• Korean Journal of Clinical Laboratory Science
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• v.53 no.2
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• pp.158-164
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• 2021

Hypertriglyceridemia is the main risk factor for atherosclerosis. It is reported that triglyceride (TG) induces macrophage cell death, and is involved in the formation of plaques and development of atherosclerosis. We previously reported that TG-induced cell death of macrophages is mediated via pannexin-1 activation, which increases the extracellular ATP and subsequent increase in potassium efflux, thereby activating the caspase-2/caspase-1/apoptotic caspases, including the caspase-8 pathway. Contrarily, some studies have reported that caspase-8 is an upstream molecule of caspase-1 and caspase-2 in several cellular processes. Therefore, this study was undertaken to investigate whether caspase-8 influences its upstream molecules in TG-stimulated macrophage cell death. We first confirmed that caspase-8 induces caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage in TG-treated macrophages. Next, we determined that the inhibition of caspase-8 results in reduced caspase-1 and -2 activity, which are upstream molecules of caspase-8 in TG-induced cell death of macrophages. We also found that ATP treatment restores the caspase-8 inhibitor-induced caspase-2 activity, thereby implying that caspase-8 affects the upstream molecules responsible for increasing the extracellular ATP levels in TG-induced macrophage cell death. Taken together, these findings indicate that caspase-8 potentiates the TG-induced macrophage cell death by activating its upstream molecules.

• BMB Reports
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• v.50 no.10
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• pp.510-515
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• 2017

Triglyceride (TG) accumulation causes macrophage cell death, which affects the development of atherosclerosis. Here, we examined whether caspase-2 is implicated in TG-induced macrophage cell death. We found that caspase-2 activity is increased in TG-treated THP-1 macrophages, and that inhibition of caspase-2 activity drastically inhibits TG-induced cell death. We previously reported that TG-induced macrophage cell death is triggered by caspase-1, and thus investigated the relationship between caspase-2 and caspase-1 in TG-induced macrophage cell death. Inhibition of caspase-2 activity decreased caspase-1 activity in TG-treated macrophages. However, caspase-1 inhibition did not affect caspase-2 activity, suggesting that caspase-2 is upstream of caspase-1. Furthermore, we found that TG induces activation of caspase-3, -7, -8, and -9, as well as cleavage of PARP. Inhibition of caspase-2 and -1 decreased TG-induced caspase-3, -7, -8, and -9 activation and PARP cleavage. Taken together, these results suggest that TG-induced macrophage cell death is mediated via the caspase-2/caspase-1/apoptotic caspases/PARP pathways.

• Animal cells and systems
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• v.12 no.3
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• pp.127-136
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• 2008

Caspase-11 has been known as a dual regulator of cytokine maturation and apoptosis. Although the role of caspase-11 under pathological conditions has been well documented, its physiological role has not been studied much. In the present study, we investigated a possible physiological function of caspase-11 during immune response. In the absence of caspase-11, immunized spleen displayed increased cellularity and abnormal germinal center structure with disrupted microarchitecture. The rate of cell proliferation and apoptosis in the immunized spleen was not changed in the caspase-11-deficient mice. Furthermore, the caspase-11-deficient peritoneal macrophages showed normal phagocytotic activity. However, caspase-11-/-splenocytes and macrophages showed defective migrating capacity. The dysregulation of cell migration did not seem to be mediated by caspase-3, interleukin-$1{\alpha}$ or interleukin-$1{\beta}$ which acts downstream of caspase-11. These results suggest that a direct regulation of immune cell migration by caspase-11 is critical for the formation of germinal center microarchitecture during immune response. However, humoral immunity in the caspase-11-deficient mice was normal, suggesting the formation of germinal center structure is not essential for the affinity maturation of the antibodies.

• Food Science and Biotechnology
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• v.17 no.6
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• pp.1305-1309
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• 2008

Baicalein, one of the major flavonoid in Scutellaria baicalensis, has been known for its effects on proliferation and apoptosis of many tumor cell lines. Most biological effects of baicalein are thought to be from its antioxidant and prooxidant activities. In this report, baicalein was found to induce apoptosis in HL60 human promyelocytic leukemia cell line. Baicalein treatment induced DNA fragmentation and typical morphological features of apoptosis. To elucidate the mechanism of baicalein-induced apoptosis, the activities of the members of caspase family were measured. Interestingly caspase 2, 3, and 6 were significantly activated whereas caspase 1, 8, and 9 were not activated, suggesting selective involvement of specific caspases. Further, treatment with caspase inhibitors also supports the involvement of caspase 2 in apoptosis process. Although it has been reported that baicalein can induce apoptosis through many caspase pathways, the present study indicates that caspase 2 not caspase 9 pathway may be the important step in apoptosis on HL60 cell line.

• Journal of Life Science
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• v.27 no.2
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• pp.164-171
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• 2017

Our previous study suggested that S-allylcysteine (SAC) inhibits the proliferation of the human cervical cancer cell line, HeLa, at least in part through the induction of apoptosis and cell cycle arrest. To further analyze the specific molecular mechanism(s) by which SAC mediates its antiproliferative effects, this study examined the role of SAC in regulating the protein expression of initiator caspase (caspase-9), effector caspases (caspase-3 and caspase-7), and poly-ADP-ribose polymerase (PARP) in HeLa. Western blot analysis showed that when cells were treated with 50 mM SAC for 48 hr, the expression of procaspase-3, -7, and -9 and PARP was reduced by 94%, 38%, 95%, and 64%, respectively, as compared to the untreated control. In contrast, the expression of caspase-3, -7, and -9 and cleaved-PARP was markedly increased by SAC treatment. The SAC-mediated changes in the expression of these proteins were correlated with the concomitant inhibition of cellular proliferation by SAC. The cell proliferation assay showed that HeLa treatment with more than 20 mM SAC for 6-48 hr resulted in both concentration- and time-dependent inhibition of cellular proliferation. These results indicate that the SAC-induced antiproliferative effect in HeLa may be mediated at least in part through the activation of caspase-9, followed by the activation of caspase-3 and caspase-7 as well as the inactivation of PARP, thus leading to cellular apoptosis.

• Journal of Radiation Protection and Research
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• v.32 no.4
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• pp.134-139
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• 2007

In order to find out the Radioprotective effect of algin-oligosaccharide(AOS), this study, with a mouse of which whole frame irradiated by 3 Gy radiation once, measured caspase-3 and caspase-9 amid cell signaling connected to apoptosis in order to observe cell activation. In Caspase-3 and Caspase-9 test for observing cell activation, both of Caspase-3 and Caspase-9 showed highly increased O.D. value in the irradiation control group, while the whole groups treated with algin-oligosaccharide before or after irradiation indicated lower O.D. value than the irradiation control group, especially showed big difference in 7 day's treatment group of before irradiation (P<0.001). It confirmed that Caspase generation was restrained in AOS treatment group. Consequently, this study inquired into the fact that algin-oligosaccharide with superior antioxidant activity performed radiation protection by inducing restraint of Caspase generation and confirmed that natural product with less chemical toxicity was able to be applied as radioprotector.

• Biomedical Science Letters
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• v.16 no.4
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• pp.307-310
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• 2010

Apoptosis is an important significance in the pathogenesis of cancer. Caspase 3 and p53 have been identified as important members of the apoptosis related proteins. This study was performed to define roles of caspase 3 expression and its relationship with p53 expression in endometrial cancers by immunohistochemistry. Immunoreactivity for caspase 3 was found in 13 (65.0%) out of 20 endometrial hyperplasia cases and 8 (36.4%) out of 22 endometrial cancers. Seven (87.5%) of the 8 cases with a positive caspase 3 immunoreactivity showed a positive p53 expression in 22 endometrial cancers. There were no significant associations between caspase 3 and p53 expressions. These findings suggest that caspase 3 expression might be associated with carcinogenesis of endometrial cancers. Further studies are needed to define the relationship between caspase 3 and p53 and apoptosis for examining the mechanisms of tissue-specific apoptosis related protein.

• BMB Reports
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• v.46 no.9
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• pp.471-476
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• 2013

The PIDDosome, which is an oligomeric signaling complex composed of PIDD, RAIDD and caspase-2, can induce proximity-based dimerization and activation of caspase-2. In the PIDDosome assembly, the adaptor protein RAIDD interacts with PIDD and caspase-2 via CARD:CARD and DD:DD, respectively. To analyze the PIDDosome assembly, we purified all of the DD superfamily members and performed biochemical analyses. The results revealed that caspase-2 CARD is an insoluble protein that can be solubilized by its binding partner, RAIDD CARD, but not by full-length RAIDD; this indicates that full-length RAIDD in closed states cannot interact with caspase-2 CARD. Moreover, we found that caspase-2 CARD can be solubilized and interact with full-length RAIDD in the presence of PIDD DD, indicating that PIDD DD initially binds to RAIDD, after which caspase-2 can be recruited to RAIDD via a CARD:CARD interaction. Our study will be useful in determining the order of assembly of the PIDDosome.

• Biomedical Science Letters
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• v.25 no.1
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• pp.66-74
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• 2019

Hyperlipidemia is defined as conditions of the accumulation of lipids such as free fatty acids (FFA), triglyceride (TG), cholesterol and/or phospholipid in the bloodstream. Hyperlipidemia can cause lipid accumulation in non-adipose tissue, which is lipid-cytotoxic effects in many tissues and mediates cell dysfunction, inflammation or programmed cell death (PCD). TG is considered to be a major cause of atherosclerosis through inflammatory necrosis of vascular endothelial cells. Recently, TG have also been shown to exhibit lipid-cytotoxicity and induce PCD. Therefore, we investigated the effect of TG on the cytotoxic effect of various cell types. When exposed to TG, the cell viability of U937 monocytes and Jurkat T lymphocytes, as well as the cell viability of MCF-7, a non-immune cell, decreased in time- and dose-dependent manner. In U937 cells and Jurkat cells, caspase-9, an intrinsic apoptotic caspase, and caspase-8, an extrinsic apoptotic caspase, were increased by exposure to TG. However, in TG-treated MCF-7 cells, caspase-8 activity increased only without caspase-9 activity. In addition, the reduction of cell viability by TG was recovered when all three cell lines were treated with pan-caspase inhibitor. These results suggest that activation of apoptotic caspases by TG causes lipotoxic effect and decreases cell viability.

• BMB Reports
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• v.56 no.3
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• pp.166-171
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• 2023

Monocytes are peripheral leukocytes that function in innate immunity. Excessive triglyceride (TG) accumulation causes monocyte death and thus can compromise innate immunity. However, the mechanisms by which TG mediates monocyte death remain unclear to date. Thus, this study aimed to elucidate the mechanisms by which TG induces monocyte death. Results showed that TG induced monocyte death by activating caspase-3/7 and promoting poly (ADP-ribose) polymerase (PARP) cleavage. In addition, TG induced DNA damage and activated the ataxia telangiectasia mutated (ATM)/checkpoint kinase 2 and ATM-and Rad3-related (ATR)/checkpoint kinase 1 pathways, leading to the cell death. Furthermore, TG-induced DNA damage and monocyte death were mediated by caspase-2 and -8, and caspase-8 acted as an upstream molecule of caspase-2. Taken together, these results suggest that TG-induced monocyte death is mediated via the caspase-8/caspase-2/DNA damage/executioner caspase/PARP pathways.