Objective:To study the effect of baicalein on the expression of glutamate receptor related protein in PC12 cells injured by Aβ 25-35. Methods:PC12 cells were divided into control group, model group, estradiol group and baicalein group with different concentrations. The survival condition of PC12 cells in each group were detected by thiazole blue (MTT). PC12 cells were divided into control group, model group, estradiol group and baicalein group. The control group and model group were cultured with DMEM medium, and the estradiol group was added with 1×10 -3 μmol/L estradiol DMEM medium, baicalein group was added with 1 μmol/L baicalein DMEM medium. After 2 hours of intervention, 20 μmol/L Aβ 25-35 was added to the model group, estradiol group and baicalein group with induced PC12 cell injury. After 22 hours of intervention, flow cytometry was used to detect the apoptosis of PC12 cells. The expression of estrogen receptor β (ER β), phosphorylated c-Jun N-terminal kinase (p-JNK/JNK) and ionic receptor N-methyl-D-aspartate receptor 1 (NMDAR1), glutamate receptor 2 (GluR2) and calcium/calmodulin dependent protein kinase Ⅱ (CaMK Ⅱ) were detected by Western blot. Results:Compared with model group, 1 μmol/L baicalein significantly increased the proliferation rate [(95.80±2.47)% vs. (64.34±3.84)%]. The apoptosis rate of PC12 cells[(7.83±0.67)% vs. (12.84±0.91)%] was significantly decreased in baicalein group ( P<0.01). The expression of NMDAR1 (0.582±0.012 vs. 0.352±0.012), GluR2(0.538±0.017 vs. 0.355±0.006), ER β (0.362±0.015 vs. 0.262±0.018) in baicalein group were significantly increased ( P<0.01), the expression of p-JNK/JNK (0.476±0.013 vs. 0.752±0.014) and CaMK Ⅱ(0.499±0.019 vs. 0.670±0.016) in baicalein group were significantly decreased ( P<0.01). Conclusions:Baicalein has a protective effect on PC12 cells injured by Aβ 25-35. Its mechanism may be related to the inhibition of p-JNK/JNK activity by activating ERβ and regulating the expression of glutamate receptor related protein.

Grid management plays an important role in improving the efficiency of social service management. The authors explored the establishment of a nosocomial infection grid management model and implemented it at a tertiary general hospital in Shanghai. χ2 test results showed that since the hospital fully implemented the grid management model in early 2016, the number of hospital infections, surgical site infections, type I surgical incision infections, and ventilator-related pneumonia had shown a downward trend year by year. The number of inspections before the use of antibacterial drugs, the number of blood cultures submitted for fever patients, and the timing of hand hygiene compliance showed an increasing trend year by year( P<0.05), and the management of nosocomial infection was more effective than the previous period. The application of grid management model required establishment of grid organization structure, control of key links, implementation of the special personnel responsibility, formulation of a performance evaluation system, and implementation of incentive measures. The grid management model can significantly reduce the risk of hospital infection, improve the efficiency of hospital infection management, and was valuable to be applicated and promoted in medical institutions.

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both

Objective:To investigate the role of Sestrin2 overexpression in regulating mitochondrial fission and its mechanism in human neuroblastoma SH-SY5Y cell model of glucose and oxygen deprivation/recovery (OGD/R). Methods:(1) SH-SY5Y cells were divided into normal control group, OGD/R group, Vector group, and Sestrin2 overexpression group; Sestrin2 overexpression or empty vector stable cell lines in the Sestrin2 overexpression group and Vector group were constructed by lentivirus infection; cells in the later 3 groups were subjected to oxygen-glucose deprivation (OGD) for 4 h followed by restoration of O 2 supply for 18 h. The cell survival rate was detected by cell counting kit (CCK)-8 assay. The protein levels of Sestrin2, dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Kelch-like ECH-related protein 1 (Keap1) in the cytoplasm and nuclear factor E2-related factor (Nrf2) in the nucleus were detected by Western blotting. The mitochondria ultrastructure was observed by transmission electron microscope. The Nrf2 nuclear translocation was detected by immunofluorescence staining. (2) Cell lines with Sestrin2 overexpression were divided into Sestrin2 overexpression group, Brusatol+ Sestrin2 overexpression group, and DMSO+ Sestrin2 overexpression group. Cells in the Brusatol+ Sestrin2 overexpression group were pretreated with normal medium containing Brusatol (Keap1/Nrf2 pathway inhibitor, final concentration: 100 nmol/L) for 4 h before OGD/R; cells in the DMSO+ Sestrin2 group were pretreated with normal medium containing DMSO (final volume fraction: 0.1%) for 4 h before OGD/R. Cells in these groups were then subjected to OGD for 4 h followed by restoration of O 2 supply for 18 h. The protein levels of Drp1, Fis1, Keap1 in the cytoplasm, and Nrf2 in the nucleus were measured by Western blotting. Results:(1) As compared with those in the OGD/R group, cells in the Sestrin2 overexpression group had significantly increased survival rate (61.33%±1.15% vs. 81.00%±3.00%), significantly up-regulated Bcl-2/Bax ratio (0.467±0.006 vs. 0.880±0.010), significantly decreased Drp1, Fis1 and cytoplasmic Keap1 protein levels (1.089±0.033 vs. 0.865±0.014; 0.829±0.009 vs. 0.350±0.007; 0.967±0.017 vs. 0.881±0.024), and significantly up-regulated nuclear Nrf2 protein level (0.627±0.025 vs. 0.957±0.015, P<0.05). The mitochondrial structure in the Sestrin2 overexpression group under electron microscope was more complete than that in the OGD/R group, and obvious nuclear translocation of Nrf2 was noted. (2) As compared with the Sestrin2 overexpression group, Brusatol+ Sestrin2 overexpression group had significantly decreased nuclear Nrf2 protein level (0.920±0.013 vs. 0.627±0.035), and statistically increased Drp1 and Fis1 protein levels (0.994±0.020 vs. 1.084±0.005; 0.728±0.010 vs. 0.906±0.022, P<0.05). Conclusion:Sestrin2 overexpression could suppress mitochondrial fission, reduce cell apoptosis, and attenuate OGD/R injury of SH-SY5Y cells by activating Keap1/Nrf2 pathway via down-regulating cytoplasmic Keap1 protein level and promoting Nrf2 nuclear translocation.

Cullin-RING E3 ligases (CRLs) are the major components of ubiquitin-proteasome system, responsible for ubiquitylation and subsequent degradation of thousands of cellular proteins. CRLs play vital roles in the regulation of multiple cellular processes, including cell cycle, cell apoptosis, DNA replication, signalling transduction among the others, and are frequently dysregulated in many human cancers. The discovery of specific neddylation inhibitors, represented by MLN4924, has validated CRLs as promising targets for anti-cancer therapies with a growing market. Recent studies have focused on the discovery of the CRLs inhibitors by a variety of approaches, including high through-put screen, virtual screen or structure-based drug design. The field is, however, still facing the major challenging, since CRLs are a large multi-unit protein family without typical active pockets to facilitate the drug design, and enzymatic activity is mainly dependent on undruggable protein-protein interactions and dynamic conformation changes. Up to now, most reported CRLs inhibitors are aiming at targeting the F-box family proteins (e.g., SKP2, β-TrCP and FBXW7), the substrate recognition subunit of SCF E3 ligases. Other studies reported few small molecule inhibitors targeting the UBE2M-DCN1 interaction, which specifically inhibits CRL3/CRL1 by blocking the cullin neddylation. On the other hand, several CRL activators have been reported, such as plant auxin and immunomodulatory imide drugs, thalidomide. Finally, proteolysis-targeting chimeras (PROTACs) has emerged as a new technology in the field of drug discovery, specifically targeting the undruggable protein-protein interaction. The technique connects the small molecule that selectively binds to a target protein to a CRL E3 via a chemical linker to trigger the degradation of target protein. The PROTAC has become a hotspot in the field of E3-ligase-based anti-cancer drug discovery.
Antineoplastic Agents ; pharmacology ; therapeutic use ; Drug Design ; Drug Discovery ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Humans ; Neoplasms ; enzymology ; Ubiquitin-Protein Ligases ; metabolism ; Ubiquitination ; drug effects

Objective To investigate the distribution characteristics and risk factors of intracranial and extracranial aterial lesions in Chinese patients with ischemic stroke . Methods In this multi‐center study ,2 310 continuously inpatients with ischemic stroke diagnosed in 20 stroke screening and prevention project base hospitals from June 2015 to M ay 2016 were enrolled . Carotid ultrasonography and transcranial color‐coded sonography or transcranial Doppler were performed in all patients to confirm the presence of cerebral artery stenosis or occlusion . According to the distribution of lesions ,the subjects were divided into 2 groups :the simple intracranial artery stenosis group and the simple extracranial artery stenosis group . T he difference of risk factors between the two groups was compared . Results Of the 2 310 patients with ischemic stroke ,1 516 ( 65 .6% ) had simple intracranial artery stenosis and 794 ( 34 .4% ) had simple extracranial artery stenosis . T he incidence of anterior circulation artery stenosis was higher in the group of intracranial artery stenosis than that in the extracranial artery stenosis group ( 68 .1% vs 48 .7% , P ＜0 .001) . Posterior circulation artery stenosis and combined anterior with posterior circulation artery stenosis were more common in patients with extracranial artery stenosis group than those in intracranial artery stenosis group ( 36 .4% vs 22 .1% ,14 .9% vs 9 .8% ;all P ＜0 .001) . Univariate analysis of risk factors for stroke showed that patients with intracranial arterial stenosis had a higher prevelence of hypertension , diabetes ,obesity ,and family history of stroke ,and their systolic blood pressure ,diastolic blood pressure , body mass index ( BM I) ,fasting blood‐glucose ,glycosylated hemoglobin ,triacylglycerol ,total cholesterol , and low‐density lipoprotein cholesterol were significantly higher than those in the extracranial arterial stenosis group ( all P ＜ 0 .05 ) . T he proportion of elderly ( ≥ 65 years old ) ,male and smokers in the extracranial arterial stenosis group was significantly higher than that in the intracranial arterial stenosis group ( all P ＜0 .05) . Multivariate logistic regression analysis showed that elderly ( ≥65 years old) ,male , and smoking history were independent risk factors for extracranial arterial stenosis ( OR＝ 2 .012 ,1 .637 , 1 .325 ,respectively ;all P ＜0 .05) . While hypertension ,diabetes ,less physical activity ,and high BM I levels were independent risk factors for simple intracranial arterial disease ( OR ＝ 1 .301 ,1 .252 ,1 .248 ,1 .030 , respectively ;all P ＜0 .05) . Conclusions There are significant differences in the distribution characteristics and risk factors of intracranial and extracranial aterial lesions in patients with ischemic stroke in China .

Objective To investigate the therapeutic effect of children's growth patch combined with recombinant human growth hormone on idiopathic short stature. Methods A retrospective analysis of 45 children patients with idiopathic short stature from February 2016 to February 2017 was carried out, according to the treatment method, they were divided into the control group, the observation group 1 and the observation group 2, with 15 cases in each group. The control group was those who rejected all medications. The observation group 1 was those who were given children's growth patch; the observation group 2 was those who were given growth patch combined with recombinant human growth hormone therapy. The treatment lasted for 12 months. The height growth, genetic height, and predicted adult height were compared. Results The control group, the observation group 1 and the observation group 2 were compared, and the height growth values were (3.87±1.25) cm, (7.93±1.53) cm, and (10.20±1.97) cm, respectively, and the difference was significant (F=59.48, P<0.01); the genetic heights were (156.80±4.94) cm, (156.07±3.97) cm, (156.13±4.58) cm, respectively, and the difference was not significant (F=0.12, P>0.05); the predicted adult heights were (155.73±3.31) cm, (164.80±5.24) cm, and (167.87±5.68) cm, respectively, and the difference was significant (F=25.35, P<0.01). Conclusion Children's growth patch combined with recombinant human growth hormone in the treatment of idiopathic short stature can significantly increase the height growth value and increase the predicted value of adult height.

Objective? To develop the Traditional Chinese Medicine (TCM) nursing skill training program for community nurses and to evaluate its effects based on Kirkpatrick Model. Methods? Totally 83 community nurses from 2 districts of Hangzhou between April and August 2017 were selected using convenient sampling and divided into the control group (n=42) and the observation group (n=41). Community nurses in the control group received conventional training, while community nurses received TCM nursing skill training, and its effects were evaluated in terms of reaction, learning, behavior and result layers based on Kirkpatrick Model. Results? There was no statistically significant difference in general information and student analysis data between the two groups (P＞0.05). The attendance rates of both groups were above 85% after the training, and the total satisfaction, theoretical performance of TCM and skill examination of the observation group scored (95.05±5.32), (79.90± 6.03) and (88.52±2.47), respectively. The scores of self-evaluated behavior and others-evaluated behavior were (44.75±3.58) and (40.15±2.85); and patients＇ satisfaction score was (95.35±3.61), higher than that of the control group (P＜0.05), which was (91.95±4.56). The number of TCM nursing items launched in the departments to which the two groups belonged to was 3.(5 3.00, 4.75) and [3(?2, 4);(P＞0.05)]. Conclusions? The TCM nursing skill training program can benefit community nurses in terms of reaction, learning, behavior and result layers, which is worth promoting in clinical practice.

Objective To forecast the number of healthcare professionals at China′s primary medical institutions from 2016 to 2020 ,so as to provide the healthcare authorities with references for optimizing healthcare human resource allocation .Methods The Grey model was used to predict numbers of healthcare professionals in China from 2016 to 2020 on the base of health technicians data from 2010 to 2015 .Results The forecast results show that the number of healthcare professionals may be increased to about 600000 people a yearfrom 2015 to 2020 .The number of healthcare professionals at China′s primary medical institutions is expected to grow about 204000 people a year ,and general practitioner is increased to about 22000 people a year .The annual growth rates of medical(assistant) practitioners ,medical practitioners ,registered nurses ,pharmaceutical personnel and examiners in China are expected to be 3.20％ ,2.81％ ,6.88％ ,1.53％ and 2.16％ respectively. The annual average growth rates of postgraduates ,undergraduates and junior college graduates are expected to be 16.95％ ,12.08％ and 5.46％ respectively .Conclusions in the future ,the requirements for healthcare professionals at primary institutions will still be higher than demand in China ,with a gap to be filled and their professional makeup and academic title make to be optimized. Therefore greater efforts are required for their development to enhance their competence and professionalism ,with reasonable staffing of the human resources .