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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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BACKGROUND: Adipose-derived stem cells have the advantages of easy access, easy separation, small trauma, and rapid proliferation. Current treatments for kidney injury are more limited, and adipose-derived stem cells may provide a new treatment route. OBJECTIVE: To investigate the effects of adipose-derived stem cell transplantation on the kidney function of rats with acute kidney injury induced by crush injury in rats. METHODS: Cryopreserved adipose-derived stem cells were recovered in vitro and cultured to prepare cell suspension following labeling with PKH-26. Twenty rats were randomly selected from 66 experimental Sprague-Dawley rats (provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.) as normal control group. In the 40 of the remaining 46 rats, a pathological model of acute kidney injury caused by compression injury was successfully established by the use of forceps to double the proximal hind limbs. The 40 rat models were divided into model group and cell transplantation group, with 20 rats in each group. After 6 hours of modeling, the rats in the model group were given intravenous injection of normal saline (20 μL) , and the rats in the cell group were given intravenous injection of PKH-26-labeled adipose-derived stem cells (20 μL, 3×106/L) , once a day for 3 continuous days. The levels of serum creatinine and urea nitrogen were measured in each group at 1, 3, 14 and 21 days after transplantation. The left kidney of the rats in each group was observed using hematoxylin-eosin staining, TUNEL staining, RT-PCR and western blot assay at 3 and 21 days after cell transplantation. RESULTS AND CONCLUSION: (1) The levels of creatinine and urea nitrogen in the serum of rats at 1, 3, 14 and 21 days after cell transplantation were significantly higher in the model group than the normal control group (P < 0.05) and cell transplantation group (P < 0.05). (2) At 3 and 21 days after cell transplantation, the scores on the kidney injury and apoptotic rate of kidney cells were ranked as follows: model group> cell transplantation group> normal control group, and there were significant differences between groups (P < 0.05). (3) At 3 and 21 days after cell transplantation, the expressions of bax and Caspase-3 in the kidney tissue at mRNA and protein levels were significantly higher in the model group and cell transplantation than the normal control group (P < 0.01) as well as significantly higher in the cell transplantation group than the model group (P < 0.05). To conclude, adipose-derived stem cell transplantation has obvious repairing effect on acute kidney injury caused by crush injury, and its mechanism may be related to the involvement of adipose-derived stem cells in regulating the expression of bax and Caspase-3.
RESUMO
BACKGROUND: Adipose-derived stem cells have the advantages of easy access, easy separation, small trauma, and rapid proliferation. Current treatments for kidney injury are more limited, and adipose-derived stem cells may provide a new treatment route. OBJECTIVE: To investigate the effects of adipose-derived stem cell transplantation on the kidney function of rats with acute kidney injury induced by crush injury in rats. METHODS: Cryopreserved adipose-derived stem cells were recovered in vitro and cultured to prepare cell suspension following labeling with PKH-26. Twenty rats were randomly selected from 66 experimental Sprague-Dawley rats (provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.) as normal control group. In the 40 of the remaining 46 rats, a pathological model of acute kidney injury caused by compression injury was successfully established by the use of forceps to double the proximal hind limbs. The 40 rat models were divided into model group and cell transplantation group, with 20 rats in each group. After 6 hours of modeling, the rats in the model group were given intravenous injection of normal saline (20 μL), and the rats in the cell group were given intravenous injection of PKH-26-labeled adipose-derived stem cells (20 μL, 3×106/L), once a day for 3 continuous days. The levels of serum creatinine and urea nitrogen were measured in each group at 1, 3, 14 and 21 days after transplantation. The left kidney of the rats in each group was observed using hematoxylin-eosin staining, TUNEL staining, RT-PCR and western blot assay at 3 and 21 days after cell transplantation. RESULTS AND CONCLUSION: (1) The levels of creatinine and urea nitrogen in the serum of rats at 1, 3, 14 and 21 days after cell transplantation were significantly higher in the model group than the normal control group (P < 0.05) and cell transplantation group (P < 0.05). (2) At 3 and 21 days after cell transplantation, the scores on the kidney injury and apoptotic rate of kidney cells were ranked as follows: model group> cell transplantation group> normal control group, and there were significant differences between groups (P < 0.05). (3) At 3 and 21 days after cell transplantation, the expressions of bax and Caspase-3 in the kidney tissue at mRNA and protein levels were significantly higher in the model group and cell transplantation than the normal control group (P < 0.01) as well as significantly higher in the cell transplantation group than the model group (P < 0.05). To conclude, adipose-derived stem cell transplantation has obvious repairing effect on acute kidney injury caused by crush injury, and its mechanism may be related to the involvement of adipose-derived stem cells in regulating the expression of bax and Caspase-3.
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Objective To investigate and analyze the candida infection situation at the intensive care unit (ICU) in Tianjin Fourth Central Hospital from 2008 to 2012.Methods Critically ill patients admitted in ICU Department in Tianjin Fourth Central Hospital from Jan.2008 to Dem.2012 were selected,and candida in all blood,sputum and other specimens of patients,were tested.Data on the following items as:hospital sections and distribution of candida infection on the places where the fungus was identified,distribution of different species of candida,antifungal drug resistance of candidacies commonly used in ICU department in the last five years etc.,were statistically analyzed.Results Among 4 529 cases of critically ill patients stayed in the hospital ICU Department between 2008 and 2012,76 cases of candida infection were identified,with the rate as 1.68％.In the past five years,candida in hospital ICU was mainly detected in sputum samples in 52 cases which accounted for 68.4％.Another 9 cases were detected in blood,accounted for 11.8％,8 cases were detected in urine,which accounted for 10.5％,36 cases (47.4％) of candida infection detected at the hospital ICU department in the last 5 years with major species as Candida albicans infection,followed by Candida glabrata,Candida tropicalis,Candida parapsilosis and Portugal Candida.The highest rate of resistance was to itraconazole,with a resistance rate of 19.7％,followed by voriconazole,with the rate as 15.8％.Conclusion In recent years,the number of patients infected with candida at the ICU department had increased annually with most cases as respiratory infections,which were caused by Candida albicans.The rate of resistance ofcandida to itraconazole was the highest,which called for special attention.