• Korean Journal of Acupuncture
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• v.36 no.4
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• pp.200-209
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• 2019

Objectives : The liver is rich in mitochondria and it plays a key role in whole-body energy homeostasis. Mitochondria is double membrane-bound organelle that supplies energy for intracellular metabolism including Krebs cycle and beta-oxidation. Acupuncture is known to stimulate and regulate the flow of energy. To explore the effect of acupuncture on the mitochondrial respiratory chain activity in the rats' livers, the activity of mitochondrial respiratory chain complexes I to IV was observed. Methods : The rats were divided into 4 groups; Normal 1 (no acupuncture treatment and anesthesia for 5 min), Normal 2 (no acupuncture treatment and anesthesia for 10 min), MA1 (acupuncture treatment at bilateral LR3 under anesthesia for 5 min), and MA2 (acupuncture treatment at bilateral LR3 under anesthesia for 10 min). All rats were sacrificed and the livers were examined for respiratory chain change. Results : There was no difference in ubiquinon oxidoreductase, succinate dehydrogenase, and ubiquinol cytochrome C oxidoreductase after acupuncture at LR3. Acupuncture at LR3 for 10 min increased the activity of cytochrome C oxidase compared with no acupuncture groups. Conclusions : Acupuncture at LR3 mediated mitochondrial respiratory chain activity via the cytochrome C oxidase signaling pathway in the livers of rats.

• Journal of Life Science
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• v.27 no.3
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• pp.361-369
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• 2017

Mitochondrial homeostasis is tightly regulated by two major processes: mitochondrial biogenesis and mitochondrial degradation by autophagy (mitophagy). Research in mitochondrial biogenesis in skeletal muscle in response to endurance exercise training has been well established, while the mechanisms regulating mitophagy and the relationship between mitochondrial biogenesis and degradation following endurance exercise training are not yet well defined. Studies have demonstrated that endurance exercise training increases the expression levels of mitochondrial biogenesis-, dynamics-, mitophagy-related genes in skeletal muscle. However, the increased levels of mitochondrial biogenesis marker proteins such as Cox IV and citrate synthase, by endurance exercise training were abolished when autophagy/mitophagy was inhibited in skeletal muscle. This suggests that both autophagy/mitophagy plays an important role in mitochondrial biogenesis/homeostasis and the coordination between the opposing processes may be important for skeletal muscle adaptation to endurance exercise training to improve metabolic function and endurance exercise performance. It is considered that endurance exercise training regulates each of these processes, mitochondrial biogenesis, fusion and fission events and autophagy/mitophagy, ensuring a relatively constant mitochondrial population. Exercise training may also have contributed to mitochondrial quality control which replaces old and/or unhealthy mitochondria with new and/or healthy ones in skeletal muscle. In this review paper, the molecular mechanisms regulating mitochondrial biogenesis and mitophagy and the coordination between the opposing processes is involved in the cellular adaptation to endurance exercise training in skeletal muscle will be discussed.

• Biomedical Science Letters
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• v.17 no.3
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• pp.177-184
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• 2011

Potassium cyanate (KOCN) is an inorganic compound and induces the carbamylation of proteins with cytotoxic effects on human cells. Although there is a potential cytotoxic molecule, the role of KOCN on the apoptosis of cancer cell is not well understood. The present study investigated the effects of KOCN on the human colorectal cancer cell line, HCT 116 cells. To understand the anti-cancer effect of KOCN on HCT 116 cells, we examined alteration of apoptosis, the intracellular $Ca^{2+}$ concentration, the intracellular signaling pathway and generation of reactive oxygen species (ROS) in these cells treated with KOCN. The apoptosis of HCT 116 cells was induced by KOCN in a dose-dependent manner at 24 hours and 48 hours, respectively. The apoptosis was processed via the cleavage of poly ADP-ribose polymerase (PARP) and activation of caspase 3 in HCT 116 cells. KOCN induced the elevation of intracellular $Ca^{2+}$ concentration and changed the expressions of Bcl-2 family proteins. The pro-apoptotic Bax was continuously up-regulated, and the anti-apoptotic Bcl-2 was down-regulated by KOCN. KOCN also induced the hyperpolarization of mitochondria and the generation of ROS in HCT 116 cells. Taken together, these results indicate that KOCN induces the apoptosis of HCT 116 cells by disruption of $Ca^{2+}$ homeostasis and via mitochondrial pathway. This study provides the compound that may be used as a potent agent for the treatment of colorectal cancer.

• Molecules and Cells
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• v.43 no.8
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• pp.671-685
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• 2020

The regulator of calcineurin (RCAN) was first reported as a novel gene called DSCR1, encoded in a region termed the Down syndrome critical region (DSCR) of human chromosome 21. Genome sequence comparisons across species using bioinformatics revealed three members of the RCAN gene family, RCAN1, RCAN2, and RCAN3, present in most jawed vertebrates, with one member observed in most invertebrates and fungi. RCAN is most highly expressed in brain and striated muscles, but expression has been reported in many other tissues, as well, including the heart and kidneys. Expression levels of RCAN homologs are responsive to external stressors such as reactive oxygen species, Ca²⁺, amyloid β, and hormonal changes and upregulated in pathological conditions, including Alzheimer's disease, cardiac hypertrophy, diabetes, and degenerative neuropathy. RCAN binding to calcineurin, a Ca²⁺/calmodulin-dependent phosphatase, inhibits calcineurin activity, thereby regulating different physiological events via dephosphorylation of important substrates. Novel functions of RCANs have recently emerged, indicating involvement in mitochondria homeostasis, RNA binding, circadian rhythms, obesity, and thermogenesis, some of which are calcineurin-independent. These developments suggest that besides significant contributions to DS pathologies and calcineurin regulation, RCAN is an important participant across physiological systems, suggesting it as a favorable therapeutic target.

• Biomedical Science Letters
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• v.29 no.3
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• pp.121-129
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• 2023

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects millions of people worldwide. The conventional treatment model for PD have harmful side effects, such as dyskinesia, hallucinations, nausea, and fatigue, and are expensive. As a result, natural products derived from medicinal herbs, fruits, and vegetables have emerged as potential therapeutic strategies for PD. These natural products have been traditionally used to treat various diseases and have been shown to possess anti-oxidative and anti-inflammatory properties, as well as inhibitory roles in protein misfolding, mitochondrial homeostasis, neuroinflammation and other neuroprotective processes. In addition, they have fewer side effects and are generally less expensive than conventional drugs. It also discusses the limitations of current treatments and the potential of natural remedies derived from plants to treat PD in new ways or as supplements to existing treatments. The multifunctional mechanisms of medicinal plants that may be utilized to treat PD are also discussed, including the modulation of neurotransmitter systems, the enhancement of neurotrophic factors, and the inhibition of apoptosis. While more research is needed to fully understand their mechanisms of action and efficacy, natural products have the potential to provide safer and more effective treatment options for patients with PD.

• Experimental and Molecular Medicine
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• v.50 no.11
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• pp.5.1-5.14
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• 2018

Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of intervertebral disc degeneration (IVDD). Sirtuin 3 (SIRT3), a sirtuin family protein located in mitochondria, is essential for mitochondrial homeostasis; however, the role of SIRT3 in the process of IVDD has remained elusive. Here, we explored the expression of SIRT3 in IVDD in vivo and in vitro; we also explored the role of SIRT3 in senescence, apoptosis, and mitochondrial homeostasis under oxidative stress. We subsequently activated SIRT3 using honokiol to evaluate its therapeutic potential for IVDD. We assessed SIRT3 expression in degenerative nucleus pulposus (NP) tissues and oxidative stress-induced nucleus pulposus cells (NPCs). SIRT3 was knocked down by lentivirus and activated by honokiol to determine its role in oxidative stress-induced NPCs. The mechanism by which honokiol affected SIRT3 regulation was investigated in vitro, and the therapeutic potential of honokiol was assessed in vitro and in vivo. We found that the expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol ($10{\mu}M$) improved the viability of NPCs under oxidative stress and promoted their properties of anti-oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-$1{\alpha}$ signaling pathway. Moreover, honokiol treatment ameliorated IVDD in rats. Our study indicated that SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD.

• Biomolecules & Therapeutics
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• v.31 no.4
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• pp.446-455
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• 2023

The mechanistic functions of 3-deoxysappanchalcone (3-DSC), a chalcone compound known to have many pharmacological effects on lung cancer, have not yet been elucidated. In this study, we identified the comprehensive anti-cancer mechanism of 3-DSC, which targets EGFR and MET kinase in drug-resistant lung cancer cells. 3-DSC directly targets both EGFR and MET, thereby inhibiting the growth of drug-resistant lung cancer cells. Mechanistically, 3-DSC induced cell cycle arrest by modulating cell cycle regulatory proteins, including cyclin B1, cdc2, and p27. In addition, concomitant EGFR downstream signaling proteins such as MET, AKT, and ERK were affected by 3-DSC and contributed to the inhibition of cancer cell growth. Furthermore, our results show that 3-DSC increased redox homeostasis disruption, ER stress, mitochondrial depolarization, and caspase activation in gefitinib-resistant lung cancer cells, thereby abrogating cancer cell growth. 3-DSC induced apoptotic cell death which is regulated by Mcl-1, Bax, Apaf-1, and PARP in gefitinib-resistant lung cancer cells. 3-DSC also initiated the activation of caspases, and the pan-caspase inhibitor, Z-VAD-FMK, abrogated 3-DSC induced-apoptosis in lung cancer cells. These data imply that 3-DSC mainly increased mitochondria-associated intrinsic apoptosis in lung cancer cells to reduce lung cancer cell growth. Overall, 3-DSC inhibited the growth of drug-resistant lung cancer cells by simultaneously targeting EGFR and MET, which exerted anti-cancer effects through cell cycle arrest, mitochondrial homeostasis collapse, and increased ROS generation, eventually triggering anti-cancer mechanisms. 3-DSC could potentially be used as an effective anti-cancer strategy to overcome EGFR and MET target drug-resistant lung cancer.

• Nutrition Research and Practice
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• v.4 no.6
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• pp.462-469
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• 2010

Protamine has been widely used as a pharmaceutical product and natural food preservative. However, few studies have been conducted to assess the beneficial function of dietary protamine. This study examined the effects of dietary salmon protamine on serum and liver lipid levels and the expression levels of genes encoding proteins involved in lipid homeostasis in the liver of rats. Groups of male Wistar rats were fed AIN93G diet containing 2% or 5% protamine. After 4 weeks of feeding these diets, markedly decreased serum and liver cholesterol (CHOL) and triacylglycerol levels were noted. Increased activity of liver carnitine palmitoyltransferase-2 and acyl-CoA oxidase, which are key enzymes of fatty acid ${\beta}$-oxidation in the mitochondria and peroxisomes, was found in rats fed on protamine. Furthermore, rats fed protamine showed enhanced fecal excretion of CHOL and bile acid and increased liver mRNA expression levels of ATP-binding cassette (ABC) G5 and ABCG8, which form heterodimers and play a major role in the secretion of CHOL into bile. The decrease in triacylglycerol levels in protamine-fed rats was due to the enhancement of liver ${\beta}$-oxidation. Furthermore, rats fed protamine exhibited decreased CHOL levels through the suppression of CHOL and bile acid absorption and the enhancement of CHOL secretion into bile. These results suggest that dietary protamine has beneficial effects that may aid in the prevention of lifestyle-related diseases such as hyperlipidemia and atherosclerosis.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.6
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• pp.509-516
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• 2014

Radiation therapy for variety of human solid tumors utilizes mechanism of cell death after DNA damage caused by radiation. In response to DNA damage, cytochrome c was released from mitochondria by activation of pro-apoptotic Bcl-2 family proteins, and then elicits massive $Ca^{2+}$ release from the ER that lead to cell death. It was also suggested that irradiation may cause the deregulation of $Ca^{2+}$ homeostasis and trigger programmed cell death and regulate death specific enzymes. Thus, in this study, we investigated how cellular $Ca^{2+}$ metabolism in RKO cells, in comparison to radiation-resistant A549 cells, was altered by gamma (${\gamma}$)-irradiation. In irradiated RKO cells, $Ca^{2+}$ influx via activation of NCX reverse mode was enhanced and a decline of $[Ca^{2+}]_i$ via forward mode was accelerated. The amount of $Ca^{2+}$ released from the ER in RKO cells by the activation of $IP_3$ receptor was also enhanced by irradiation. An increase in $[Ca^{2+}]_i$ via SOCI was enhanced in irradiated RKO cells, while that in A549 cells was depressed. These results suggest that ${\gamma}$-irradiation elicits enhancement of cellular $Ca^{2+}$ metabolism in radiation-sensitive RKO cells yielding programmed cell death.

• IMMUNE NETWORK
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• v.6 no.3
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• pp.128-137
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• 2006

Background: Apoptosis is a physiologic phenomenon involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. The mouse myeloma cell P3-X63-Ag8.653 (v653) is an HGPRT deficient $(HGPRT^-)$ mutant strain. High dependency on de novo transcription and translation of aminopterin induced apoptosis of this cell seems to be an ideal experimental system for searching apoptosis-induced genes. Methods & Results: For searching apoptosis-related genes we carried out GE-array (dot blot), Affymetrix GeneChip analysis, Northern analysis and differential display-PCR techniques. The chip data were analyzed with three different programs. 66 genes were selected through Affymetrix GeneChip analyses. All genes selected were classified into 8 groups according to their known functions. They were Genes of 1) Cell growth/maintenance/death/enzyme, 2) Cell cycle, 3) Chaperone, 4) Cancer/disease-related genes, 5) Mitochondria, 6) Membrane protein/signal transduction, 7) Nuclear protein/nucleic acid binding/transcription binding and 8) Translation factor. Among these groups number of genes were the largest in the genes of cell growth/maintenance/death/enzyme. Expression signals of most of all groups were peaked at 3 hour of apoptosis except genes of Nuclear protein/nucleic acid binding/transcription factor which showed maximum signal at 1 hour. Conclusion: This study showed induction of wide range of proapoptotic factors which accelerate cell death at various stage of cell death. In addition apoptosis studied in this research can be classified as a type 2 which involves cytochrome c and caspase 9 especially in early stages of death. But It also has progressed to type 1 in late stage of the death process.