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Objective: To elucidate the anti-inflammatory mechanism of Reduning Injection (RDN) by analyzing the potential biomarkers and metabolic pathways of the carrageenan-induced inflammatory model from the overall metabolic level. Methods: Rat inflammatory model was established by carrageenan. UPLC-Q-TOF/MS was used to detect and analyze changes of endogenous metabolites in the serum and urine of carrageenan-induced inflammatory rats. Combined with multivariate analysis and databases analysis, inflammatory-related potential biomarkers were screened and identified to analyze possible metabolic pathways. The reliability and biological significance of these biomarkers was verified by metabolic network analysis and correlation analysis with pharmacodynamic indicators. Results: A total of 16 potential biomarkers were screened and identified by multivariate analysis and metabolite databases, among which 13 species could be adjusted by RDN. The metabolism pathway analysis revealed that histidine metabolism, sphingolipid metabolism, and tyrosine metabolism were greatly disturbed. Their biomarkers involved urocanic acid, sphingosine, and norepinephrine, all of which showed a callback trend after RDN treatment. The three biomarkers had a certain correlation with some known inflammatory-related small molecules (histamine, arachidonic acid, Leukotriene B4, and PGE
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Objective To compare the efficacy and safety of icotinib therapy alone versus icotinib combined with thoracic radiotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) patients with an activating epidermal growth factor receptor (EGFR) gene mutation.Methods A total of 83 patients with advanced NSCLC harboring an activating EGFR gene mutation was enrolled in this study.All the patients were randomly divided into 2 groups.Patients in group A (n =41) received thoracic radiotherapy (prescribed at 60-66 Gy) combined with icotinib (three times per day,125 mg once).Patients in group B (n =42) were given icotinib therapy alone (three times per day,125 mg once).Treatment was continued until disease progression or unacceptable toxicity or death.The primary end points were median progression-free survival (mPFS) and 12 month-PFS rate.The secondary end points included objective response rate (ORR),disease control rate (DCR) and adverse events.Results With a median follow-up of 18.2 months,mPFS was 15.2 months (95％ CI:12.2-17.4) in group A and 13.2 months (95％ CI:10.8-14.9) in group B (x2 =4.29,P=0.036).PFS rates of 12 months for group A and group B were 70.3％ and 61.2％,respectively.The ORR were 78.0％ vs.57.1％ (x2 =5.16,P =0.028),and the DCR were 95.1％ vs.92.9％ (P＞0.05) in groups A and group B,respectively.No grade 3-4 adverse events was observed in both groups except the rashes (4 cases in each group).Besides,10 patients had grade 1-2 radiation-related pneumonitis and 15 patients suffered grade 1-2 radiation-related oesophagitis in group A.Conclusions In advanced NSCLC patients with an activating EGFR gene mutation,the combination of thoracic radiotherapy and icotinib had achieved an improvement on ORR and PFS with good tolerance.Clinical trial registration Chinese clinical trial registry,ChiCTRINR-16010262.
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To investigate the radiosensitizing effects of dihydroartemisinin [DHA] and its underlying mechanisms in cervical cancer cells. This experimental study was conducted between May 2009 and August 2012 in the School of Radiation Medicine and Protection, Soochow University, Suzhou, China. HeLa and Siha cells were assigned as the control group and DHA as treated group. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-2H-tetrazolium bromide [MTT] assay, clonogenic assay, cell cycle analysis, and apoptosis analysis were carried out in 2 cell lines of both groups. The inhibitory effect of DHA on the HeLa and Siha cell lines was dependent on both concentration and time. Dihydroartemisinin increased the radiosensitivity of HeLa cells, but not of Siha cells. Apoptosis and the gap2/mitosis [G2/M] phase transition induced by x-irradiation was enhanced by DHA treatment in HeLa cells. Irradiation, combined with DHA, decreased Wee1 expression while increasing Cyclin B1 expression in HeLa cells. Dihydroartemisinin potently abrogates G2 checkpoint control in HeLa cells. It can relieve the G2/M arrest induced by irradiation; thus, it can be used as an effective radiosensitizer, which will probably promote the entry of more irradiation-damaged cells into mitosis
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Uterine Cervical Neoplasms , Cell Cycle , HeLa Cells , Radiation-Sensitizing AgentsABSTRACT
Objective To investigate the radiosensitizing effects of artemisinin on CNE human nasopharyngeal carcinoma cells in vitro.Methods CNE human nasopharyngeal carcinoma cell line was used in this study.Cell growth kinetics was determined by MTT assay.Effect of the drug on radiosensitivity of CNE cells was analyzed by clonogenic assay.The change of cell cycle was measured by flow cytometry.Results The inhibition of CNE cells growth by artemisinin was increased with concentrations.Artemisinin (1 μmol/L)could enhance the radiosensitizing effects on CNE cell line,and the sensitizing enhancement ratio(SER)was 1.26.Artemisinin abrogated radiation-induced G2/M arrest of the tested CNE cells.Compared with the radiation alone group,the proportion of G2/M phase cells increased in radiation combined with drug group.Conclusions Artemisinin could reduce radiation-induced G2/M arrest and enhance the cytotoxicity of γ-irradiation on the CNE ceils.
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Objective To evaluate the effect of artemether on the cell cycle and the radiosensitivity in human nasopharyngeal carcinoma cell line CNE-1.Methods Cell growth inhibition was assessed with MTT.The method of colony-forming was used to detect the radiation sensitivity.Cell cycle distribution was analyzed by using flow cytometry.The protein expressions of clyclin B1 and Weei were detected by using Western blot.Results The growth of CNE-1 cells was inhibited in a dose-dependent manner.The concentration of 20 μmol/L artemether had radiosensitive effect on CNE-1 cells at 24 h after administration,and SER was 1.481.When CNE-1 cell was irradiated,the G2/M cells increased (t =4.59,P ＜ 0.05).After exposure to combination of artemether and irradiation,the G2/M cells were decreased (t= 10.60,P ＜ 0.05).Western blot showed that artemether increased the level of cyclin B1 expression and inhibited the level of Weel expression.Conclusions The noncytotoxic concentration of artemether could enhance radiosensitization of CNE-1 cells.The radiosensitivity enhancement of artemether might depend on the exposure time.The effect is most obvious when radiation is delivered 24 h after expose to artemetherr.The radiosensitizing effect could be related to apoptosis.
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Objective To investigate the radiosensitizing effects of artesunate on human HeLa cells of cervical cancer in vitro.Methods Hela cells were irradiated with 60Co γ-rays.The dose rate was 0.635 Gy/min and the radiation dose was 0,1,2,4,6 Gy,respectively.The anti-proliferation activities of artesunate on HeLa cells were evaluated with MTT assay,to determine the most appropriate drug concentration.The effect of radiosensitivity was observed by using clonogenic assay.The single-hit multitarget model was used to plot the HeLa cell's dose-survival curve,to calculate mean lethal dose,quasithreshold dose and sensitization enhancement rate,and to evaluate its radiosensitization effect.The apoptosis was analyzed with flow cytometry (FCM) to further test the radiation senseitization of artesunate on HeLa cells.Results The inhibition of artesunate on HeLa cells increased with concentration.In radiation group,the cell cloning efficiency were 91.67% ,82.02% ,58.60% ,25.01%,respectively,and in artesunate (2.0 μ mol/L) + radiation group,the cell cloning efficiency were 74.93% ,60.53% ,22.38% ,5.05%.In radiation group and artesunate (2.0 μmol/L) + radiation group,the mean lethal dose(D0) was 2.95 and 2.07 Gy,respectively,while the qusai-threshold dose (Dq) were 2.01 and 1.24 Gy,respectively,and SER was 1.43.Compared with 2 and 6 Gy radiation group,the apoptosis rate of drug + radiation group increased from 12.26% ,40.08% to 22.71% ,59.92%.Conclusions The inhibiting effect of artesunate on HeLa cells is concentration-dependent.Artesunate has radiosensitizing effect on HeLa cells in vitro.
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Objective To observe the changes of cell cycle on cancer cells after dihydroartemisinin and X-ray irradiation. Methods Human HeLa cells of cervical cancer with p53 mutation was used and human SiHa cells of cervical cancer with wild p53 was used as control. Flow cytometry was used to detect the effect of dihydroartemisinin (20 and 100 μmol/L) and irradiation (6 Gy)on cell cycle. Western blot was used to measure the levels of cell cycle protein. Results G2 arrest was observed in irradiated HeLa cells, which the proportion of cells in G2 phase was increased from 14.45% to 73. 58% after 6 Gy X-ray irradiation, but it was abrogated by dihydroartemisinin from 73. 58% to 48.31%in HeLa cells, and it had no change on the SiHa cells. The elevated Weel protein and the lowered Cyclin B1 protein were observed with the G2 arrest severity. The expression of radiation-induced Weel protein was suppressed and the Cyclin B1 protein was increased after dihydroartemisinin treatment, which was in accordance with the abrogation of radiation-induced G2 delay. Conclusions The main effect of irradiation on cell cycle of p53 mutated HeLa cells is G2 arrest. Dihydroartemisinin could abrogate it, which is associated with the changes of Weel protein and Cyclin B1 protein. In Siha cells, the main effect of irradiation on cell cycle is G1 arrest, and dihydroartemisinin has no effect on it.
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Objective To study the radiosensitizing effect of caffic acid phenethyl ester(CAPE)on human cervical cancer HeLa cells.Methods MTT assay was used to measure the relation between the inhibition effect and CAPE concentrations by CAPE with different concentrations on HeLa cells for 24 hours.HeLa cells were divided into the control and experimental groups,both of which were given 0,2,4,6 and 8 Gy of 60Co γ-irradiation,respectively.The cell clones were counted.Meanwhile HeLa cells were divided into the control,CAPE,irradiation and combination groups.Flow cytometric analysis was adopted to detect the changes of cell cycle distribution induced by CAPE.Results The inhibition rate of CAPE acting on Hela cells increased with concentrations(F=126.49～3654.88,P＜0.01).HeLa cells cloning survival decreased with the increase of radiation dose(F=174.42～9422.81,P＜0.01).At the game radiation dose,HeLa cells cloning survival was less in experimental group than conlrol group(F=120.14～251.91,P＜0.01).The mean lethal dose(D0)(1.45 and 1.82 Gy)and the quasi-threshold dose(Dq)(1.89 and 3.21 Gy)of HeLa cells in experimental group decreased comparing with control group,SER was 1.26.Compared with the sole irradiation group,cells in G2/M phase of the CAPE group and the sole irradiation group increased(P＜0.01)while the combination group decreased(P＜0.01).Conclusions CAPE could increase the radiation sensitivity of HeLa cells by G2/M arrest and may be related to the inhibition of the sub-lethal damage repair.
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Objective To investigate the radiosensitizing effects of dihydroartemisinin(DHA)on human HeLa cells of cervical cancer irradiated by X rays.Methods Cell growth kinetics was determined using MTF assay.Cell survival was analyzed by elonogenic assay.The change of cell cycle and apeptosis was measured by flow cytometry.Results Dihydroartemisinin inhibited the growth of HeLa cells of human cervical cancer and showed a dose-dependent and time-dependent manner.Dihydroartemisinin(20 μmol/L)showed the radiosensitizing effects on HeLa cells,and the sensitizing enhancement ratio(SER)was 1.47.Dihydroartemisinin abrogated radiation-induced G2 arrest of the tested HeLa cells,the G2 ratio of medicine + radiation group dechned from 73.58% to 48.31%.Dihydroartemisinin enhanced the apoptosis of HeLa cells by X-irradiation,the apoptosis rates of medicine + radiation group significantly increased from 29.46%,48.04%,70.21% to 45.79%,66.36% and 79.58%,respectively for 2,4 and 6 Gy.Conclusions Dihydroartemisinin could increase the radiesensitivity of HeLa cells of human cervical cancer.Abrogation of radiation-induced C2 arrest could be part of the mechanism.