ABSTRACT
Objective:To evaluate the role of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway in 17β estradiol-induced reduction of long-term cognitive impairment induced by multiple propofol anesthesia in developing rats.Methods:Eighty 7-day-old clean-grade healthy newborn Sprague-Dawley rats of both sexes, weighing 11-17 g, were divided into 4 groups ( n=20 each) using a random number table method: control group (group C), propofol group (group P), 17β estradiol plus propofol group (EP group) and 17β estradiol plus propofol plus BDNF/TrkB signaling pathway blocker K252a group (K group). Propofol 80 mg/kg was intraperitoneally injected every day for 5 days in P, EP and K groups.The equal volume of fat emulsion was given instead in group C. In EP and K groups, 17β estradiol 600 μg/kg was subcutaneously injected at 30 min before propofol injection.BDNF/TrkB signaling pathway blocker K252a 100 μg/kg was intraperitoneally injected in group K. Morris water maze test was performed on days 30-34 after birth to assess the cognitive function.The rats were sacrificed after the end of Morris water maze test, and the hippocampal tissues were removed for determination of the apoptosis rate of hippocampal neurons (by flow cytometry), expression of BDNF, p-Trkb and cleaved caspase-3 (by Western blot and immunofluorescence), and expression of Bcl-2 and Bax mRNA (by real-time polymerase chain reaction) and for microscopic examination of the pathological changes in hippocampal CA1 region (with a light microscope). Bax mRNA/Bcl-2 mRNA ratio was calculated. Results:Compared with group C, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, the expression of BDNF and p-TrkB was down-regulated, the expression of cleaved caspase-3 was up-regulated, the apoptosis rate of hippocampal neurons and Bax mRNA/Bcl-2 mRNA ratio were increased ( P<0.05), and the pathological changes in hippocampal CA1 region were accentuated in group P. Compared with group P, the escape latency was significantly shortened, the number of crossing the original platform was increased, the expression of BDNF and p-TrkB was up-regulated, the expression of cleaved caspase-3 was down-regulated, the apoptosis rate of hippocampal neurons and Bax mRNA/Bcl-2 mRNA ratio were decreased( P<0.05), and the pathological changes in hippocampal CA1 region were attenuated in group EP.Compared with group EP, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, the expression of BDNF and p-TrkB was down-regulated, the expression of cleaved caspase-3 was up-regulated, the apoptosis rate of hippocampal neurons and Bax mRNA/Bcl-2 mRNA ratio were increased( P<0.05), and the pathological changes in hippocampal CA1 region were accentuated in group K. Conclusions:BDNF/TrkB signaling pathway is involved in 17β estradiol-induced reduction of long-term cognitive impairment induced by multiple propofol anesthesia in developing rats.
ABSTRACT
Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes, and it is the main cause of vision loss in diabetic patients. Angiopoietin (Ang), a superfamily of secreted proteins, is a vascular growth factor that regulates the stability of vascular environment, participates in angiogenesis and repair, and lipid metabolism. It plays an important role in the development of DR and has become a new target for the treatment of diabetic retinopathy. With the in-depth study of Ang and the research and development of various drugs for Ang, it is expected to bring new ideas and strategies for the treatment of DR in the future.
ABSTRACT
Objective:To evaluate the role of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling pathway in pre-injection of young rat plasma-induced reduction of sevoflurane-caused cognitive dysfunction in aged rats.Methods:Eighty SPF healthy male Sprague-Dawley rats, aged 18 months, weighing 550-650 g, were divided into 4 groups ( n=20 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S), young rat plasma group (group Y) and BDNF/TrkB signaling pathway inhibitor K252a group (group K). The plasma 100 μl obtained from 3-month-old young rats was injected via the tail vein in group Y and group K, while the equal volume of normal saline was given via the tail vein in group C and group S, twice a week, for 4 weeks.In S, Y and K groups, 3% sevoflurane was inhaled for 3 h starting from the end of treatment, and BDNF/TrkB signaling pathway inhibitor K252a was injected via the tail vein before anesthesia in group K. The open field test and Morris water maze test were performed at 3 days after anesthesia to assess the spontaneous motor ability and cognitive function.Then the rats were sacrificed, and the hippocampal tissues were isolated for determination of the expression of BDNF, phosphorylated TrkB (p-TrkB), postsynaptic dense protein-95 (PSD-95) and synaptic vesicle protein (SYN) (by Western blot), dendritic length and dendritic ridge density of neurons in hippocampal CA1 area (by Golgi staining), and the number of synapses and length of synaptic active area (with a transmission electron microscope). Results:Compared with group C, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, the expression of p-TrkB, BDNF, PSD-95 and SYN was down-regulated, and the dendritic length, dendritic ridge density, the number of synapses and length of synaptic active area were decreased in group S ( P<0.05). Compared with group S, the escape latency was significantly shortened, the number of crossing the original platform was increased, the expression of p-TrkB, BDNF, PSD-95 and SYN was up-regulated, and the dendritic length, dendritic ridge density, the number of synapses and length of synaptic active area were increased in group Y ( P<0.05). Compared with group Y, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, the expression of p-TrkB, BDNF, PSD-95 and SYN was down-regulated, and the dendritic length, dendritic ridge density, the number of synapses and length of synaptic active area were decreased in group K ( P<0.05). Conclusions:The mechanism by which pre-injection of young rat plasma reduces sevoflurane-induced cognitive dysfunction is related to activation of BDNF/TrkB signaling pathway and improvement in synaptic plasticity in the hippocampus of aged rats.
ABSTRACT
Objective To investigate the dynamic changes of soluble fms-like tyrosine kinase 1 (sFlt-1),Amylase (AMY) and high sensitvie C reactive protein (hs-CRP) in the early diagnosis of acute pancreatitis (AP) and its clinical significance.Methods 72 patients with AP were selected and divided into mild group (n =45) and severe group (n =27).Another 30 healthy subjects in the same period were selected as control group (n =30).Serum sFlt-1 levels were measured by enzyme-linked immunosorbent assay (ELISA) on the 1st,3rd and 7th day after admission.Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score was used to assess acute physiology and chronic health status,and AMY and hsCRP levels were measured.Results Serum levels of sFlt-1,AMY and hs-CRP in the severe group were significandy higher than those in the mild group on the 1 st,3rd and 7th day after admission (all P ＜ 0.01).The levels of sFlt-1,AMY and hs-CRP in the mild group were significantly higher than those in the control group (all P ＜ 0.01).The scores of APACHE Ⅱ in the severe group were significantly higher than those in the mild group on the 1st,3rd and 7th day after admission (all P ＜ 0.01).There was a positive correlation between serum sFlt-1 level and AMY,hs-CRP,APACHE Ⅱ scores on the first day of admission (respectively r =0.738,P =0.00;r =0.563,P =0.000;r =0.233,P =0.028),on the third day of admission (respectively r =0.622,P =0.000;r =0.584,P =0.000;r =0.218,P =0.032),on the seventh day of admission (respectively r =0.593,P =0.000;r =0.547,P =0.000;r =0.227,P =0.030).Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of serum sFlt-1,AMY and hs-CRP were 0.918 (95％ CI:0.865-0.971,P =0.000),0.948 (95％ CI:0.908-0.989,P=0.000) and 0.789 (95％ CI:0.696-0.882,P=0.000),respectively.Conclusions The level of sFlt-1 in peripheral blood is significantly increased in patients with AP,which is closely related to the severity of AP.Dynamic monitoring of serum sFlt-1,AMY and hs-CRP has important clinical value in the diagnosis,treatment,severity and prognosis of AP.
ABSTRACT
Objective To study the expression of BDNF and TrkB in hippocampal microglia cells of poststroke depression (PSD) rats.Methods Forty healthy adult SD rats were randomly divided into normal group,depression group,stroke group and PSD group (10 in each group).Expression of BDNF and TrkB in OX42-marked hippocampal microglia cells of PSD rats was detected with immunofluorescence staining on day 29 and 57 after a MCAO model rats was established and a chronic stress depression model of rats was established by chronic unpredictable mild stress (CUMS) combined with separate breeding.Results The absorbance value of BDNF and TrkB was 83.35t5.74 and 82.35±5.74 respectively in PSD group on day 29 after the CUMS of rats was established,which was significantly lower than other 3 groups (P＜0.05),and was significantly higher in depression group than in stroke group (141.23±9.16 vs 133.31±7.89;141.23± 8.07 vs 128.62±6.92,P＜0.05).The absorbance value of BDNF and TrkB was 81.63±7.19 and 74.43±7.42 respectively in PSD group on day 57 after the CUMS of rats was established,which was lower than in other 3 groups,and was significantly lower in stroke group than normal group and depression group (93.36±7.56 vs 124.11±11.39、116.65±10.55,87.14±6.56 vs 112.58± 10.99、108.05±10.57,P＜0.05).Conclusion Hippocampal microglia cells play an important role in the pathogenesis of PSD by down-regulating the expression of BDNF and TrkB in PSD rats.
ABSTRACT
Abstract: Gastrointestinal stromal tumor is rare digestive tract mesenchymal tumor, most often in the wall of the stomach. It is a benign neoplasm, but it can become malignant if not treated. We report a case of gastrointestinal stromal tumor that was discovered after abdominal ultrasonography during staging of a patient with primary cutaneous amelanotic melanoma. Mutation in the tyrosine kinase receptor could explain the development of two types of tumors in the same patient.
Subject(s)
Humans , Male , Middle Aged , Skin Neoplasms/diagnosis , Melanoma, Amelanotic/diagnosis , Gastrointestinal Stromal Tumors/diagnosis , Gastrointestinal Neoplasms/diagnosis , Neoplasms, Multiple Primary/diagnosis , Biopsy , Immunohistochemistry , Tomography, X-RayABSTRACT
Malignant transformation of ovarian endometriosis is known as endometriosis associated ovarian cancer (EAOC). However, the carcinogenic pathways by which EAOC develops remained poorly understood, and numerous studies found the risk factors of malignant transformation. Recent studies have provided evidence that estrogen receptor-β(ER-β) can influence the proliferation, motility and apoptosis of ovarian cancer cells. The signal pathway of tyrosine kinase receptor-B (TrkB)/brain-derived neurotrophic factor (BDNF) has a direct relation with the endometriosis, and its anti-anoikis plays a prerequisite role in proliferation of cancer. In the nervous system, estradiol and estrogen receptor can be combined through a variety of ways to promote BDNF/TrkB high expression and activity enhancement. Therefore,the relationship between high-risk factors of malignant transformation and ER-β expression and ER-β and TrkB/BDNF signal pathways need to be explored in EAOC.
ABSTRACT
Neuregulin-1 (NRG-1) can bind with its tyrosine kinase receptor via paracrine and autocrine, activate downstream pathways and perform a series of biological reactions, and reduce pressure load and improve heart function through inhibiting sympathetic nerve excitement.Recent study identified that NRG-1 can induce pluripotent stem cell differentiation;clinical trials proved that recombinant human NRG-1 can reduce level of N terminal pro brain natriuretic peptide, rehospitalization rate and onset times of heart failure.The present article made a review on research progress of NRG-1 in cardiovascular field.
ABSTRACT
Objective To screen 8 series of LY compounds, c-Met tyrosine kinase inhibitors, and evaluate their anti-tumor effects in vitro and in vivo. Methods Preliminary screening was carried out by detecting the c-Met kinase phosphor?ylation inhibition activity of the compounds. CCK-8 assay was adopted for secondary anti-tumor screen of the selected com?pounds using MKN-45, U87MG, Caki-1 and PC-3 cell lines in vitro. The transplanted tumor model of U87MG cells in nude mice was established to evaluate the antitumor activity in vivo. Results Four compounds (LY22, LY25, LY28 and LY32) with better activities were selected by HTRF method, in which LY28 had better inhibitory effect on c-Met than that of Crizo?tinib. The above active compounds showed different degrees of inhibition on the four kinds of target cells (MKN-45, U87MG, Caki-1 and PC-3) detected by CCK-8 method, and the inhibitory effect of LY28 showed the most obvious. Antitumor activi?ty in vivo showed that LY28 can significantly inhibited tumor growth in a dose-dependent manner. The tumor inhibitory rate in high-dose of LY28 was 78.13%. Conclusion The compound LY28 has good antitumor activity in vitro and in vivo, which will be a new tyrosine kinase inhibitor.
ABSTRACT
Discoidin domain receptor 1(DDR1)is a kind of receptor tyrosine kinases(RTKs),which is expressed abnormally in many tumors. It is involved in the development,invasion and metastasis process of tumors and may become a potential target of tumor therapy. This article reviewed the expression and significance of DDR1 in tumors of digestive system.
ABSTRACT
It is important to analyze the epidermal growth factor receptor ( EGFR) mutation before makingstrategyonnon-small cell lung cancer ( NSCLC) patients scheduled to EGFR tyrosine kinase inhibitor ( TKI) therapy .Digital PCR is a new generation of molecular diagnostic technique that provides ultra-highersensitive, specific and absolute nucleic acid quantification based on its unique principle.The application of digital PCR indetecting circulate tumor DNA can be the truly tumorliquid biopsy, helps to acquire the accurate EGFR mutation status from peripheral blood and screen out the most appropriate patients for TKI therapy.This breakthrough technology will also contribute to tumor surveillance and drug resistance monitoring.
ABSTRACT
Osteosarcoma and ewing sarcoma are the two most common types of primary malignant bone tumors. Receptor tyrosine kinases(RTKs),including varieties of cell growth factors and proto-oncogene pro-ducts,are the high-affinity cell surface receptors which play an important role in the normal physiological func-tion of cells. A large number of studies have demonstrated that the abnormal RTKs signaling pathways may pro-mote the tumorigenesis and development of osteosarcoma and ewing sarcoma by affecting tumor cell survival, proliferation,invasion and metastasis. Targeting treatment of RTKs is a promising therapeutic approach for osteosarcoma and ewing sarcoma.
ABSTRACT
Brain-derived neurotrophic factor (BDNF)is both a neurotrophic substance and a neurotransmitter.BDNF and its receptors are highly expressed in enteric nervous system,intestinal mucosal epithelium and intestinal muscularis, which play an important role in regulating intestinal sensitivity and motility.This article reviewed the expression and role of BDNF in intestinal tract.
ABSTRACT
The prognosis of patients with brain metastases from non-small cell lung cance (NSCLC) is dismal,and whole brain radiation therapy(WBRT) cannot simultaneously control the extracranial lesions.Study results of Tyrosine kinase inhibitor(TKI) for brain metastases in patients with lung cancer are encouraging,and treatment efficacy is related to EGFR mutation status.The sensitizing theoretical foundation exists in utilizing erlotinib combined with WBRT for the treatment in brain metastases patients with lung cancer.Currently,a small clinical trial data shows that erlotinib combined with WBRT has better efficacy compared to erlotinib alone,and the toxicity can be tolerated.
ABSTRACT
Objective To evaluate the effect of penehyclidine hydrochloride (PHC) on the level of angiopoietin-1 (Ang-1) and tyrosine kinase receptor-2 (Tie-2) during endotoxin-induced acute lung injury (ALI) in rats.Methods Forty adult male Sprague-Dawley rats,weighing 180-220 g,were randomly divided into 4 groups using a random number table (n =10 each):control group (group C),ALI group,low-dose PHC group (group L-PHC) and high-dose PHC group (group H-PHC).ALI was induced with iv injection of lipopolysaccharide 5.0 mg/kg via the tail vein.In L-PHC and H-PHC groups,PHC 0.6 and 2 mg/kg were injected,respectively,via the tail vein at 1 and 24 h after lipopolysaccharide injection.The rats were sacrificed at 48 h after the initial injection of PHC to measure the lung water content,protein concentration in bronchoalveolar lavage fluid (BALF),and the expression of Ang-1,Tie-2 and phosphorylated Tie-2 in lung tissues.The morphological changes of lung tissues were observed under light microscope and the ultrastructural changes of alveolar epithelial barrier under transmission electron microscope.Results Compared with group C,the lung water content and protein concentrations in BALF were significantly increased,and the expression of Ang-1 and phosphorylated Tie-2 was down-regulated in the other three groups (P ＜ 0.05).Compared with group ALI,the lung water content and protein concentrations in BALF were significantly decreased,and the expression of Ang-1 and phosphorylated Tie-2 was up-regulated in H-PHC group (P ＜ 0.05),and no significant changes were found in the parameters mentioned above in group L-PHC (P ＞0.05).The damage to lung tissues was significantly reduced in group H-PHC as compared with group ALI.Conclusion PHC can improve the permeability of pulmonary microvascular and reduce injury to alveolar epithelial barrier,thus ameliorating endotoxin-induced ALI in rats,and the effect is dose-related and up-regulation of Ang-1 expression and inhancement of Tie-2 activity are involved in the mechanism.
ABSTRACT
Regorafenib,an oral multi-kinase inhibitor,can inhabit a class of receptor tyrosine kinase,such as angiogenic,stromal,oncogenic and so on.Studies in vitro and clinical trials indicate that Regorafenib has significant antitumor activity.The results of clinical trials are encouraging for the treatment of Refractory solid tumors,especially for colorectal carcinoma.
ABSTRACT
Objective To investigate the effect of gefitinib on mucus hypersecretion by inhibiting epidermal growth factor receptor (EGFR) activity in chronic obstructive pulmonary disease (COPD).Methods Human airway epithelail cell lines 16HBE cells were exposed to cigarette smoke extraction (CSE) to establish the COPD model.EGFR activity was inhibited by tyrosine kinase inhibitor gefitinib.The mRNA expressions of EGFR and MUC5AC were detected by real-time PCR.EGFR,p-EGFR and MUC5AC protein levels were determined by Western blot and ELISA.Results EGFR mRNA level was increased by 12.7％ in CSE and 8.6％ in gefitinib group,but had no significant differences among CSE,gefitinib group and control group (all P＞ 0.05).MUC5AC mRNA levels were enhanced by 141.7％,26.4％ in CSE group and gefitinib group respectively,and there were significant differences among CSE,gefitinib group and control group (all P＜0.05).EGFR protein levels were (600.34±64.58) μg/mg,(632.58±72.94) μg/mg,(584.57±67.39) μg/mg,in control,CSE and gefitinib groups,respectively,and there were no significant differences between groups (all P＞0.05).p-EGFR protein levels were (338.62±45.28) μg/mg,(679.43±78.23) μg/mg,(292.74±59.17) μg/mg in control,CSE and gefitinib groups,respectively.MUC5AC protein levels were(72.80±6.25)μg/mg,(187.00±±10.26)μg/mg,(92.57±8.32)μg/mg in control,CSE and gefitinib groups respectively.Compared with control group,p-EGFR and MUC5AC protein levels were increased significantly in CSE group (both P＜0.05),and had no significant differences in p EGFR and MUC5AC protein levels between control group and gefitinib group.Conclusions CSE may lead to mucus hypersecretion through activating the EGFR-mediated signaling pathways.Gefitinib may inhibit mucus hypersecretion by inhibiting EGFR tyrosine kinanse activity.EGFR may serve as a potential target for COPD.
ABSTRACT
Over the past decade, several kinase inhibitors have been approved based on their clinical benefit in cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. To date, several major mechanisms of acquired resistance, such as secondary mutation of the epidermal growth factor receptor (EGFR) gene, amplification of the MET gene and overexpression of hepatocyte growth factor, have been reported. This review describes the recent findings on the mechanisms of primary and acquired resistance to EGFR tyrosine kinase inhibitors and acquired resistance to anaplastic lymphoma kinase inhibitors, primarily focusing on non-small cell lung carcinoma.
Subject(s)
Humans , Drug Resistance , Epidermal Growth Factor , Hepatocyte Growth Factor , Lung , Lymphoma , Phosphotransferases , Protein Kinase Inhibitors , Protein-Tyrosine Kinases , Receptor Protein-Tyrosine Kinases , ErbB ReceptorsABSTRACT
Phosphatidylinositol 3-kinase (PI3K) is essential for both G protein-coupled receptor (GPCR)- and receptor tyrosine kinase (RTK)-mediated cancer cell migration. Here, we have shown that maximum migration is achieved by full activation of phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) in the presence of Gbetagamma and PI3K signaling pathways. Lysophosphatidic acid (LPA)-induced migration was higher than that of epidermal growth factor (EGF)-induced migration; however, LPA-induced activation of Akt was lower than that stimulated by EGF. LPA-induced migration was partially blocked by either Gbetagamma or RTK inhibitor and completely blocked by both inhibitors. LPA-induced migration was synergistically increased in the presence of EGF and vice versa. In correlation with these results, sphingosine-1-phosphate (S1P)-induced migration was also synergistically induced in the presence of insulin-like growth factor-1 (IGF-1). Finally, silencing of P-Rex1 abolished the synergism in migration as well as in Rac activation. Moreover, synergistic activation of MMP-2 and cancer cell invasion was attenuated by silencing of P-Rex1. Given these results, we suggest that P-Rex1 requires both Gbetagamma and PI3K signaling pathways for synergistic activation of Rac, thereby inducing maximum cancer cell migration and invasion.
Subject(s)
Humans , Cell Line, Tumor , Cell Movement/drug effects , Enzyme Activation/drug effects , GTP-Binding Protein beta Subunits/metabolism , GTP-Binding Protein gamma Subunits/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Lysophospholipids/pharmacology , Neoplasms/enzymology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal TransductionABSTRACT
Imatinib mesylate was the first BCR-ABL-target agent approved for the treatment of chronic myeloid leukemia. Although most patients respond well to imatinib therapy, the literature shows that one third develops resistance or intolerance. The timing of second-line treatment after failure of initial treatment may have a significant impact on long-term outcome. Thus, appropriate monitoring to identify resistance and/or intolerance is crucial to early intervention with second generation tyrosine kinase inhibitors and attainment of better results.