2 level （P<0.01）， and down-regulated the mRNA levels of FasL and Fadd （P<0.05） and the protein levels of Fas， FasL， Fadd， cleaved Caspase-3， and cleaved Caspase-8 （P<0.05） in the hippocampus. ConclusionHei Xiaoyaosan can protect neurons in the cortex and hippocampus of AD rats by inhibiting the apoptosis mediated by the Fas/FasL/Caspase-8/Caspase-3 signaling pathway.

ObjectiveTo explore the effect and mechanism of Hei Xiaoyaosan in modulating the synaptic plasticity in APP/PS1 mice by regulating the cyclic adenosine monophosphate （cAMP）/protein kinase A （PKA）/N-methyl-D-aspartate receptor （NMDAR） signaling pathway. MethodTwelve 4-month-old male C57BL/6J mice were selected as the blank control group， and 60 4-month-old male APP/PS1 double transgenic mice were randomized into model， KW-6002 （adenosine receptor antagonist， 3 mg·kg^-1）， and high-， medium-， and low-dose （22.10， 11.05， 5.53 g·kg^-1， respectively） Hei Xiaoyaosan groups， with 12 mice in each group. Mice were administrated with corresponding drugs for 90 days. Transmission electron microscopy was employed to observe the synaptic ultrastructure of hippocampal neurons， and Golgi staining was used to observe the dendritic spine density of neurons in hippocampal CA1 region. Western blot was employed to measure the protein levels of cAMP， PKA， N-methyl-D-aspartate receptors 1， 2A， and 2B （NR1， NR2A， and NR2B， respectively）， postsynaptic density protein 95 （PSD95）， and synapsin 1 （SYN1）. Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） was performed to determine the mRNA levels of cAMP， PKA， and NR1. Enzyme-linked immunosorbent assay was employed to determine the content of interleukin-12 （IL-12） and interleukin-4 （IL-4） in the hippocampus. ResultCompared with the blank group， the model group showed blurred boundaries between presynaptic membrane and postsynaptic membrane in hippocampal CA1 region， reduced and scattered synaptic vesicles， and decreased density of postsynaptic membrane， and irregular， disarranged， and loosened dendritic spines of neurons in hippocampal CA1 region （P<0.01）. In addition， the model group presented down-regulated protein levels of cAMP， PKA， NR1， NR2A， NR2B， PSD95， and SYN1 and mRNA levels of cAMP， PKA， and NR1， elevated IL-12 level， and lowered IL-4 level in the hippocampus （P<0.01）. Compared with the model group， the drug intervention groups showed clear and intact boundaries between presynaptic membrane and postsynaptic membrane in hippocampal CA1 region， increased synaptic vesicles with dense arrangement， increased density of postsynaptic membrane， and improved morphology， arrangement， and density of neuronal dendritic spines （P<0.05， P<0.01）. In addition， the drug interventions up-regulated the protein levels of cAMP， PKA， NR1， NR2A， NR2B， PSD95， and SYN1 （P<0.05，P<0.01） and mRNA levels of cAMP， PKA， and NR1 （P<0.01）， lowered the IL-12 level （P<0.01）， and elevated the IL-4 level （P<0.01） in the hippocampus. ConclusionHei Xiaoyaosan can improve the structure and morphology of hippocampal neurons in APP/PS1 mice by activating the cAMP/PKA/NMDAR signaling pathway and repairing synaptic plasticity.

ObjectiveTo investigate the role and mechanism of Hei Xiaoyaosan in intervening in oxidative stress in the rat model of Alzheimer's disease （AD） via modulating the rat sarcoma （RAS）/rapidly accelerating fibrosarcoma （RAF）/mitogen-activated protein kinase kinase （MEK）/extracellular signal-regulated kinase （ERK） signaling pathway. MethodOne hundred 4-month-old SPF-grade Wistar male rats were randomly grouped as follows： 10 in the blank group， 10 in the sham group （bilateral hippocampus injected with 1 μL normal saline）， and 80 in the modeling group ［bilateral hippocampus injected with 1 μL amyloid beta protein 1-42 （Aβ_1-42） solution for the modeling of AD］. Fifty rats qualified for modeling were selected and randomized into the model， donepezil hydrochloride （0.5 mg·kg^-1）， and high-， medium-， and low-dose （15.30， 7.65， 3.82 g·kg^-1， respectively） Hei Xiaoyaosan groups. The rats were administrated with corresponding drugs by gavage once a day for 42 consecutive days. At the end of gavage， Morris water maze test was performed to examine the learning and memory abilities of the rats， and Nissl staining was used to observe the pathological changes of neurons in CA3 region of the hippocampus. The immunofluorescence assay was used to observe Aβ deposition and tau phosphorylation. Western blot was employed to determine the protein levels of RAS， RAF， phosphorylated （p）-RAF， MEK， p-MEK， ERK， and p-ERK in the hippocampal tissue. Biochemical methods were used to determine the levels of reactive oxygen species （ROS）， malondialdehyde （MDA）， and superoxide dismutase （SOD） in the hippocampal tissue. ResultCompared with the sham group， the model group showed prolonged escape latency （P<0.01）， shortened swimming distance in the target quadrant （P<0.01）， reduced and uneven stained Nissl bodies， enhanced fluorescence intensity of Aβ and p-tau （P<0.01）， up-regulated protein levels of RAS， p-RAF， p-MEK， and p-ERK in the hippocampal tissue （P<0.01）， increased ROS and MDA content （P<0.01）， and decreased SOD activity （P<0.01） on day 5. Compared with the model group， donepezil hydrochloride and high-， medium-， and low-dose Hei Xiaoyaosan shortened the escape latency （P<0.01）， increased the swimming distance in the target quadrant （P<0.01）， improved the arrangement， morphology， and structures of neurons and the number and distribution of Nissl bodies， decreased the fluorescence intensity of Aβ and p-tau （P<0.01）， up-regulated the protein levels of RAS， p-RAF， p-MEK， and p-ERK （P<0.05， P<0.01）， decreased the ROS and MDA content （P<0.01）， and increased the SOD activity （P<0.01） on day 5. ConclusionHei Xiaoyaosan may ameliorate oxidative stress， reduce Aβ and p-tau levels， and inhibit hippocampal neuronal damage by regulating the RAS/RAF/MEK/ERK signaling pathway， thus improving learning and memory abilities.

Alzheimer's disease （AD） is a neurodegenerative disease that predominantly affects the elderly. It belongs to the category of dementia in traditional Chinese medicine （TCM）， with the onset and progression closely associated with the functions of the kidney， liver， and spleen. The classic TCM formula Hei Xiaoyaosan， which regulates the three Yin of liver， spleen， and kidney， shows broad prospects in treating neurodegenerative diseases. This article reviews the experimental studies reported in the past decade to summarize the mechanisms of Hei Xiaoyaosan and its active components in intervening in AD. Hei Xiaoyaosan can treat AD via multiple targets， levels， and aspects comprehensively. The clinical studies have demonstrated that Hei Xiaoyaosan alone or in combination with other therapies has a definite therapeutic effect on AD. Specifically， it can ameliorate the cognitive impairment， mitigate oxidative stress， and inhibit the overexpression of soluble apoptotic factors in AD patients. This review aims to provide a theoretical basis for the treatment of AD with Hei Xiaoyaosan and explore new research directions. Moreover， it gives new insights into the clinical application of Hei Xiaoyaosan and the development of products with both medicinal and edible values.

Objective:To investigate whether there are differences in clinical outcomes and perinatal outcomes associated with different initial dosages of gonadotropin (Gn) in expected poor prognosis young patients, diagnosed according to the POSEIDON criteria, undergoing the early-follicular phase long-acting gonadotropin-releasing hormone agonist (GnRH-a) long protocol.Methods:This retrospective cohort study analyzed clinical data from patients who underwent their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI)-fresh embryo transfer (ET) cycle at the Reproductive Medicine Center of the First Affiliated Hospital of Zhengzhou University between January 1, 2016, and June 30, 2022. Patients included in the study were those who underwent ovarian stimulation with the early-follicular phase long-acting GnRH-a long protocol and young expected poor prognosis. Patients were divided into three groups based on the starting Gn dosage: low-dose group (Gn<225 U), medium-dose group (225 U≤Gn<300 U), and high-dose group (Gn=300 U). Clinical and perinatal outcomes were compared among the three groups. Results:A total of 1 659 cycles were included in the study, with 316 cycles in the low-dose group, 536 cycles in the medium-dose group, and 807 cycles in the high-dose group. The number of oocytes retrieved in the high-dose group [6.00 (4.00,9.00)] was less than that in the medium-dose group [8.00 (6.00,11.00)] and the low-dose group [11.00 (7.00,13.00)], which in the medium-dose group was less than that in the low-dose group, and the differences were statistically significant (all P<0.017). There were no significant statistical differences in oocyte maturation rate, normal fertilization rate of IVF/ICSI, or high-quality embryo rate among the three groups (all P>0.05). The blastocyst formation rates decreased sequentially in the low-dose group [20.33% (425/2 090)], medium-dose group [17.28% (510/2 951)], and high-dose group [14.62% (518/3 542)], with significant differences between each pair of groups (all P<0.017). There were no significant differences in clinical pregnancy rate, biochemical pregnancy rate, ectopic pregnancy rate, miscarriage rate, chromosomal abnormalities in miscarriage tissues, or preterm birth rate among the three groups (all P>0.05). However, the live birth rate was significantly lower in the high-dose group [47.83% (386/807)] than in the low-dose group [57.28% (181/316), P=0.004]. After adjusting for confounding factors using multivariate logistic regression, the high starting Gn dosage was found to be an independent risk factor for decreased live birth rate (a OR=0.659, 95% CI: 0.462-0.941, P=0.022). There were no significant differences in perinatal outcomes among the groups, regardless of whether confounding factors were adjusted for (all P>0.05). Conclusion:In young patients with expected poor prognosis undergoing their first ovarian stimulation with the long-acting follicular phase protocol, increasing the starting Gn dosage does not increase the number of oocytes retrieved and is associated with a lower blastocyst formation rate and a reduced live birth rate, but does not increase the risk of adverse perinatal outcomes.

Objective:To investigate whether there are differences in clinical outcomes and perinatal outcomes associated with different initial dosages of gonadotropin (Gn) in expected poor prognosis young patients, diagnosed according to the POSEIDON criteria, undergoing the early-follicular phase long-acting gonadotropin-releasing hormone agonist (GnRH-a) long protocol.Methods:This retrospective cohort study analyzed clinical data from patients who underwent their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI)-fresh embryo transfer (ET) cycle at the Reproductive Medicine Center of the First Affiliated Hospital of Zhengzhou University between January 1, 2016, and June 30, 2022. Patients included in the study were those who underwent ovarian stimulation with the early-follicular phase long-acting GnRH-a long protocol and young expected poor prognosis. Patients were divided into three groups based on the starting Gn dosage: low-dose group (Gn<225 U), medium-dose group (225 U≤Gn<300 U), and high-dose group (Gn=300 U). Clinical and perinatal outcomes were compared among the three groups. Results:A total of 1 659 cycles were included in the study, with 316 cycles in the low-dose group, 536 cycles in the medium-dose group, and 807 cycles in the high-dose group. The number of oocytes retrieved in the high-dose group [6.00 (4.00,9.00)] was less than that in the medium-dose group [8.00 (6.00,11.00)] and the low-dose group [11.00 (7.00,13.00)], which in the medium-dose group was less than that in the low-dose group, and the differences were statistically significant (all P<0.017). There were no significant statistical differences in oocyte maturation rate, normal fertilization rate of IVF/ICSI, or high-quality embryo rate among the three groups (all P>0.05). The blastocyst formation rates decreased sequentially in the low-dose group [20.33% (425/2 090)], medium-dose group [17.28% (510/2 951)], and high-dose group [14.62% (518/3 542)], with significant differences between each pair of groups (all P<0.017). There were no significant differences in clinical pregnancy rate, biochemical pregnancy rate, ectopic pregnancy rate, miscarriage rate, chromosomal abnormalities in miscarriage tissues, or preterm birth rate among the three groups (all P>0.05). However, the live birth rate was significantly lower in the high-dose group [47.83% (386/807)] than in the low-dose group [57.28% (181/316), P=0.004]. After adjusting for confounding factors using multivariate logistic regression, the high starting Gn dosage was found to be an independent risk factor for decreased live birth rate (a OR=0.659, 95% CI: 0.462-0.941, P=0.022). There were no significant differences in perinatal outcomes among the groups, regardless of whether confounding factors were adjusted for (all P>0.05). Conclusion:In young patients with expected poor prognosis undergoing their first ovarian stimulation with the long-acting follicular phase protocol, increasing the starting Gn dosage does not increase the number of oocytes retrieved and is associated with a lower blastocyst formation rate and a reduced live birth rate, but does not increase the risk of adverse perinatal outcomes.

Objective     To investigate the effect of intravenous analgesia with a wireless or traditional analgesia pump system in thoracoscopic lung resection. Methods     Patients who used the patient-controlled intravenous analgesia after thoracoscopic lung resection between June 2016 and June 2021 were enrolled in the study. They were allocated into a wireless pump group (a ZigBee-based wireless analgesia pump system collecting data automatically) and a traditional analgesia pump group. Perioperative analgesia management followed the routine standard operation protocol of Shanghai Chest Hospital. The patients’ numeric rating scale (NRS) for pain and postoperative nausea and vomiting (PONV) scores were collected for analysis from the Anesthesia Information Record System. The incidence of postoperative analgesia insufficiency (defined as NRS≥4 points) within 48 h, the incidence of PONV within 24 h, and the 48 h completion rate of analgesia pump infusion were compared. Results    A total of 59 431 patients were collected, including 24 855 males and 34 576 females, 17 209 patients in the wireless pump group, and 42 222 patients in the traditional analgesia pump group. The incidence of analgesia insufficiency within 48 h after operation (3.75% vs. 4.98%, P=0.007), the incidence of PONV within 24 h after operation (13.60% vs. 16.70%, P=0.030) in the wireless pump group were lower than those in the traditional analgesia pump group. The 48 h completion rate of analgesia pump infusion in the wireless pump group was higher than that in the traditional analgesia pump group (83.40% vs. 71.90%, P<0.001). The wireless pump group could monitor the pressing times and use of the analgesia pump, while the traditional analgesia pump group could not record the relevant data. Conclusion    Compared with the traditional analgesia pump, the wireless analgesia management system may be convenient for timely, accurate and individualized management, and has good analgesic effect and low incidence of adverse reactions, and may be more suitable for perioperative analgesia management.

Objective:To investigate the application of objective-based teaching combined with Roy adaptive situational teaching in emergency nursing teaching.Methods:A total of 110 nursing students who were assigned to Emergency Department of Xijing Hospital, The First Affiliated Hospital of Air Force Medical University, as interns were selected and divided into control group and observation group according to the order of admission, with 55 students in each group. The students in the control group received traditional teaching, while those in the observation group received objective-based teaching combined with Roy adaptive situational teaching. The two groups were evaluated in terms of the assessment score of situational simulation and the ability for emergency medicine and treatment. SPSS 22.0 was used to perform the t-test and the chi-square test. Results:For the nursing students in the observation group, the mean scores of theoretical knowledge objective, skill objective, and attitude objective were (9.09±1.21) points, (13.98±1.87) points, and (9.32±0.95) points, respectively, and for those in the control group, the mean scores of these objectives were (8.41±1.17) points, (12.43±1.72) points, and (8.72±0.83) points, respectively, suggesting that compared with the control group, the observation group had a significantly higher mastery degree of the teaching objectives (theoretical knowledge objective, skill objective, and attitude objective) ( P < 0.05). The observation group had significantly better abilities for emergency medicine and treatment than the control group ( P < 0.05). Conclusion:Objective-based teaching combined with Roy adaptive situational teaching can be used in emergency nursing teaching and may help to improve the theoretical and practical skills of nursing students and cultivate the abilities for emergency medicine and treatment.