• 한국콘텐츠학회논문지
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• 제9권4호
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• pp.355-363
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• 2009

비정상적인 미토콘드리아에 의해 산화 스트레스가 증가하면 세포내 신호전달 및 유전자 발현에 손상을 일으켜 인슐린 저항성이나 당뇨병 등의 여러 질환들을 유발한다. 그런데 자식작용은 산화 스트레스로 기능이 저하된 미토콘드리아를 제거하여 인슐린 저항성 등을 억제해준다. 한편 운동도 미토콘드리아 생합성을 강화시켜 조직의 기능저하나 퇴행을 회복시켜준다. 따라서 운동과 자식작용이 서로 연관되어 미토콘드리아 생합성을 유도하는 신호체계로 작용할 가능성이 있고, 이 연구를 통해 운동 혹은 AICAR (aminoimidazole-4-carboxamide-1-${\beta}$-D-ribofuranoside)처치로 활성 화된 AMPK(5'-AMP- activated protein kinase) 신호전달체계가 미토콘드리아 생합성을 증가시키는 경로에 자식작용이 관여하는지의 여부를 확인하고자 하였다. 연구결과에 따르면, 6시간의 급성운동으로 쥐의 골격근에서 PGC-1(peroxisome proliferator-activated receptor gamma coactivator 1)과 mtTFA (mitochondrial transcription factor A)의 mRNA 발현이 유의하게 증가하였다. 하지만 자식작용 표지제인 LC3(microtubule-associated proteinl light chain 3)의 mRNA 발현은 증가경향을 나타냈지만 유의하지 않았다. 한편 C2C12 근세포에서도 AICAR 처치에 의해 PGC-1, mtTFA mRNA 발현이 모두 증가하였지만, 이러한 증가는 LC3 SiRNA에 의해서 억제되지 않는 것으로 나타났다. 이러한 결과들을 통해 자식작용은 AMPK에 의해 조절되는 신호전달 전달체계와는 다른 경로로 미토콘드리아 생합성에 영향을 미칠 것으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권8호
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• pp.3803-3807
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• 2012

Prohibitin (PHB), an evolutionarily-conserved protein, has been found to be over-expressed in gastric cancer and be closely related with tumor malignancy. In this study, to investigate the relationship between PHB expression and cell apoptosis in the BGC823 gastric cancer cell line, low and high expression PHB in BGC823 cells was accomplished using RNA interference technology and gene transfer techniques. Cell proliferation, cell cycling, apoptosis, Bax, Bcl-2 and Cyt.c protein expression and the activation of Caspase-3,9 were assessed after 48h. Over-expression of PHB gene in BGC823 cells resulted in slow cell growth, cell arrest in G2 phase, and an increased apoptosis ratio while the opposite was found for PHB under-expressing cells. In PHB over-expressing cells, the expression of Bax gene was increased, the expression of Bcl-2 was decreased, the activation level of Caspase-3, 9 was increased, but the activation level of Caspase-8 demonstrated no change. These results indicate that PHB induced apoptosis through the mitochondrial pathway.

• Molecular & Cellular Toxicology
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• 제4권2호
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• pp.144-149
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• 2008

Despite versatile activity (cancericidal, antimicrobial, hypoxia inducible factor (HIF) inhibition, immune deactivation of DNA bis-intercalation agent, echinomycin, its specific mechanism has been elusive. Of these novel mechanisms, we reported that using human colon cancer cells (HT-29), apoptotic machinery induced by echinomycin might be dependent of caspase-3 pathway. Despite a partial enlightenment of prototypic signal path triggered by echinomycin, the role of Bcl-2 in this signaling pathway is unclear. To address this issue, we explored whether or not echinomycin would overcome the anti-apoptotic impact of Bcl-2 in HT-29 cells by the controlled Bcl-2 overexpression. Prior to this proof, we confirmed that echinomycin induces mitochondrial depolarization, then triggering the mitochondrial pathway of apoptosis with an involvement of upstream cas-pases-3. Transiently transfection with inactive Bax-DNA failed to prevent echinomycin-induced apoptosis in HT-29 cells. To dissect the role of Bcl-2 in echinomycin-induced apoptosis, HT-29 cells were transiently transfected with Bcl-2 DNA for overexpression and then treated with echinomycin for 24h. Combined analyses of DNA fragmentation and flow cytometric analysis clearly verified that echinomycin-induced apoptosis was drastically attenuated by Bcl-2 overexpression, whereas a control vector rarely affected echinomycin-induced apoptosis. Collectively, these data verify that Bcl-2 regulates echinomycin-induced apoptosis in HT-29 cells. To my knowledge, this is the first evidence that of diverse, structured minor groove binders (MGB), the prototypic echinomycin might control the apoptotic signaling via Bcl-2-mitochondrial pathway.

• Asian Pacific Journal of Cancer Prevention
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• 제15권13호
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• pp.5201-5205
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• 2014

Emodin, a natural anthraquinone isolated from the traditional Chinese medicine Radix rhizoma Rhei, can induce apoptosis in many kinds of cancer cells. This study demonstrated that emodin induces apoptosis in human colon cancer HCT116 cells by provoking oxidative stress, which subsequently triggers a p53-mitochondrial apoptotic pathway. Emodin induced mitochondrial transmembrane potential loss, increase in Bax and decrease in Bcl-2 expression and mitochondrial translocation and release of cytochrome c to cytosol in HCT116 cells. In response to emodin-treatment, ROS increased rapidly, and subsequently p53 was overexpressed. Pretreatment with the antioxidant NAC diminished apoptosis and p53 overexpression induced by emodin. Transfecting p53 siRNA also attenuated apoptosis induced by emodin, Bax expression and mitochondrial translocation being reduced compared to treatment with emodin alone. Taken together, these results indicate that ROS is a trigger of emodin-induced apoptosis in HCT116 cells, and p53 expression increases under oxidative stress, leading to Bax-mediated mitochondrial apoptosis.

• Journal of Ginseng Research
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• 제47권1호
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• pp.144-154
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• 2023

Background: As the major pathophysiological feature of obstructive sleep apnea (OSA), chronic intermittent hypoxia (CIH) is vital for the occurrence of cardiovascular complications. The activation of calpain-1 mediates the production of endothelial reactive oxygen species (ROS) and impairs nitric oxide (NO) bioavailability, resulting in vascular endothelial dysfunction (VED). Ginsenoside Rg1 is thought to against endothelial cell dysfunction, but the potential mechanism of CIH-induced VED remains unclear. Methods: C57BL/6 mice and human coronary artery endothelial cells (HCAECs) were exposed to CIH following knockout or overexpression of calpain-1. The effect of ginsenoside Rg1 on VED, oxidative stress, mitochondrial dysfunction, and the expression levels of calpain-1, PP2A and p-eNOS were detected both in vivo and in vitro. Results: CIH promoted VED, oxidative stress and mitochondrial dysfunction accompanied by enhanced levels of calpain-1 and PP2A and reduced levels of p-eNOS in mice and cellular levels. Ginsenoside Rg1, calpain-1 knockout, OKA, NAC and TEMPOL treatment protected against CIH-induced VED, oxidative stress and mitochondrial dysfunction, which is likely concomitant with the downregulated protein expression of calpain-1 and PP2A and the upregulation of p-eNOS in mice and cellular levels. Calpain-1 overexpression increased the expression of PP2A, reduced the level of p-eNOS, and accelerated the occurrence and development of VED, oxidative stress and mitochondrial dysfunction in HCAECs exposed to CIH. Moreover, scavengers of O₂^·-, H₂O₂, complex I or mitoKATP abolished CIH-induced impairment in endothelial-dependent relaxation. Conclusion: Ginsenoside Rg1 may alleviate CIH-induced vascular endothelial dysfunction by suppressing the formation of mitochondrial reactive oxygen species through the calpain-1 pathway.

• Biomolecules & Therapeutics
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• 제24권2호
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• pp.147-155
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• 2016

Chaetominine is a quinazoline alkaloid originating from the endophytic fungus Aspergillus fumigatus CY018. In this study, we showed evidence that chaetominine has cytotoxic and apoptotic effects on human leukemia K562 cells and investigated the pathway involved in chaetominine-induced apoptosis in detail. Chaetominine inhibited K562 cell growth, with an $IC_{50}$ value of 35 nM, but showed little inhibitory effect on the growth of human peripheral blood mononuclear cells. The high apoptosis rates, morphological apoptotic features, and DNA fragmentation caused by chaetominine indicated that the cytotoxicity was partially caused by its pro-apoptotic effect. Under chaetominine treatment, the Bax/Bcl-2 ratio was upregulated (from 0.3 to 8), which was followed by a decrease in mitochondrial membrane potential, release of cytochrome c from mitochondria into the cytosol, and stimulation of Apaf-1. Furthermore, activation of caspase-9 and caspase-3, which are the main executers of the apoptotic process, was observed. These results demonstrated that chaetominine induced cell apoptosis via the mitochondrial pathway. Chaetominine inhibited K562 cell growth and induced apoptotic cell death through the intrinsic pathway, which suggests that chaetominine might be a promising therapeutic for leukemia.

• Animal Bioscience
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• 제34권4호
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• pp.652-661
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• 2021

Objective: Wooden breast (WB) is a novel myopathy affecting modern broiler chickens, which causes substantial economic losses in the poultry industry. The objective of this study was to evaluate the effect of WB abnormality on meat quality, redox status, as well as the expression of genes of the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Methods: A total of 80 broilers (Ross 308, 42 days of age, about 2.6 kg body weight) raised at Jiujin farm (Suqian, Jiangsu, China) were used. Twelve unaffected (no detectable hardness of the breast area) and twelve WB-affected (diffuse remarkable hardness in the breast muscle) birds were selected from the commercial broiler farm according to the criteria proposed by previous studies. Results: The results indicated that WB showed histological lesions characterized by fiber degeneration and fibrosis, along with an increase of muscle fiber diameter (p<0.05). Moreover, higher pH value, lightness, yellowness, drip loss and cooking loss were observed in the WB group (p<0.05). Compared with the normal breast (NOR) group, the WB group showed higher formation of reactive oxygen species (p<0.05), increased level of oxidation products and antioxidant activities (p<0.05), accompanied with mitochondrial damages and lower mitochondrial membrane potential (p<0.05). Meanwhile, the relative mRNA expressions of Nrf2 and its downstream antioxidant genes including heme oxygenase-1, NAD(P)H qui none dehydrogenase 1, glutathione peroxidase, superoxide dismutase, and glutamate-cysteine ligase were higher than those of the NOR group (p<0.05). Conclusion: In conclusion, WB myopathy impairs meat quality by causing oxidative damages and mitochondrial dysfunction in broilers, even though the activated Nrf2/antioxidant response element pathway provides protection for the birds.

• BMB Reports
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• 제41권1호
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• pp.11-22
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• 2008

Apoptosis (programmed cell death) is a cellular self-destruction mechanism that is essential for a variety of biological events, such as developmental sculpturing, tissue homeostasis, and the removal of unwanted cells. Mitochondria play a crucial role in regulating cell death. $Ca^{2+}$ has long been recognized as a participant in apoptotic pathways. Mitochondria are known to modulate and synchronize $Ca^{2+}$ signaling. Massive accumulation of $Ca^{2+}$ in the mitochondria leads to apoptosis. The $Ca^{2+}$ dynamics of ER and mitochondria appear to be modulated by the Bcl-2 family proteins, key factors involved in apoptosis. The number and morphology of mitochondria are precisely controlled through mitochondrial fusion and fission process by numerous mitochondria-shaping proteins. Mitochondrial fission accompanies apoptotic cell death and appears to be important for progression of the apoptotic pathway. Here, we highlight and discuss the role of mitochondrial calcium handling and mitochondrial fusion and fission machinery in apoptosis.

• Biomolecules & Therapeutics
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• 제19권4호
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• pp.445-450
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• 2011

Preciously, we demonstrated that a novel NHE-1 inhibitor, KR-33028 attenuated cortical neuronal apoptosis induced by glutamate. In the present study, we investigated the signaling mechanism of neuroprotective effect of KR-33028 against glutamate-induced neuronal apoptosis, especially focusing on mitochondrial death pathway. Our data showed that glutamate induces a biphasic rise in mitochondrial $Ca^{2+}$ and that KR-33028 significantly prevents the second phase increase, but not the first phase increase in mitochondrial $Ca^{2+}$. Furthermore, KR-33028 restored the ${\Delta}{\Psi}_m$ dissipation and cytochrome c release into cytoplasm induced by glutamate in a concentration-dependent manner. The inhibition of mitochondrial $Ca^{2+}$ overload by ruthenium red also inhibited glutamate-induced apoptotic cell death, mitochondrial membrane potential, ${\Delta}{\Psi}_m$ dissipation and cytochrome c release. These data suggest that inhibition of mitochondrial $Ca^{2+}$ overload is likely to be attributable to anti-apoptotic effect of KR-33028. Taken together, our results suggest that anti-apoptotic effects of NHE-1 inhibitor, KR-33028 may be mediated through maintenance of mitochondrial function.

• BMB Reports
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• 제48권10호
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• pp.539-540
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• 2015

It has been proposed that the selective elimination of cancer stem cells (CSCs) using targeted therapy could greatly reduce tumor growth, recurrence, and metastasis. To develop effective therapeutic targets for CSC elimination, we aimed to define the properties of CSC mitochondria, and identify CSC-mitochondria-specific targets in colon cancer. We found that colon CSCs utilize mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP. We also found that forkhead box protein 1 (FOXM1)-induced peroxiredoxin 3 (PRDX3) maintains the mitochondrial function, and the FOXM1/PRDX3 mitochondrial pathway maintains survival of colon CSCs. Furthermore, FOXM1 induces CD133 (PROM1/prominin 1) expression, which maintains the stemness of colon CSCs. Together, our findings indicate that FOXM1, PRDX3, and CD133 are potential therapeutic targets for the elimination of CSCs in colon cancer.