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1.
Article in Chinese | WPRIM | ID: wpr-1021747

ABSTRACT

BACKGROUND:Icariin,with antiinflammatory,antioxygenatory and immunoregulatory effects,can be a potential drug for preventing and treating acute liver injury. OBJECTIVE:To investigate the protective effect and possible mechanism of icariin in mice with acute liver injury induced by carbon tetrachloride. METHODS:Thirty-two Kunming mice were equally and randomly divided into the following groups:normal,model,low-dose icariin and high-dose icariin groups.The low-and high-dose icariin groups were continuously gavaged with icariin(100 and 200 mg/kg,respectively)once a day for 7 continuous days.The normal group and model group were injected with physiological saline(10 mL/kg)at the same time point.After the last administration,all the groups except for the normal group were injected with carbon tetrachloride to induce acute liver injury.The mice were killed 24 hours later,and the liver index was detected.Serum levels of alanine aminotransferase and aspartate aminotransferase were detected by automated biochemical analysis.Tumor necrosis factor α and interleukin 6 levels in serum were detected using ELISA.The levels of superoxide dismutase,glutathione peroxidase and malondialdehyde in liver tissue were detected through a reagent kit.The histopathology changes of the liver were observed by hematoxylin-eosin staining.TUNEL method was used to detect the apoptosis in hepatocytes.Western blot was performed to detect the expression levels of glucose-regulated protein 78 kDa,endoplasmic reticulum stress-related protein(C/-EBP homologous protein),mixed lineage kinase domain-like protein and Caspase-3 in liver tissue. RESULTS AND CONCLUSION:Compared with the normal group,the liver index and serum levels of alanine aminotransferase,aspartate aminotransferase,tumor necrosis factor α and interleukin 6 were increased in the model group(P<0.05).Compared with the model group,the above indexes were decreased in the low-dose and high-dose icariin groups(P<0.05).Compared with the normal group,the activities of superoxide dismutase and glutathione peroxidase in the liver tissue of mice were decreased in the model group(P<0.05)and the level of malondialdehyde was increased(P<0.05).Compared with the model group,the activities of superoxide dismutase and glutathione peroxidase were increased in the low-and high-dose icariin groups(P<0.05)and the level of malondialdehyde was decreased(P<0.05).Hematoxylin-eosin and TUNEL staining showed that mice in the model group had severe structural destruction of liver tissue,extensive necrosis of hepatocytes and high apoptotic rate of hepatocytes,while the structural destruction of liver tissue and the area of necrosis of hepatocytes in the low-and high-dose icariin groups were significantly milder than those in the model group,and the apoptotic rate of hepatocytes was lower than that in the model group(P<0.05).Western blot assay showed that the protein expression of glucose-regulated protein 78 kDa,C/-EBP homologous protein,mixed lineage kinase domain-like protein and Caspase-3 in liver tissue of mice in the model group was increased compared with that in the normal group(P<0.05),while the expression levels of these proteins in liver tissue of mice were significantly reduced after low-and high-dose icariin intervention(P<0.05).To conclude,icariin can produce a protective effect against carbon tetrachloride-induced acute liver injury,and its mechanism may be related to the regulation of endoplasmic reticulum stress and reduction of programmed necrosis.

2.
Article in Chinese | WPRIM | ID: wpr-927885

ABSTRACT

Programmed necrosis,a mode of cell death independent of Caspase,is mainly mediated by receptor-interacting protein kinase-1 (RIPK1),receptor-interacting protein kinase-3 (RIPK3),and mixed lineage kinase domain-like protein (MLKL).Studies have demonstrated that programmed necrosis has the dual role of promoting and inhibiting tumor growth and thus we can control the development of tumor by regulating programmed necrosis.The drugs capable of inducing programmed necrosis show potential anti-tumor activity.In addition,inducing programmed necrosis is an effective way to overcome tumor resistance to apoptosis.This paper summarized the mechanisms of programmed necrosis and its relationship with tumors.We focused on the antitumor activity of programmed necrosis inducers including natural products,chemotherapeutic drugs,death receptor ligands,kinase inhibitors,inorganic salts,metal complexes,and metal nanoparticles.These agents will provide new therapeutic candidates for the treatment of tumors,especially the tumors acquiring resistance to apoptosis.


Subject(s)
Humans , Apoptosis , Cell Death , Necrosis/pathology , Neoplasms/drug therapy , Protein Kinases/pharmacology
3.
China Pharmacy ; (12): 2342-2346, 2021.
Article in Chinese | WPRIM | ID: wpr-886914

ABSTRACT

OBJECTIVE:To explore the therap eutic effects and its mech anism of Jianpi yiqi decoction on diethylnitrosamine (DEN)induced liver cancer model rats. METHODS :Totally 80 male SD rats were divided into normal group ,model group , Nod-like receptor family 3(NLRP3)inhibition group (MCC950,4.5 mg/kg),caspase-1 inhibitory group (VX-765,4.5 mg/kg), Jianpi yiqi decoction low-dose ,medium-dose and high-dose groups (5.25,10.5,21 g/kg),with 10 rats in each group except for 20 rats in model group (10 of them were only used to judge whether modeling was successful ). Rats in each group were intraperitoneally injected with DEN (70 mg/kg)to induce liver cancer model ,except for the rats in normal group which were replaced by normal saline. After modeling ,normal group and model group were given normal saline intragastrically ;inhibitor groups were given relevant medicine intraperitoneally ;Jianpi yiqi decoction groups were given relevant medicine intragastrically , once a day ,for consecutive 4 weeks. After last administration ,histopathological morphology of liver tissue was observed. The contents of serum inflammatory factors TNF-α and IL-1β were detected. The expression of NLRP3 and programmed cell necrosis associated protein (ASC,pro-caspase-1,RIP1,RIP3 and MLKL )in liver tissue were detected. RESULTS :Compared with the normal group ,the hepatocytes of model group showed varying, degrees of steatosis ,enlarged nuclei ,lumpy,bleeding and necrosis,accompanied by proliferative foci and nodules. Liver 198086, tissue injury index ,serum content of TNF-α and IL-1β as well as the protein expression of NLRP 3,ASC,pro-caspase-1,RIP1,RIP3 and MLKL in liver tissue were significantly increased (P<0.05 or P<0.01). Compared with model 防治。E-mail:sherwin_zhuo@126.com group,there were still a large number of inflammatory cell infiltration in the liver tissue of rats in Jianpi yiqi decoction low-dose and medium dose groups ,while the inflammatory cell infiltration of rats in high-dose group and inhibitor groups decreased significantly ;the liver tissue injury index and above indexes levels in serum and liver tissue were decreased significantly (P<0.05 or P<0.01). CONCLUSIONS :Jianpi yiqi decoction shows therapeutic effect on liver cancer model rats ,the mechanism of which may be associated with down-regulating the expression of NLRP3 inflammasome and inhibiting programmed cell necrosis.

4.
Acta Anatomica Sinica ; (6): 67-72, 2021.
Article in Chinese | WPRIM | ID: wpr-1015500

ABSTRACT

Objective To investigate the lethal effect of melittin on human hepatocellular carcinoma cell line SMMC-7721 and its possible mechanism. Methods MTT assay was used to investigate the killing effect of different concentrations melittin on human hepatocellular carcinoma cells SMMC-7721. Meanwhile, the inhibitory effect of specific programmed necrosis inhibitors necrostain-1(Nec-1) on melittin killing SMMC-7721 cells was detected. Programmed cell necrosis observed by Hoechst 33342 and PI double staining. The necrotosis rate was detected by flow cytometry. Ultrastructural changes of cell was detected by transmission electron microscopy. The expression of receptor interacting protein 1(RIP1) was detected by Western blotting. Results Compared with the control group, the proliferation activity of SMMC-7721 cells was significantly decreased after treatment with different concentrations of melittin for 24 hours (P < 0. 05) . Cells stained in dark blue and red. Cell membrane integrity was destroyed, organelle swelling, organelle membrane was destroy, that demonstrates cell was necrosis. Westen blotting result showed an increased proportion of RIP1 expression in SMMC-7721 cells. Compared with the melittin group, cell proliferation activity was significantly increased, cell necrotosis rate was decreased, and intracellular RIP1 expression was down-regulated in the Nec-1 pretreatment group. Conclusion Melittin induces cell death in SMMC-7721 cells through the RIP1-mediated programmed necrosis pathway.

5.
Article in Chinese | WPRIM | ID: wpr-960746

ABSTRACT

Background Programmed necrosis is closely related to the occurrence and development of neurodegenerative diseases, but whether lead causes programmed cell necrosis has not been reported. Objective This experiment is designed to probe into the function of programmed necrosis and the effect of its inhibitor on lead-induced microglia (BV2 cell) injury. Methods The BV2 cells at logarithmic growth phase were treated with 0, 1, 5, 10, 25, 50, 100, and 200 μmol·L−1 lead acetate for 12, 24, 36, and 48 h, respectively, and methylthiazolyldiphenyl-tetrazolium bromide (MTT) was used to determine cell viability. After treatment with 0, 25, 50, and 100 μmol·L−1 lead acetate for 24 h, enzyme-linked immunosorbent assay, Western blotting, and flow cytometry were used to determine the expressions of tumor necrosis factor-α (TNF-α), receptor-interacting protein kinase 3 (RIPK3), receptor-interacting protein kinase 1 (RIPK1), and mixed lineage kinase domain-like protein (MLKL) in the cells, and the effect of RIPK1 inhibitor Nec-1 pretreatment on lead-induced BV2 cell injury . Results The BV2 cell viability decreased with higher lead concentration (r12 h=−0.995, r24 h=−0.984, r36 h=−0.983, r48 h=−0.981, all P<0.01) and time extension (only for 5 μmol·L−1 lead acetate, r=−0.994, P<0.01). Compared with the control group, the BV2 cell viability decreased at the same exposure time when the concentration of lead was above 10 μmol·L−1 (P<0.01). Compared with the control group, the expressions of RIPK1 and MLKL were increased in the 25, 50, and 100 μmol·L−1 lead groups (P<0.05 or 0.01), accompanied by an increase in the contents of inflammatory cytokine TNF-α, especially in the 100 μmol·L−1 lead group, the increment was the highest (P<0.01). The expression levels of p-RIPK1 and p-MLKL in BV2 cells were both increased when the concentration of lead acetate was above 50 μmol·L−1 (P<0.01). In addition, pretreatment with Nec-1 increased the cell viability rate and decreased the necrosis and late apoptosis rate of BV2 cells exposed to lead compared with corresponding lead exposure groups (P<0.05). Conclusions Lead can reduce BV2 cell viability, increase necrosis rate, and up-regulate the expressions of RIPK1, RIPK3, amd MLKL, and the phosphorylation levels of RIPK1 and MLKL. The RIPK1 inhibitor Nec-1 has an intervention effect on lead-induced damage in BV2 cells, indicating that programmed necrosis may play a role in lead neurotoxicity.

6.
Journal of Clinical Hepatology ; (12): 451-455, 2020.
Article in Chinese | WPRIM | ID: wpr-820987

ABSTRACT

Liver macrophages are in a dynamic equilibrium of immune tolerance and immune response after continuous antigen stimulation. The immune response of liver macrophages to external antigen is closely associated with the immune homeostasis of the liver. This article reviews the association between the programmed necrosis pathway and the apoptotic pathway and elaborates on the important role of the activity of IKK complex in the interactive regulation of the programmed necrosis and apoptotic pathways. Further studies are needed to clarify the role of programmed necrosis in the response of liver macrophages to extrahepatic antigens.

7.
Chinese Journal of Dermatology ; (12): 302-309, 2019.
Article in Chinese | WPRIM | ID: wpr-745785

ABSTRACT

Objective To evaluate the inductive effect of interferon-γ(IFN-γ) combined with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on programmed necrosis of the human immortalized keratinocyte cell line HaCaT,and to explore its mechanisms.Methods In vitro cultured HaCaT cells were divided into several groups:negative control group receiving no treatment,IFN-γ group treated with 50 μg/L IFN-γ,TRAIL group treated with 4 μg/L TRAIL,and cytokine combination group treated with 50 μg/L IFN-γ and 4 μg/L TRAIL or zVAD combination group pretreated with 40 μmo/L zVAD for 1 hour followed by the treatment with 50 μg/L IFN-γand 4 μg/L TRAIL.After 48-hour treatment,the morphology of HaCaT cells were observed under a light microscope,methyl-thiazolyl-tetrazolium assay was performed to evaluate the inhibitory effect of the treatment on the proliferation of HaCaT cells,and double staining flow cytometry to detect the necrosis of HaCaT cells.Meanwhile,real-time fluorescence-based quantitative PCR (qPCR) was conducted to determine the mRNA expression of receptor interaction protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL),Western blot analysis to determine the expression of RIP1,RIP3,MLKL proteins and their phosphorylated forms (pRIP1,pRIP3,pMLKL),immunofluorescent staining to observe the distribution of pRIP3 and pMLKL in HaCaT cells,and the level of reactive oxygen species (ROS) in HaCaT cells in the above groups was detected by the fluorescence probe DCFH-DA.Statistical analysis was carried out with SPSS 22 software by using one-way analysis of variance (ANOVA) for comparing indices among different groups,and least significant difference (LSD)-t test for multiple comparisons.Results After 48-hour treatment,HaCaT cells in the cytokine combination group and zVAD combination group showed necrosis-like morphologic features.Methyl-thiazolyl-tetrazoliumassay revealed significant differences in the survival rate of HaCaT cells among the IFN-γgroup,TRAIL group,cytokine combination group,zVAD combination group and negative control group (73.16% ± 5.71%,81.46% ± 4.68%,72.18% ± 2.93%,69.67% ± 3.24% and 100%,respectively;F =24.34,P < 0.001).The necrosis rate of HaCaT cells was notably higher in the cytokine combination group and zVAD combination group (9.86% ± 1.31%,10.33% ± 2.16%,respectively) than in the negative control group (5.26% ± 0.91%,t =4.61,5.07,respectively,both P < 0.05).qPCR revealed that the mRNA expression of RIP3 and MLKL significantly increased in the cytokine combination group and zVAD combination group compared with the negative control group (tRIP3 =0.99,1.84,tMLKL =1.51,2.17,respectively,all P < 0.05).Western blot analysis suggested that the protein expression of RIP1,RIP3,MLKL,pRIP1,pRIP3 and pMLKL significantly increased in the cytokine combination group compared with the negative control group (all P < 0.05),and the zVAD combination group showed significantly decreased caspase 8 expression and increased expression of the above proteins compared with the cytokine combination group.Fluorescence microscopy showed that enhanced green dot-like or clump-like fluorescent spots (representing pRIP3) could be observed in the cytoplasm,and red fluorescent spots (representing pMLKL) could be seen on the cell membrane in the cytokine combination group.The average fluorescence intensity of ROS was significantly higher in the cytokine combination group than in the negative control group (t =702.00,P < 0.05).Conclusion IFN-γcombined with TRAIL can induce the programmed necrosis of HaCaT cells with increased level of ROS.

8.
Chinese Pharmacological Bulletin ; (12): 153-157, 2017.
Article in Chinese | WPRIM | ID: wpr-508253

ABSTRACT

Necrosis is also tightly controlled by signaling path-ways,thus it is called as regulated necrosis,which includes ne-croptosis,ferroptosis,parthanatos and CypD-mediated necrosis. It has been shown that regulated necrosis is closely related to the occurrence,development and prognosis of injury-relevant disea-ses such as myocardial infarction,stroke,neurodegenerative dis-eases.It will be significant for prevention and therapy of injury-relevant diseases to clarify the signal transductions and regulatory mechanisms for the regulated necrosis.

9.
Article in English | WPRIM | ID: wpr-193047

ABSTRACT

Chemotherapy has long been considered as one of useful strategies for cancer treatment. It is primarily based on the apoptosis that can selectively kill cancer cells. However, cancer cells can progressively develop an acquired resistance to apoptotic cell death, rendering refractory to chemo- and radiotherapies. Although the mechanism by which cells attained resistance to drug remains to be clarified, it might be caused by either pumping out of them or interfering with apoptotic signal cascades in response to cancer drugs. In case that cancer cells are defective in some part of apoptotic machinery by repeated exposure to anticancer drugs, alternative cell death mechanistically distinct from apoptosis could be adopted to remove cancer cells refractory to apoptosis-inducing agents. This review will mainly deal with harnessing of necrotic cell death, specifically, programmed necrosis and practical uses. Here, we begin with various defects of apoptotic death machinery in cancer cells, and then provide new perspective on programmed necrosis as an alternative anticancer approach.


Subject(s)
Apoptosis , Autophagy , Cell Death , Drug Therapy , Necrosis , Radiotherapy
10.
Journal of Clinical Hepatology ; (12): 451-455, 170.
Article in Chinese | WPRIM | ID: wpr-788417

ABSTRACT

Liver macrophages are in a dynamic equilibrium of immune tolerance and immune response after continuous antigen stimulation. The immune response of liver macrophages to external antigen is closely associated with the immune homeostasis of the liver. This article reviews the association between the programmed necrosis pathway and the apoptotic pathway and elaborates on the important role of the activity of IKK complex in the interactive regulation of the programmed necrosis and apoptotic pathways. Further studies are needed to clarify the role of programmed necrosis in the response of liver macrophages to extrahepatic antigens.

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