• 대한유전성대사질환학회지
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• 제20권1호
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• pp.1-13
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• 2020

Gaucher disease (GD)는 glucocerebrosidase 유전자(GBA)의 돌연변이에 의하여 발병하는 전세계적으로 가장 유병율이 높은 리소좀 축적질환이다. GD는 신경학적인 증상의 유무에 따라 3가지 임상형으로 구분된다. 신경병증 GD인 2형과 3형의 경우는 대뇌에서 glucosylceramide (GlcCer)와 glucosylsphingosine (GlcSph)의 농도가 증가하면서 신경세포의 심각한 손실이 야기되는 특징을 보인다. 신경교종에서 유래한 H4 세포를 GD에서 증가하는 기질인 GluCer와 GlcSph를 첨가하여 배양하였을 때, 심각한 DNA손상과 더불어 세포의 사멸이 야기되는 것과 이러한 신경세포의 사멸은 GluCer 보다는 GlcSph을 처리하였을 때 더 현저하게 증가하는 것을 관찰하였다. H4 세포에 히스톤 탈아세틸화 효소(HDAC) 6의 저해제인 tubacin과 GlcSph을 함께 처리하였을 경우에는 DNA손상은 물론 GlcSph에 의하여 유도된 세포사멸과 관련된 단백질 인자들의 발현이 모두 감소되었다. 본 연구를 통해 GlcSph이 세포사멸을 통하여 신경병증 GD의 발병에 주요한 역할을 한다는 것을 알 수 있었고, HDAC6 저해제가 신경병증 GD 환자를 위한 치료제 후보물질로 제시될 수 있는 가능성을 확인하였다.

• Archives of Pharmacal Research
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• 제22권4호
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• pp.404-409
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• 1999

The inhibitory effects of the constituents of Gastrodia elata Bl. (GE) on glutamate-induced apoptosis in human neuronal cells were investigated using IMR32 human neuroblastoma cells. Glutamate (GLU) induced DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. GLU also induced a slow and sustained increase in intracellular $Ca^{2+}$ concentration. Treatment with EGTA, an extracellular $Ca^{2+}$ chelator, in a nominal $Ca^{2+}$ -free buffer solution abolished the GLU-induced intracellular $Ca^{2+}$ increase, indicating that GLU stimulated Ca2+ influx pathway in the IMR32 cells. BAPTA, an intracellualr $Ca^{2+}$ chelator, significantly inhibited the GLU-induced apoptosis assessed by the flow cytometry measuring hypodiploid DNA content indicative of apoptosis, implying that intracellular $Ca^{2+}$ rise may mediate the apoptotic action of GLU. Vanillin (VAN) and p-hydroxybenzaldehyde(p-HB), known constituents of GE, significantly inhibited both intracellular $Ca^{2+}$ rise and apoptosis induced by GLU. These results suggest that the apoptosis-inhibitory actions of the constituents of GE may account, at least in part, for the basis of their antiepileptic activities. These results further suggest that intracelluarl $Ca^{2+}$ signaling pathway may be a molecular target of the constituents of GE.

• 대한한의학회지
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• 제29권2호
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• pp.21-31
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• 2008

Backgrounds: Singihwan is used "to strengthen inborn energy" and we suspected a protective effect on brain neuron cells. Objectives: The aim of this study was to evaluate the effects of Singihwan (SGH) on traumatic brain injury-induced delayed apoptosis in rat hippocampal dentate gyrus. Methods: For a surgical induction of traumatic brain injury (TBI), a 5 mm diameter stainless rod was used to make traumatic attack from the surface of the brain used by an impactor. The protective effect of the aqueous extract of SGH against TBI in the rat hippocampal dentate gyrus was investigated by using step-down avoidance task, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, Bax immunohistochemistry, and 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. Results: The aqueous extract of SGH suppressed the TBI-induced increase in apoptosis and cell proliferation in the hippocampal dentate gyrus. Conclusions: It is possible that the aqueous extract of SGH has a neuroprotective effect on TBI-induced neuronal cell death.

• Asian Pacific Journal of Cancer Prevention
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• 제16권18호
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• pp.8313-8319
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• 2016

We have recently shown that thymoquinone (TQ) has a potent cytotoxic effect and induces apoptosis via caspase-3 activation with down-regulation of XIAP in mouse neuroblastoma (Neuro-2a) cells. Interestingly, our results showed that TQ was significantly more cytotoxic towards Neuro-2a cells when compared with primary normal neuronal cells. In this study, the effects of TQ on cell-cycle regulation and the mechanisms that contribute to this effect were investigated using Neuro-2a cells. Cell-cycle analysis performed by flow cytometry revealed cell-cycle arrest at G2/M phase and a significant increase in the accumulation of TQ-treated cells at sub-G1 phase, indicating induction of apoptosis by the compound. Moreover, TQ increased the expression of p53, p21 mRNA and protein levels, whereas it decreased the protein expression of PCNA, cyclin B1 and Cdc2 in a dose-dependent manner. Our finding suggests that TQ could suppress cell growth and cell survival via arresting the cell-cycle in the G2/M phase and inducing apoptosis of neuroblastoma cells.

• 동의생리병리학회지
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• 제22권4호
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• pp.771-777
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• 2008

Chungpaesagan-tang which is used for treating patients of brain in cerebrovascular disease frequently from clinical doctor has not reported about the effect of neuronal aptosis caused of brain ischemia. The aim of this study is to investigate effect of Chungpaesagan-tang protecting neuronal cells from being damaged by brain ischemia through using organotypic hippocampal slice cultures. We caused ischemic damage to organotypic hippocampal slice cultures by oxygen and glucose deprivation. And added Chungpaesagan-tang extract to cultures. thereafter we measured area percentage of propidium iodide (PI)-stained neuronal cell, lactate dehydrogenase (LDH) levels in culture media and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells. Area percentage of PI-stained neuronal cells and count of TUNEL-positive cells in CA1 and DG area of organotypic hippocampal slice culture were significantly decreased in pertinent density level of Chungpaesagan-tang extract. LDH levels in culture media of organotypic hippocampal slice culture were significantly decreased in pertinent density level of Chungpaesagan-tang extract. Within pertinent density level, Chungpaesagan-tang has cell protection effect that prevents brain ischemia damaging neuronal cells and apoptosis increasing.

• Journal of Microbiology and Biotechnology
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• 제20권4호
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• pp.700-707
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• 2010

A novel antioxidative peptide (APVPH I, antioxidative peptides from venison protein hydrolysates I) was purified from venison by enzymatic hydrolysis, column chromatography of DEAE-Sephacel, and high-performance liquid chromatography. The molecular mass of the purified peptide was found to be 9,853 Da and the amino acid sequences of the purified peptide was Met-Gln-Ile-Phe-Val-Lys-Thr-Leu-Thr-Gly. The purpose of this study was to evaluate the effects of APVPH I against $H_2O_2$-induced neuronal cells damage in PC-12 cells. Antioxidative enzyme levels in cultured neuronal cells were increased in the presence of the peptide. In addition, APVPH I inhibited productions of nitric oxide (NO), reactive oxygen species (ROS), malondialdehyde (MDA), and cell death against $H_2O_2$-induced neuronal cell damage in PC-12 cells. It was presumed to be APVPH I involved in regulating the apoptosis-related gene expression in the cell environment. The present results indicate that APVPH I substantially contributes to antioxidative properties in neuronal cells.

• The Korean Journal of Physiology and Pharmacology
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• 제2권3호
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• pp.279-286
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• 1998

It has been well documented that transient forebrain global ischemia causes selective neuronal degeneration in hippocampal CA1 pyramidal neurons with a delay of a few days. The mechanism of this delayed hippocampal CA1 pyramidal neuronal death (DND) is still controversial. To delineate the mechanisms of the DND, the effects of treatment with MK-801, an NMDA receptor antagonist, kynurenic acid, a NMDA/non-NMDA receptor antagonist, and/or cycloheximide, a protein synthesis inhibitor, on the DND were investigated in male Wistar rats. To examine the participation of apoptotic neuronal death in the DND, TUNEL staining was performed in ischemic brain section. Global ischemia was induced by 4-vessel occlusion for 20 min. All animals in this study showed the DND 3 and 7 days after the ischemic insult. The DND that occured 3 days and 7 days after the ischemia were not affected by pretreatment with MK-801 (1 mg/kg), but markedly attenuated by the pretreatment with kynurenic acid (500 mg/kg). Treatment with cycloheximide (1 mg/kg) also markedly inhibited the DND. The magnitudes of attenuation by the two drugs were similar. The magnitude of attenuation by co-treatments with kynurenic acid and cycloheximide was not greater than that with any single treatment. TUNEL staining was negative in the sections obtained 1 or 2 days after the ischemic insults, but it was positive at hippocampal CA1 pyramidal cells in sections collected 3 days after the ischemia. These results suggested that the DND should be mediated by the activation of non-NMDA receptor, not by the activation of NMDA receptor and that the activation of AMPA receptor should induce the apoptotic process in the DND.

• Natural Product Sciences
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• 제18권1호
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• pp.26-31
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• 2012

Actinidia arguta (Actinidiaceae) has been reported to have several pharmacological effects such as anti-inflammatory, anti-allergic, and anti-oxidant activities. The present study investigated the protective activity of an ethanol extract from the leaf and stem of A. arguta against glutamate-induced neurotoxicity using cultured rat cortical neurons. Exposure of cultured cortical neurons to $500{\mu}M$ glutamate for 12 h triggered neuronal cell death. A. arguta inhibited glutamate-induced neuronal death and apoptosis, which were measured by a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and Hoechst 33342 staining, respectively. The increase of pro-apoptotic proteins, Bax and c-caspase-3, in glutamate-treated neurons was significantly inhibited by treatment with A. arguta. A. arguta also inhibited $500{\mu}M$ glutamate-induced elevation of intracellular calcium concentration ($[Ca^{2+}]_i$) and reactive oxygen species (ROS) generation, which were measured by fluorescent dyes, Fluo-4 AM and $H_2DCF$-DA, respectively. These results suggest that A. arguta may prevent glutamate-induced apoptotic neuronal death by inhibiting $[Ca^{2+}]_i$ elevation and ROS generation and, therefore, may have a therapeutic role for the prevention of neurodegeneration in cerebral ischemic diseases.

• 한국약용작물학회지
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• 제23권2호
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• pp.144-149
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• 2015

The peel of Citrus sunki exhibits multiple biological activities such as anti-oxidant, anti-inflammation and anti-obesity, but little is known about neurodegeneration-related activities. In this study, we investigated the protective effect of ethanolic extract from both immature and mature Citrus sunki peel on neuronal cell death. Treatment of the neuroblastoma cell line SH-SY5Y with $MPP^+$, an inducer of Parkinson disease model, increased cell death in a dose dependent manner. Increased levels of active caspase-3 and cleaved PARP were detected. Treatment with immature Citrus sunki peel extract significantly reduced $MPP^+$-induced neurotoxicity. Cytoprotection with immature Citrus sunki peel extract was associated with a decrease in caspase-3 activation and PARP cleavage. In contrast, mature Citrus sunki peel extract had no significant effects. These data suggest that immature Citrus sunki peel extract may exert anti-apoptotic effect through the inhibition of caspase-3 signaling pathway on $MPP^+$-induced neuronal cell death.

• Biomolecules & Therapeutics
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• 제30권6호
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• pp.570-575
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• 2022

Stress breaks body balance, which can cause diverse physiological disorders and worsen preexisting diseases. However, recent studies have reported that controllable stress and overcoming from stress reinforce resilience to resist against more intense stress afterwards. In this study, we investigated the protective effect of corticosterone (CORT), a representative stress hormone against hydrogen peroxide (H₂O₂)-induced neuronal cell death and its underlying molecular mechanism in SH-SY5Y cells, a human neuroblastoma cell line. The decreased cell viability by H₂O₂ was effectively restored by the pretreatment with low concentration of CORT (0.03 μM for 72 h) in the cells. H₂O₂-increased expression of apoptotic markers such as PUMA and Bim was decreased by CORT pretreatment. Furthermore, pretreatment of CORT attenuated H₂O₂-mediated oxidative damages by upregulation of antioxidant enzymes via activation of nuclear factor erythroid 2-related factor 2 (Nrf2). These findings suggest that low concentration of CORT with eustressed condition enhances intracellular self-defense against H₂O₂-mediated oxidative cell death, suggesting a role of low concentration of CORT as one of key molecules for resilience and neuronal cell survival.