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Acta Pharmaceutica Sinica B ; (6): 533-578, 2024.
Article in English | WPRIM | ID: wpr-1011275


Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Chinese Journal of Surgery ; (12): 166-171, 2017.
Article in Chinese | WPRIM | ID: wpr-808287


Objective@#To determine the feasibility and safety of anterior cervical decompression and fusion in severe cervical kyphosis treatment.@*Methods@#Totally 29 patients with severe cervical kyphosis(Cobb angle>50°) underwent anterior cervical decompression and fusion from June 2008 to May 2016 were studied retrospectively. There were 19 males and 10 females. The average age was 32.6 years ranging from 14 to 53 years. According to the etiology, 12 patients had iatrogenic deformity (11 had post-laminectomy cervical kyphosis, 1 had kyphosis due to anterior graft subsidence), 5 had neurofibromatosis, 4 had infective kyphosis, 8 had idiopathic cervical kyphosis. The curvature of cervical angle was measured by two-line Cobb method. The severity of cervical kyphosis was evaluated by kyphosis index (KI). Parameters including kyphosis levels, the apex of the kyphosis, C2-7 sagittal vertical axis(SVA) and T1 slope were also measured on lateral radiographs in the neutral position in each patient. The pre- and post-operative Japanese Orthopaedic Association(JOA) scores, visual analogue scale (VAS) of neek pain, neck disability index (NDI) and cervical alignment were compared. All patients were treated by skull traction. Motor evoked potential and somatosensory evoked potential were applied intraoperation as the spinal cord monitor.@*Results@#Skull traction was performed for an average of 6.3 days. The mean vertebral number in kyphotic region was 4.7. The average operation time was 155 minutes and blood loss was 135 ml. The preoperative C2-7Cobb angle was 46.6°±18.1° in average. It was reduced to 11.4°±6.4° in average after operation. The Cobb angle of operation region was 72.9°±19.6° in average before operation. It was reduced to 11.2°±6.4° in average after operation. The kyphosis region correction rate was 84.6%. The mean preoperative C2-7SVA changed from (3.8±14.6) mm to (12.6±7.8) mm postoperatively. The mean preoperative T1 slope changed from -10.6°±16.4° to 7.1°±14.9° postoperatively. The average postoperative C2-7 Cobb angle, Cobb angle of kyphosis region, KI, C2-7 SVA and T1 slope changed significantly compared with preoperation (F=12.700-218.200, all P<0.01). The average postoperative JOA, VAS and NDI scores improved significantly compared with preoperation (F=225.500, 217.900, 131.200, all P<0.01).@*Conclusion@#For severe cervical kyphosis, anterior correction is a safe and effective technique, sufficient decompression will be achieved.

Chinese Journal of Cerebrovascular Diseases ; (12): 225-229, 2017.
Article in Chinese | WPRIM | ID: wpr-613967


Objective To investigate the characteristics and risk factors for cognitive decline in elderly patients with cerebral infarction.Methods A cross-sectional study was performed to investigate the population of Jiang'an Town,Rugao,Jiangsu Province from November 13,2014 to December 21,2014.The samples from the Rugao longitudinal study of aging included 1 788 individuals from 31 villages aged from 70 to 84 years.They were all Han nationality,including 830 males and 958 females.History of cerebral infarction was identified according to the neurological diagnosis confirmed by the secondary hospital and above or brain CT.The modified Kyohko Hasegawa dementia scale was used to evaluate the cognitive function.Five dimensions (orientation,memory,near memory,computing power,and common sense) of this population were assessed.The total score >21.5 was non-cognitive impairment and ≤21.5 was cognitive impairment.Multivariate logistic regression was used to analyze the risk factors for cognitive decline in elderly patients with cerebral infarction.Results (1) In the 1 788 subjects,133 had cerebral infarction (7.4%),and 1 655 did not have cerebral infarction.The proportion of hypertension in patients with cerebral infarction was higher than that without cerebral infarction (63.9% [n=85] vs.41.7% [n=690]).The high-density lipoprotein cholesterol level was lower than that of the non-cerebral infarction group (1.40±0.29 mmol/L vs.1.47±0.33 mmol/L).There was statistically significant difference (all P<0.05).(2) The patients with cerebral infarction were partially impaired in orientation and computational power,and the overall cognitive function score was 20±7,which was significantly lower than patients with non-cerebral infarction (21±6).The difference between the two groups was statistically significant (P<0.05).(3) In 133 patients with cerebral infarction,76 had cognitive impairment,the incidence was 57.1%,and 59 of them were women.The average value of serum creatinine in patients with cognitive impairment was 59±15 μmol/L,which was significantly lower than those with non-cognitive impairment (66±14 μmol/L).There was significant difference (P<0.05).(4) Multivariate logistic regression analysis showed that the education level below primary school (OR,2.86,95%CI 2.19-3.72) and female (OR,1.85,95%CI 1.50-2.28) were the independent risk factors for cognitive decline in elderly patients with cerebral infarction.High serum creatinine concentration (OR,0.96,95%CI 0.95-0.97) was a protective factor for it.Conclusion The cognitive function of the elderly was decreased after cerebral infarction,especially in the aspect of orientation and calculation.The education level below primary school and women were the independent risk factors for cognitive impairment,and high serum creatinine concentration had a certain protective effect.

Chinese Traditional and Herbal Drugs ; (24)1994.
Article in Chinese | WPRIM | ID: wpr-682312


Object To study the chemical constituents of Hypericum sampsonii Hance from Yunnan Province Methods Cytotoxicity screening of extracts from wild and cultivated H sampsonii was carried out by L 1210 cell and KB cell Chemical constituents for wild H sampsonii were isolated by column chromatography The chemical structures were identified by physical and chemical properties and spectral data analysis Results Six compounds have been isolated and established as 1 benzoyl 3 (3 methyl 2 butenyl) 6, 6, 13, 13 tetramethyl 11 geranyl 5 lxatetracycol[7 3 1 0 3, 7 0 4, 11 ] tridecane 2, 12 dione (sampsonione A, Ⅰ); 1 benzoyl 5 (1 hydroxy isopropyl) 6, 6, 13, 13 tetramethyl 11 geranyl tetracycol [7 3 1 1 0 3, 7 ] tetradecane 2, 12, 14 trione (sampsonione F, Ⅱ); 3 (1 hydroxy 5 methyl 4 hexenyl) 6, 10 di (3 methyl 2 butyryl) 8 benzoyl 9, 9 dimethyl 4 oxatricycol [6 3 1 0 1, 5 ] 5 dodecene 7, 12 dione (sampsonione K, Ⅲ); 1,2 dihydro 3, 6, 8 trihydroxy 1, 1 bis (3 methyl but 2 enyl) xanthen 2, 9 dione (patulone, Ⅳ); 1, 7 dihydroxy 4 methoxy xanthone (Ⅴ) and 1, 3, 6, 7 tetrahydroxy 8 (3 methyl but 2 enyl) xanthone (Ⅵ) Conclusion Compounds Ⅳ-Ⅵ are first obtained from H sampsonii In addition, the fractions of chloroform extracting and ethyl acetate extracting possess anticancer activities by cytotoxicity tests