• Journal of Applied Biological Chemistry
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• v.66
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• pp.53-59
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• 2023

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has no effect on normal cells, but selectively can induce apoptosis in tumor cells. Gartanin, a xanthone compound in mangosteen, has been shown to inhibit cancer cell growth by arresting the cell cycle and inducing autophage. In this study, we revealed that gartanin can sensitize TRAIL-induced human liver cancer cell death. We also found that gartanin enhances DR5 expression, a death receptor for TRAIL. This effect appears to be related to CHOP activation associated with the response of endoplasmic reticulum stress. Gartanin treatment also inhibited p62 protein expression and cleaved LC3 to activate autophagy flux, which is related with TRAIL-induced cell death. Pretreatment with autophagy flux inhibitor, LY294002, inhibited gartanin-induced DR5 expression. In summary, our results reveal that the combined treatment of gartanin and TRAIL can be a valuable tool for cancer treatment.

• BMB Reports
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• v.51 no.5
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• pp.219-224
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• 2018

Necroptosis is an emerging form of programmed cell death occurring via active and well-regulated necrosis, distinct from apoptosis morphologically, and biochemically. Necroptosis is mainly unmasked when apoptosis is compromised in response to tumor necrosis factor alpha. Unlike apoptotic cells, which are cleared by macrophages or neighboring cells, necrotic cells release danger signals, triggering inflammation, and exacerbating tissue damage. Evidence increasingly suggests that programmed necrosis is not only associated with pathophysiology of disease, but also induces innate immune response to viral infection. Therefore, necroptotic cell death plays both physiological and pathological roles. Physiologically, necroptosis induce an innate immune response as well as premature assembly of viral particles in cells infected with virus that abrogates host apoptotic machinery. On the other hand, necroptosis per se is detrimental, causing various diseases such as sepsis, neurodegenerative diseases and ischemic reperfusion injury. This review discusses the signaling pathways leading to necroptosis, associated necroptotic proteins with target-specific inhibitors and diseases involved. Several studies currently focus on protective approaches to inhibiting necroptotic cell death. In cancer biology, however, anticancer drug resistance severely hampers the efficacy of chemotherapy based on apoptosis. Pharmacological switch of cell death finds therapeutic application in drug- resistant cancers. Therefore, the possible clinical role of necroptosis in cancer control will be discussed in brief.

• Korean Journal of Veterinary Service
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• v.17 no.1
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• pp.67-80
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• 1994

8-10 week old ICR mice were infected intracerebrally and intraperitoneally with different encephalomyocarditis virus(K$_3$, $K_{11}$, ATT-VR 129) to observe histopathological and immunohistochemical change. Results obtained throuh the experiments were summarized as follows : 1. No differences in clinical signs by the virus strains and the inoculation routes were found. Mice infected with EMCV showed clinical signs after 3 days of inoculation. Main clinical signs were tremors, convulsions, circling movement, and uni or bilateral hindleg paralysis followed by death on the 3-8 days. In general, most of the infected animals died or recovered closely on the 8th day of postinoculation. 2. At necropsy, petechial and ecchymotic hemorrhages in lung were observed and no specific findings in other were observed. 3. In histopathological observation, neuroal cell degeneration perivascular mononucear cell in-filtration gliosis were appeared in central nervous system. Myocarditis with myocardial degeneration and necrosis, calcification were observed along with acinar cell necrosis of exocrine glands in pancreas, severe glomerulonephritis in kidney. Also, focal necrosis of hepatocytes and interstitial pneymonia hyperemia, hemorrhages in lungs were observed. 4. By immunohistochemical staining using ABCIT method, the positive cells were recognized in intracytoplasm of acinar cell in pancreas and intracytoplasm of neuronal cells in cerebrum.

• Journal of Microbiology and Biotechnology
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• v.25 no.7
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• pp.1170-1176
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• 2015

Ginsenosides, the major active component of ginseng, are traditionally used to treat various diseases, including cancer, inflammation, and obesity. Among these, compound K (CK), an intestinal bacterial metabolite of the ginsenosides Rb₁, Rb₂, and Rc from Bacteroides JY-6, is reported to inhibit cancer cell growth by inducing cell-cycle arrest or cell death, including apoptosis and necrosis. However, the precise effect of CK on breast cancer cells remains unclear. MCF-7 cells were treated with CK ($0-70{\mu}M$) for 24 or 48 h. Cell proliferation and death were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Changes in downstream signaling molecules involved in cell death, including glycogen synthase kinase $3\beta$ ($GSK3\beta$), $GSK3\beta$, $\beta$-catenin, and cyclin D1, were analyzed by western blot assay. To block $GSK3\beta$ signaling, MCF-7 cells were pretreated with $GSK3\beta$ inhibitors 1 h prior to CK treatment. Cell death and the expression of $\beta$-catenin and cyclin D1 were then examined. CK dose- and time-dependently inhibited MCF-7 cell proliferation. Interestingly, CK induced programmed necrosis, but not apoptosis, via the $GSK3\beta$ signaling pathway in MCF-7 cells. CK inhibited $GSK3\beta$ phosphorylation, thereby suppressing the expression of $\beta$-catenin and cyclin D1. Our results suggest that CK induces programmed necrosis in MCF-7 breast cancer cells via the $GSK3\beta$ signaling pathway.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2569-2574
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• 2015

Necroptosis, also known as "programmed necrosis", has emerged as a critical factor in a variety of pathological and physiological processes and is considered a cell type-specific tightly regulated process with mechanisms that may vary rather greatly due to the change of cell line. Here we used HT-29, a human colon cancer cell line, to establish a necroptosis model and elucidate associated mechanisms. We discovered that cobalt chloride, a reagent that could induce hypoxia-inducible $factor-1{\alpha}(HIF1{\alpha})$ expression and therefore mimic the hypoxic microenvironment of tumor tissue in some aspects induces necroptosis in HT-29 cells when caspase activity is compromised. On the other hand, apoptosis appears to be the predominant death form when caspases are functioning normally. HT-29 cells demonstrated significantly increased RIPK1, RIPK3 and MLKL expression in response to cobalt chloride plus z-VAD treatment, which was accompanied by drastically increased $IL1{\alpha}$ and IL6 expression, substantiating the notion that necrosis can induce profound immune reactions. The RIPK1 kinase inhibitor necrostatin-1 and the ROS scavenger NAC each could prevent necrosis in HT-29 cells and the efficiency was enhanced by combined treatment. Thus by building up a necroptosis model in human colon cancer cells, we uncovered that mechanically RIP kinases collaborate with ROS during necrosis promoted by cobalt chloride plus z-VAD, which leads to inflammation. Necroptosis may present a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.

• Reproductive and Developmental Biology
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• v.29 no.2
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• pp.101-108
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• 2005

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a well-known inducer of apoptotic cell death in many tumor cells. 1RAIL is expressed in human placenta, and cytotrophoblast cells express 1RAIL receptors. However, the role of TRAIL in human placentas and cytotrophoblast cells is not. well understood. In this study a trophoblast cell line, JEG-3, was used as a model system to examine the effect of TRAIL. on key intracellular signaling pathways involved in the control of trophoblastic cell apoptosis and survival JEG-3 cells expressed receptors for 1RAIL, death receptor (DR) 4, DR5, decoy receptor (OcR) 1 and DeR2. Recombinant human TRAIL (rhTRAIL) did not have a cytotoxic effect determined by MIT assay and did not induce apoptotic cell death determined by poly-(ADP-ribose) polymerase cleavage assay. rhTRAIL induced a rapid and transient nuclear translocation of nuclear $factor-{\kappa}B(NF-{\kappa}B)$ determined by immunoblotting using nuclear protein extracts. rhTRAIL rapidly activated extracellular signal-regulated protein kinase (ERK) 1/2 as determined by immnoblotting for phospho-ERK1/2. However, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK) and Akt (protein kinase B) were not activated by rhTRAIL. The ability of 1RAIL to induce $NF-{\kappa}B$ and ERK1/2 suggests that interaction between TRAIL and its receptors may play an important role in trophoblast cell function during pregnancy.

• Journal of Evidence-Based Herbal Medicine
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• v.1 no.1
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• pp.7-11
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• 2008

The purpose of this study was to investigate the anti-inflammatory effects of extract from Hwang lyun tang (HLT) on the THP-1 cell and HMC-1 cell. To evaluate of anti-inflammatory of HLT, we examined cytokines production in lipopolysacchride (LPS)-induced THP-1 cell and A23187, PMA-induced HMC-1 cell. Extract of HLT inhibit LPS-induced interleukin (IL)-8 production in human monocyte THP-1 cells. Extract of HLT inhibit A23187, PMA-induced IL-8, tumor necrosis factor-$\alpha$ (INF-$\alpha$) production in HMC-1 cells. HLT down-regulated LPS-induced IL-8 production and A23187, PMA-induced IL-8, TNF-$\alpha$ production, which may be provide a clinical basis for anti-inflammatory properities of HLT.

• Journal of Evidence-Based Herbal Medicine
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• v.1 no.1
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• pp.1-5
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• 2008

Objectives : The purpose of this study was to investigate the anti-inflammatory effects of extract from Jak-Yak Tang (JYT) on the THP-1 cell and HMC-1 cell. Method : To evaluate of anti-inflammatory of JYT, we examined cytokines production in lipopolysacchride (LPS)-induced THP-1 cell and A23187, PMA-induced HMC-1 cell. Result : Extract of JYT inhibit LPS-induced interleukin (IL)-8 production in human monocyte THP-1 cells. Extract of JYT inhibit A23187, PMA-induced IL-8, tumor necrosis factor-$\alpha$ (INF-$\alpha$) production in HMC-1 cells. Conclusion : NT down-regulated LPS-induced IL-8 production and A23187, PMA-induced IL-8, TNF-$\alpha$ production, which may be provide a clinical basis for anti-inflammatory properities of JYT.

• Journal of Microbiology and Biotechnology
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• v.31 no.6
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• pp.875-881
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• 2021

The mitochondrial targeting domain (MTD) of Noxa contributes to its mitochondrial localization and to apoptosis induction. As a peptide, MTD fused with octa-arginine (R8), a CPP, induces necrosis related to intracellular calcium influx and destruction of mitochondria and endoplasmic reticulum. We searched for homologs of MTD, and compared their cell killing capability when fused with R8. Three of the seven peptides triggered cell death with similar mechanisms. The comparative analysis of peptide sequences showed that four amino acid sites of MTD are critical in regulating necrosis, suggesting the potential to generate artificial, adjustable cytotoxic peptides, which could be effective medicines for many diseases. Thus, homologs functionality could hint to the functions of their belonging proteins.

• Korean Journal of Veterinary Research
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• v.38 no.2
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• pp.423-435
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• 1998

In acute pancreatitis group, all the dogs are showed increase of amylase and lipase after the 1st day of surgery, and amylase and lipase activity were significantly more increased than those of control group. The methemalbumin was increased significantly after the 2nd day of surgery in the acute pancreatitis group. In pancreatitis group, ultrasonographic findings included thickened duodenal wall and poorly circumscribed hyperechoic lesion of pancreatic mass after the 2nd day of surgery. And the lesion was exacerbated until the 4th day and reduced after the 6th day of surgery. To identify the lesion of pancreas, it is considered that transverse view is more useful Than sagittal view. Gross findings showed increase of pancreatic parenchymal consistency, surface nodule, and extensive pancreatic necrosis. Necrosis of peripancreatic fat tissue was also a prominent feature. The microscopic appearance of the pancreas was characterized by pancreatic acinar cell necrosis, hemorrhage, infiltration of the inflammatory cell and fat necrosis and saponification were also observed.