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Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an glioma model, PCC0208017 showed robust anti-tumor activity, blood-brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.
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Heat shock protein 70 (HSP70) family is one ofthe most conserved proteinin evolutionand plays critical,role in proteostasis.HSP70 is becoming an interesting target for multiple diseases such as cancer and Alzheimer's disease.There are many drugs targeted to HSP70 in preclinical study.In this review,the classification,the structure,the function of HSP70,and the drugs of the HSP70 family are reviewed.
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Objective To evaluate the efficacy and safety of mosapride in the treatment of gastroesophageal reflux disease (GERD). Methods Papers of PubMed,EMBASE,OVID,VIP Database and WANGFANG Data were searched and reviewed according to international Cochrane Collaboration.Results A total of 21 trials (1666 patients) were included.The treatment group was with mosapride and PPI,the control group was with single PPI or PPI and placebo.The Results of Meta analysis showed:for non-erosive negative reflux disease,there was no significant difference in efficacy between two groups.As for erosive esophagitis treated with mosapride (5mg):There was no significant difference in the 4-week healing rates between treatment group and control group (P =0.06).The 4-week symptom relief rate of treatment group was better than that of control group (P＜0.01).The 6-week healing rate of treatment group was better than that of control group (P＜0.01).The 6-week symptom relief rate of treatment group was better than that of control group (P＜0.01).There was no significant difference in the 8-week healing rate of esophagitis between treatment group and control group (P =0.05).The 8-week symptom relief rate of treatment group was better than that of control group (P＜0.01).For erosive esophagitis treated with mosapride 10mg,.The 8-week symptom relief rate of treatment group was better than that of control group (P=0.02).Conclusion According to the meta-analysis of these 21 trails,mosapride was safe and effective in the treatment of GERD.However due to the quality of the literatures,the above findings should be treated with caution.
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Objective To investigate the effect of Da-Cheng-Qi decoction on enteric functional disturbance in rats with acute experimental pancreatitis and its potential mechanism. Methods Seventy-two SD rats were randomly divided into sham operation group, acute pancreatitis (AP) group and Da-Cheng-Qi decoction treated group with 24 each. The AP model was induced by retrograde injection of sodium taurocholate (0.1 ml/100 g) into bitiopancreatic duet. Before modeling, the rats in treatment group received Da-Cheng-Qi decoction (2 g/100 g), and the rats in other two groups received 0.9% NaCl solution. The rats were sacrificed at 3, 6 and 12 hours with 8 each, and the blood samples were taken for detecting the level of amylase and the contents of 5-hydroxytryptamine (5-HT) by enzyme-linked immunosorbent assay. The colonic tissues 10 cm apart from trans-ligament incluing jejunum, terminal ileum and sigmoid colon were collected for examining the expressions of 5-HT_3 and 5-HT_4mRNA and proteins by RT-PCR and Western blotting respectively. Results ① The levels of serum amylase and 5-HT in AP group and treatment group were significantly higher than those in sham operation group (P<0. 01), but they were lower in treatment group than in AP group at each time points (P<0. 05). The level of 5-HT was increased in the initial stage and then decreased gradually both in AP group and treatment group. ③ The expressions of 5-HT_3 and 5-HT_4 mRNA and proteins were significantly decreased in the jejunum, terminal ileum and sigmoid colon in AP group compared with sham operation group (P<0. 01). Whereas the expressions of 5-HT_3 mRNA and protein,but not 5-HT_4, were increased in the treatment group in comparison with AP group (P<0.05). Conclusions The level of 5-HT is significantly increased in acute pancreatitis, but its receptors (5-HT_3 and 5-HT_4) are decreased, which may induce enteric functional disturbance. The Da-Cheng-Qi decoction may improve enteric dynamic failure by increasing the expression of 5-HT_4 and may be a choice for treatment of acute pancreatitis with enteric dynamic failure
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Objective To determine the level and clinical significance of 5-hydroxytryptamine (5-HT) and intestinal fatty acid binding protein (iFABP) in patients of severe acute pancreatitis (SAP) with intestinal dysfunction. Methods The serum and urine in 42 cases of SAP with intestinal dysfunction were collected at day 1, 3 and 7 after admission, respectively. The numbers of bowel sounds were recorded. 20 health subjects were selected as the control. Results The numbers of bowel sounds in health subjects were 5.6 ± 2.3/min. The numbers of bowel sounds in SAP patients at day 1,3 and 7 were 2.3 ± 0.7/min, 1.7 ± 0.2/min and 3.1 ± 1.1/min, respectively;which were significantly lower than that in the control group (P < 0.01). The level of 5-HT in the control group was(86.7 ± 9.5)ng/ml, while the levels of 5-HT in the SAP patients at day 1, 3 and 7 were (112.0 ± 17.8) ng/ml, (130.5 ± 19.7) ng/ml, (107.9 ± 16.3) ng/ml. The level of urine iFABP in the control group was (90.5 ± 19.8) pg/ml, while the levels of urine iFABP in the SAP patients were (1250.2 ± 425.3) pg/ml, (1586.9 ± 523.4) pg/ml, (1154.6 ± 394.0) pg/ml. The levels of 5-HT and urine iFABP in the SAP patients all were significantly higher than those in the control group (P <0.01). The levels of 5-HT and urine iFABP in the SAP patients at day 3 were significantly higher than those in the day 1 and day 7, while there was no significant difference between the two groups. Conclusions Determination of serum 5-HT and urine iFABP in patients with early SAP could effectively evaluate the intestinal function, and it may have potential clinical significance.
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Objective To introduce the method of reconstructing posterolateral complex injury of the knee with the autogenous middle 1/3 of biceps femoris tendon and gracilis and evaluate its short-term outcome. Methods There were 21 cases of posterolateral complex injury of the knee reconstructed with the middle 1/3 of biceps femoris tendon and gracilis from January 2003 to December 2006. There were 13males and 1 female at age range of 18-49 years ( mean 34.3 years). The reconstructed ligaments included popliteal tendon, lateral collateral ligament and poplitrofibular ligament. An autogenous folded gracilis tendon was extracted and placed through trastibial bony tunnel from anterolateral to the posterior condylar of the tibia to reconstruct the popliteal tendon. An autogenous folded middle 1/3 of biceps femoris tendon was fixed in the isometric bony tunnel of the femoral lateral condyle. The anterior half was used to reconstruct the lateral collateral ligament, and the posterior half to reconstruct the poplitrofibular ligament. The posterolateral stability of the knee was evaluated mainly through examination varus instability of knee and external rotation range of leg. Results All cases were followed up for average 26 months (6-24months). Lysholm score of the knee was (43 ± 2) points preoperatively and (90 ± 3 ) points half year after operation, with significant improvement. Conclusions PCL injury may result in functional deficiency of the injured extremity. While the autogenous middle 1/3 of biceps femoris tendon and gracilis can yield a stable knee with good function, mini-trauma and satisfactory clinical results in reconstructing the posterolateral complex of the knee joint.
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Objective To investigate the therapeutic effect of Da-Cheng-Qi Decoction on gut dysfunction in patients with severe acute pancreatitis (SAP). Methods Forty-eight SAP patients complicated with gut dysfunction were randomly divided into two groups according to the number of admission, which were treatment group and control group. The therapy in t reatment group was Da-Cheng-Qi Decoction infusion through gastric tube (one paste/day, b. i. d), however the therapy of control group was normal saline infusion through gastric tube (the amount was the same as the former, b. i. d), and other management in the two groups was similar. The first passage of gas by anus and defecation after treatment was observed. Serum amylase, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6 were examined before and one week after treatment;complications and mortality were compared between the two groups. Results The first passage of gas by anus and defecation in the treatment group was ( 12.3 ± 5.7 ) h and ( 24.8 ± 11.2 ) h, respectively, and shorter than ( 22. 1 ± 9.7 ) h and 46.2 ± 17.4) h of control group ( P <0.01) ;the numerical values of serum amylase, CRP, TNF-α and IL-6 one week after treatment were ( 120.3 ± 35.8 ) U/L, ( 10.8 ±2.0) ng/ml, (36.3 ± 5.8) U/L and (4.8 ± 1.0) U/L, which were significantly decreased when compared with the values before treatment, and these values were significantly lower than (267.2 ± 78.9 )U/L, ( 19.5 ± 2.7 ) ng/ml, (80.1 ± 9.0) U/L, ( 10.5 ± 1.2 ) U/L of the control group ( P < 0.05 ). The total complications and mortality of treatment group was 12.5% and 4.4%, respectively, which were significantly lower than those in the control group (37.5% and 25%, P <0.05). Conclusions Treatment with Da-Cheng-Qi Decoction in SAPpatients complicated with gut dysfunction was effective to reverse gut dysfunction and reduce total complications and mortality.
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85 adult(42 right,43 left),30 newborn(18 right,12 left)and 32 fetal(13 right,19 left)samples were investigated.The vertical and transverse diameters of the tympanic mendrane were measured.The results might be for reference in isop- lastic transplantation.