As the most common primary malignant bone tumor in children and adolescents, osteosarcoma has the characteristics of high malignancy, easy metastasis and poor prognosis. The recurrence, metastasis and multi-drug resistance of osteosarcoma are the main problems that limit the therapeutic effect and survival rate of osteosarcoma. Among them, lung metastasis is often the main target organ for distant metastasis of osteosarcoma. In recent years, people have paid attention to the signaling pathway of the occurrence and development of osteosarcoma and made in-depth studies on its mechanism. A variety of relevant signaling pathways have been constantly clarified. At present, there is still a lack of systematic and multi-directional exploration and summary on the signaling pathway related to the pulmonary metastasis of osteosarcoma. This paper explores the new direction of targeted therapy for osteosarcoma by elucidating the relationship between the signaling pathway associated with osteosarcoma and the pulmonary metastasis of osteosarcoma.
Objective To explore the protective effect of rapamycin on brain tissues injury in severe acute pancreatitis (SAP) and its possible mechanism in experimental rats. Methods Ninety SPF males SD rats were randomly divided into 3 groups by random envelope opening method: sham operation group (SO group), SAP group, and rapamycin group (RAPA group), then the rats of each group were divided into 24 h, 36 h, and 48 h 3 subgroups by random number table method. Rats in each group underwent laparotomy, the model was prepared by retrograde injection of solutions into biliopancreatic duct, rat of the SO group was injected with 0.9% normal saline (2 mL/kg), rats of the SAP group and the RAPA group were injected with 5% sodium taurocholate solution (2 mL/kg), but rat of the RAPA group was injected with rapamycin (1 mg/kg) at 30 min before narcosis. All survival rats in each subgroup were killed at 24 h, 36 h, and 48 h respectively, then the pancreas and brain tissues of rats were collected, pancreas and brain tissues were stained by hematoxylin-eosin staining, brain tissues were stained by Luxol fast blue additionally, pathological changes of brain tissues were scored under light microscope. The protective effect of rapamycin on brain tissues injury was determined by comparing the differences in the degree of brain tissues among 3 groups. The phosphorylated mammaliantarget of rapamycin (p-mTOR) and phosphorylated ribosomal 40S small subunitS6 protein kinase (p-S6K1) expression levels in brain tissues were detected by Western blot. In addition, the correlations between the expression levels of p-mTOR and p-S6K1 in brain tissues and the degree of brain tissues injury were analyzed to further explore the possible mechanism of rapamycin’s protective effect on brain tissues injury in SAP. Results① At the point of 24 h, 36 h, and 48 h, the order of the relative expression levels of p-mTOR and p-S6K1 in brain tissues of three groups were all as follows: the SO group < the RAPA group < the SAP group (P<0.05). ② At the point of 24 h, 36 h, and 48 h, the order of brain histological score in three groups were all as follows: the SO group < the RAPA group < the SAP group (P<0.05). ③ The relative expression levels of p-mTOR and p-S6K1 in brain tissues were positively correlated with pathological scores of brain tissues (r=0.99, P<0.01; r=0.97, P<0.01). ConclusionRapamycin plays a protective role in pancreatic brain tissues injure by down-regulating the expression levels of p-mTOR and p-S6K1 in mTOR signaling pathway.
After the articular cartilage injury, the metabolic level is increased during the progressive degeneration, the chondrocytes secrete a variety of inflammatory factors, and the original cell phenotype is gradually changed. For a long time, a large number of researchers have done a lot of researches to promote anabolism of chondrocytes and to maintain the stability of chondrocyte phenotype. There are many molecular signaling pathways involved in the process of promoting cartilage repair. This review focuses on the key signaling molecules in articular cartilage repair, such as transforming growth factor-beta and bone morphogenetic protein, and reveals their roles in the process of cartilage injury and repair, so that researchers in related fields can understand the molecular mechanism of cartilage injury and repair widely and deeply. Based on this, they may find promising targets and biological methods for the treatment of cartilage injury.
ObjectiveTo study the effect of Tangeretin on non-small cell lung cancer (NSCLC) and the tumor stemness, and to find the molecular mechanism of its effect. MethodsWe used cell counting and cell cloning experiments to study the effect of Tangeretin on the proliferation of NSCLC cells in vitro. The effect of Tangeretin on the invasion of NSCLC cells was detected by transwell assay. We detected the effect of Tangeretin on the proliferation of NSCLC cells in vivo by nude mouse tumor-bearing experiment. The effect of Tangeretin on tumor stemness of NSCLC cells was detected by self-renew assay, and CD133 and Nanog protein expressions. The expressions of PI3K/AKT/mTOR signaling pathway-related proteins were detected by Western blotting (WB). ResultsTangeretin had a good inhibitory effect on the proliferation of NSCLC cells in vivo and in vitro. Cell counting experiment, clonal formation experiment and nude mouse tumor-bearing experiment showed that Tangeretin could inhibit the proliferation activity, clonal formation ability, and tumor size of NSCLC cells in vivo. Self-renew experiments showed that Tangeretin could inhibit the self-renew ability of NSCLC cells. WB experiments showed that Tangeretin inhibited the expressions of tumor stemness markers CD133 and Nanog in NSCLC cells. Tangeretin could inhibit the activation of PI3K/AKT/mTOR signaling pathway-related proteins in NSCLC cells, and the activation of PI3K/AKT/mTOR signaling pathway could partially remit the inhibitory effect of Tangeretin on tumor stemness of NSCLC cells. ConclusionTangeretin can inhibit the tumor stemness of NSCLC cells, which may be related to the regulation of PI3K/AKT/mTOR signaling pathway.
ObjectiveTo understand the molecular mechanisms and targeted therapy research progress of gastric cancer associated with the RTK/RAS signaling pathway, in order to provide reference for treatment of gastric cancer. MethodThe related literatures about the molecular mechanism and targeted therapy of RTK/RAS signaling pathway related gastric cancer at home and abroad in recent years were reviewed. ResultsTargeted therapy had been widely applied in the treatment of gastric cancer associated with the RTK/RAS signaling pathway, showing good efficacy and significantly prolonging patients’ survival time, further deepening the understanding of the molecular mechanisms of gastric cancer. Targeted therapies for gastric cancer associated with the RTK/RAS signaling pathway focused on human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptor, fibroblast growth factor receptor 2, cellular-mesenchymalepithelial transition factor and Kirsten ratsarcoma viral oncogene homolog associated targets. Currently, there were many drugs targeting HER-2 target, while research on other targets mostly remains in the clinical trial stage, and showing promising prospects. ConclusionTargeted therapy can benefit most patients with gastric cancer, but the drug resistance and multi-drug combination therapy are still difficult problems that we need to overcome in the future.
Objective To explore the effect of natural hirudin on proliferation of human microvascular endothelial cells (HMVECs) and its preliminary mechanism of promoting angiogenesis. Methods Three-dimensional culture models of HMVECs were established in vitro and observed by inverted phase contrast microscopy after 24 hours of culturing. Then, the three-dimensional culture models of HMVECs were treated with different concentrations (1, 4, and 7 ATU/mL) of the natural hirudin, respectively, and Dulbecco’s modified Eagle’s medium containing 10% fetal bovine serum as control. The cell proliferations of 4 groups were detected by cell counting kit 8 (CCK-8) method at 24, 48, and 72 hours; the angiogenesis of 4 groups were observed by tube formation assay at 24 hours; the expressions of vascular endothelial growth factor (VEGF) and Notch1 of HMVECs in 4 groups were observed by immunofluorescence staining at 24 hours. Results The observation of cells in three-dimensional culture models showed that HMVECs attached to Matrigel well, and the cells formed tube structure completely after 24 hours. The results of CCK-8 test showed that the absorbance (A) value of 1 and 4 ATU/mL groups were higher than that of control group at each time point (P<0.05), andA value of 4 ATU/mL group was the highest. The A value of 7 ATU/mL group was significantly lower than those of 1 and 4 ATU/mL groups and control group (P<0.05). The tube formation assay showed that the tube structure was more in 1 and 4 ATU/mL groups than in 7 ATU/mL group and control group, and in 4 ATU/mL group than in 1 ATU/mL group, showing significant differences (P<0.05). There was no significant difference between 7 ATU/mL group and control group (P>0.05). The results of immunofluorescence staining showed that compared with control group, the Notch1 expression was higher in 1 and 4 ATU/mL groups and lower in 7 ATU/mL group; and there was significant difference between 4 and 7 ATU/mL groups and control group (P<0.05). The VEGF expression was higher in 1, 4, and 7 ATU/mL groups than in control group, in 4 ATU/mL group than in 1 and 7 ATU/mL groups, showing significant differences (P<0.05). Conclusion Natural hirudin can promote angiogenesis at low and medium concentrations, but suppress angiogenesis at high concentrations. Its mechanism may be related to the VEGF-Notch signal pathway.
Rheumatoid arthritis (RA) is a chronic autoimmune disease remarkably characterized by synovitis of joints, whose pathogenesis is complicated and not yet fully elucidated. A variety of cells, cytokines and intercellular signaling pathways are involved in the occurrence and development of RA. The mitogen activation protein kinase (MAPK) signaling pathway is closely related to the pathogenesis of RA, and plays an important role in the formation of pannus, synovitis, and bone destruction. This paper reviews the research progress of MAPK signaling pathway in RA from the aspects of the interaction of MAPK signaling pathway with a variety of key cells and cytokines in the pathogenesis of RA, in order to provide a direction and theoretical basis for anti-RA drug therapy research.
Objective To investigate the structure characteristics， functions， and research progress of Notch signaling pathway in digestive tumors. Methods The related literatures about the molecular genetic mechanism of Notch signaling pathway were reviewed. Results The Notch signaling pathway plays an important role not only in normal cells’ growth， differentiation， proliferation， and apoptosis but also in a variety of tumors’ occurrence and development. Conclusion The reasonable regulation to Notch signaling pathway may open up new ways to the treatment of the tumor.
Objective To investigate the role of mitochondrial autophagy mediated by PINK1 (homologous phosphatase tensin induced kinase 1) /Parkin (Parkinson’s protein) signaling pathway in severe pneumonia of rats. Methods Twenty rats were randomly divided into control group and model group (severe pneumonia model), with 10 rats in each group, to explore the effects of severe pneumonia on lung function and pathology in rats. Then, 30 rats were randomly divided into control group, model group and mdivi-1 (mitochondrial autophagy inhibitor) group, with 10 rats in each group, to further explore the effects of severe pneumonia on mitochondrial autophagy indicators of rats. ResultsCompared with the control group, the resting ventilation volume [(3.44±0.22) vs. (1.58±0.18) mL/min] and airway resistance ratio (77.48±3.84 vs. 47.76±5.54) in the model group were decreased (P<0.05). In the model group, the lung tissue was injured and a large number of inflammatory cells were infiltrated. The protein and mRNA expression levels of Parkin, PINK1 and microtubule-associated protein1 light chain 3 in lung tissues of model group were increased (P<0.05). Compared with model group, the ratio of resting ventilator-to-airway resistance in mdivi-1 group increased (P<0.05). The injury and inflammatory infiltration of lung tissue were improved in mdivi-1 group. The expression levels of Parkin, PINK1 and microtubule-associated protein1 light chain 3 protein and mRNA in lung tissues of mdivi-1 group were decreased (P<0.05). Conclusion Mdivi-1 can improve the abnormal lung function structure in rats with severe pneumonia, and the mechanism may be related to mitochondrial autophagy mediated by PINK1/Parkin signaling pathway.
Objective To study the effect of signal-selective parathyroid hormone (PTH) analogue peptide on Wnt signal ing factors in osteoblasts isolated from neonatal mouse, and provide theoretical basis for the mechanism of PTH’s function in bone metabolism. Methods Osteoblasts were isolated from calvaria of 2-3-day-old C57BL neonatal mouse and identified by alkal ine phosphatase (ALP) staining, and Alizarin red staining. The cells at passage 1 were divided into 4 groups: control group, PTH (1-34) group, G1R19 (1-34) group, and G1R19 (1-28) group. Then the medium was changed to α-MEM supplemented with 1%FBS. After 12 hours, trifluoroacetic acid or three peptides [(10 nmol/L PTH (1-34), 10 nmol/L G1R19 (1-34), and 100 nmol/L G1R19 (1-28)] were added into the culture medium. After 4 hours, the cells were washed gently ithcold PBS 3 times before total RNA was isolated. The expressions of Wnt related genes were measured by quantitative eal-time PCR. Results Most of the cells were polygonal and triangular; the cells were positive for ALP staining with blue cytoplasm at 14 days and the Al izarin red staining showed the formation of red mineral ized nodules in the special mineral ization induction medium at 28 days. The expressions of osteocalcin mRNA and Wnt5b mRNA in PTH (1-34) group, G1R19 (1-34) group, and G1R19 (1-28) group were significantly higher than those in control group (P lt; 0.05); the expression of Wnt2 mRNA was significantly lower than that in control group (P lt; 0.05); the expression of β-catenin mRNA in PTH (1-34) group was significantly higher than that in control group (P lt; 0.05); the expression of Wnt7b mRNA in PTH (1-34) group and G1R19 (1- 34) group was higher than that in control group, and the G1R19 (1-34) group was higher than PTH (1-34) group and G1R19 (1-28) group (P lt; 0.05). Conclusion In the Wnt-related factors, PTH (1-34) and G1R19 (1-34) affect mainly canonical Wnt signal factors, but the G1R19 (1-28) chiefly acts on non-canonical Wnt signal factors.