pISSN 1226-4512 eISSN 2093-3827

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    January, 2021 | Volume 25, No. 1
  • Review Article 2021-01-01

    Genetic approaches toward understanding the individual variation in cardiac structure, function and responses to exercise training

    Minsun Kim and Seung Kyum Kim

    Abstract : Cardiovascular disease (CVD) accounts for approximately 30% of all deaths worldwide and its prevalence is constantly increasing despite advancements in medical treatments. Cardiac remodeling and dysfunction are independent risk factors for CVD. Recent studies have demonstrated that cardiac structure and function are genetically influenced, suggesting that understanding the genetic basis for cardiac structure and function could provide new insights into developing novel therapeutic targets for CVD. Regular exercise has long been considered a robust nontherapeutic method of treating or preventing CVD. However, recent studies also indicate that there is inter-individual variation in response to exercise. Nevertheless, the genetic basis for cardiac structure and function as well as their responses to exercise training have yet to be fully elucidated. Therefore, this review summarizes accumulated evidence supporting the genetic contribution to these traits, including findings from population-based studies and unbiased large genomic-scale studies in humans.

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  • Original Article 2021-01-01

    Whitening effect of novel peptide mixture by regulating melanosome biogenesis, transfer and degradation

    Eung-Ji Lee, Jandi Kim, Min Kyeong Jeong, Young Min Lee, Yong Ji Chung, and Eun Mi Kim

    Abstract : Peptides are short chain of amino acids linked by peptide bonds. They are widely used as effective and biocompatible active ingredients in cosmetic industry. In this study, we developed novel peptide mixture and identified its anti-pigmentation effect on melanocytes and keratinocytes. Our results revealed that peptide mixture inhibited melanosome biogenesis through the regulation of microphthalmia-associated transcription factor, a key factor of melanogenesis in melanocytes. And we observed that peptide mixture inhibited melanosome uptake through the reduction of protease-activated receptor 2, a phagocytosis-related receptor in keratinocytes. Furthermore, peptide mixture activated autophagy system resulting in degradation of transferred melanosomes in keratinocytes. The anti-pigmentation effect of multi-targeting peptide mixture was assessed in a human skin equivalent model (MelanoDerm). Melanin contents in epidermal layer were significantly decreased by topical treatment of peptide mixture, suggesting that it can be applied as a novel cosmetics material having a whitening function.

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  • Original Article 2021-01-01

    Gamma-aminobutyric acid-salt attenuated high cholesterol/high salt diet induced hypertension in mice

    Myeongjoo Son, Seyeon Oh, Hye Sun Lee, Junwon Choi, Bae-Jin Lee, Joung-Hyun Park, Chul Hyun Park, Kuk Hui Son, and Kyunghee Byun

    Abstract : Excessive salt intake induces hypertension, but several gamma-aminobutyric acid (GABA) supplements have been shown to reduce blood pressure. GABAsalt, a fermented salt by L. brevis BJ20 containing GABA was prepared through the post-fermentation with refined salt and the fermented GABA extract. We evaluated the effect of GABA-salt on hypertension in a high salt, high cholesterol diet induced mouse model. We analyzed type 1 macrophage (M1) polarization, the expression of M1 related cytokines, GABA receptor expression, endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation, and medial thicknesses in mice model. GABA-salt attenuated diet-induced blood pressure increases, M1 polarization, and TNF-α and inducible nitric oxide synthase (NOS) levels in mouse aortas, and in salt treated macrophages in vitro. Furthermore, GABA-salt induced higher GABAB receptor and endothelial NOS (eNOS) and eNOS phosphorylation levels than those observed in salt treated ECs. In addition, GABA-salt attenuated EC dysfunction by decreasing the levels of adhesion molecules (E-selectin, Intercellular Adhesion Molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) and of von Willebrand Factor and reduced EC death. GABA-salt also reduced diet-induced reductions in the levels of eNOS, phosphorylated eNOS, VSMC proliferation and medial thickening in mouse aortic tissues, and attenuated Endothelin-1 levels in salt treated VSMCs. In summary, GABA-salt reduced high salt, high cholesterol diet induced hypertension in our mouse model by reducing M1 polarization, EC dysfunction, and VSMC proliferation.

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  • Original Article 2021-01-01

    Ovariectomy, but not orchiectomy, exacerbates metabolic syndrome after maternal high-fructose intake in adult offspring

    Mina Kim and Inkyeom Kim

    Abstract : High fructose diet is associated with the global metabolic syndrome (MtS) pandemic. MtS develops in early life, depending on prenatal and postnatal nutritional status. We hypothesized that ovariectomy increases the chances of developing MtS in adult offspring following high fructose intake by the mother. Pregnant C57BL/6J mouse dams drank water with or without 20% fructose during pregnancy and lactation. After weaning, the pups were fed regular chow. The offspring were evaluated until they were 7 months of age after the mice in each group, both sexes, were gonadectomized at 4 weeks of age. The offspring (both sexes) of the dams who had high fructose intake developed MtS. In the offspring of dams who drank tap water, orchiectomy increased the body weight gain and body fat accumulation, while ovariectomy increased the body fat accumulation as compared to the sham controls. In the offspring of dams with high fructose intake, orchiectomy decreased the body weight gain, body fat accumulation, visceral adiposity, and glucose intolerance, while ovariectomy exacerbated all of them as compared to the sham operations. These data indicate that ovariectomy encourages the development of MtS in adult offspring after maternal high fructose intake, while orchiectomy prevents the development of MtS. The sex difference indicates that male and female sex hormones play contradictory roles in the development of MtS.

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  • Original Article 2021-01-01

    Oxidative stress-induced aberrant G9a activation disturbs RE-1-containing neuron-specific genes expression, leading to degeneration in human SH-SY5Y neuroblastoma cells

    Ho-Tae Kim, Takbum Ohn, Sin-Gu Jeong, Anji Song, Chul Ho Jang, and Gwang-Won Cho

    Abstract : Oxidative stress-induced neurodegeneration is one of several etiologies underlying neurodegenerative disease. In the present study, we investigated the functional role of histone methyltransferase G9a in oxidative stress-induced degeneration in human SH-SY5Y neuroblastoma cells. Cell viability significantly decreased on H2O2 treatment; however, treatment with the G9a inhibitor BIX01294 partially attenuated this effect. The expression of neuron-specific genes also decreased in H2O2- treated cells; however, it recovered on G9a inhibition. H2O2-treated cells showed high levels of H3K9me2 (histone H3 demethylated at the lysine 9 residue), which is produced by G9a activation; BIX01294 treatment reduced aberrant activation of G9a. H3K9me2 occupancy of the RE-1 site in neuron-specific genes was significantly increased in H2O2-treated cells, whereas it was decreased in BIX01294-treated cells. The differentiation of H2O2-treated cells also recovered on G9a inhibition by BIX01294. Consistent results were observed when used another G9a inhibitor UCN0321. These results demonstrate that oxidative stress induces aberrant activation of G9a, which disturbs the expression of neuron-specific genes and progressively mediates neuronal cell death. Moreover, a G9a inhibitor can lessen aberrant G9a activity and prevent neuronal damage. G9a inhibition may therefore contribute to the prevention of oxidative stress-induced neurodegeneration

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  • Original Article 2021-01-01

    Ref-1 protects against FeCl3-induced thrombosis and tissue factor expression via the GSK3β–NF-κB pathway

    Ikjun Lee, Harsha Nagar, Seonhee Kim, Su-jeong Choi, Shuyu Piao, Moonsang Ahn, Byeong Hwa Jeon, Sang-Ha Oh, Shin Kwang Kang, and Cuk-Seong Kim

    Abstract : Arterial thrombosis and its associated diseases are considered to constitute a major healthcare problem. Arterial thrombosis, defined as blood clot formation in an artery that interrupts blood circulation, is associated with many cardiovascular diseases. Oxidative stress is one of many important factors that aggravates the pathophysiological process of arterial thrombosis. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ref-1) has a multifunctional role in cells that includes the regulation of oxidative stress and anti-inflammatory function. The aim of this study was to investigate the therapeutic effect of adenovirus-mediated Ref-1 overexpression on arterial thrombosis induced by 60% FeCl3 solution in rats. Blood flow was measured to detect the time to occlusion, thrombus formation was detected by hematoxylin and eosin staining, reactive oxygen species (ROS) levels were detected by high-performance liquid chromatography, and the expression of tissue factor and other proteins was detected by Western blot. FeCl3 aggravated thrombus formation in carotid arteries and reduced the time to artery occlusion. Ref-1 significantly delayed arterial obstruction via the inhibition of thrombus formation, especially by downregulating tissue factor expression through the Akt-GSK3β-NF-κB signaling pathway. Ref1 also reduced the expression of vascular inflammation markers ICAM-1 and VCAM1, and reduced the level of ROS that contributed to thrombus formation. The results showed that adenovirus-mediated Ref-1 overexpression reduced thrombus formation in the rat carotid artery. In summary, Ref-1 overexpression had anti-thrombotic effects in a carotid artery thrombosis model and could be a target for the treatment of arterial thrombosis.

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  • Original Article 2021-01-01

    The effect of adenosine triphosphate on propofol-induced myopathy in rats: a biochemical and histopathological evaluation

    Kezban Tuna Ozkaloglu Erdem, Zehra Bedir, Irem Ates, Ufuk Kuyrukluyildiz, Taha Abdulkadir Coban, Gulce Naz Yazici, Yusuf Kemal Arslan, Zeynep Suleyman, and Halis Suleyman

    Abstract : Propofol infusion syndrome characterized by rhabdomyolysis, metabolic acidosis, kidney, and heart failure has been reported in long-term propofol use for sedation. It has been reported that intracellular adenosine triphosphate (ATP) is reduced in rhabdomyolysis. The study aims to investigate the protective effect of ATP against possible skeletal muscle damage of propofol in albino Wistar male rats biochemically and histopathologically. PA-50 (n = 6) and PA-100 (n = 6) groups of animals was injected intraperitoneally to 4 mg/kg ATP. An equal volume (0.5 ml) of distilled water was administered intraperitoneally to the P-50, P-100, and HG groups. One hour after the administration of ATP and distilled water, 50 mg/kg propofol was injected intraperitoneally to the P-50 and PA-50 groups. This procedure was repeated once a day for 30 days. The dose of 100 mg/kg propofol was injected intraperitoneally to the P-100 and PA-100 groups. This procedure was performed three times with an interval of 1 days. Our experimental results showed that propofol increased serum CK, CK-MB, creatinine, BUN, TP I, ALT, AST levels, and muscle tissue MDA levels at 100 mg/kg compared to 50 mg/kg and decreased tGSH levels. At a dose of 100 mg/ kg, propofol caused more severe histopathological damage compared to 50 mg/ kg. It was found that ATP prevented propofol-induced muscle damage and organ dysfunction at a dose of 50 mg/kg at a higher level compared to 100 mg/kg. ATP may be useful in the treatment of propofol-induced rhabdomyolysis and multiple organ damage.

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  • Original Article 2021-01-01

    Immunohistochemical detection of GluA1 subunit of AMPA receptor in the rat nucleus accumbens following cocaine exposure

    Wen Ting Cai, Joonyeup Han, Wha Young Kim, and Jeong-Hoon Kim

    Abstract : α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are differentially regulated in the nucleus accumbens (NAcc) of the brain after cocaine exposure. However, these results are supported only by biochemical and electrophysiological methods, but have not been validated with immunohistochemistry. To overcome the restriction of antigen loss on the postsynaptic target molecules that occurs during perfusion-fixation, we adopted an immersion-fixation method that enabled us to immunohistochemically quantify the expression levels of the AMPA receptor GluA1 subunit in the NAcc. Interestingly, compared to saline exposure, cocaine significantly increased the immunofluorescence intensity of GluA1 in two sub-regions, the core and the shell, of the NAcc on withdrawal day 21 following cocaine exposure, which led to locomotor sensitization. Increases in GluA1 intensity were observed in both the extra-post synaptic density (PSD) and PSD areas in the two sub-regions of the NAcc. These results clearly indicate that AMPA receptor plasticity, as exemplified by GluA1, in the NAcc can be visually detected by immunohistochemistry and confocal imaging. These results expand our understanding of the molecular changes occurring in neuronal synapses by adding a new form of analysis to conventional biochemical and electrophysiological methods.

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  • Original Article 2021-01-01

    Nootkatol prevents ultraviolet radiation-induced photoaging via ORAI1 and TRPV1 inhibition in melanocytes and keratinocytes

    Joo Han Woo, Da Yeong Nam, Hyun Jong Kim, Phan Thi Lam Hong, Woo Kyung Kim, and Joo Hyun Nam

    Abstract : Skin photoaging occurs due to chronic exposure to solar ultraviolet radiation (UV), the main factor contributing to extrinsic skin aging. Clinical signs of photoaging include the formation of deep, coarse skin wrinkles and hyperpigmentation. Although melanogenesis and skin wrinkling occur in different skin cells and have different underlying mechanisms, their initiation involves intracellular calcium signaling via calcium ion channels. The ORAI1 channel initiates melanogenesis in melanocytes, and the TRPV1 channel initiates MMP-1 production in keratinocytes in response to UV stimulation. We aimed to develop a drug that may simultaneously inhibit ORAI1 and TRPV1 activity to help prevent photoaging. We synthesized nootkatol, a chemical derivative of valencene. TRPV1 and ORAI1 activities were measured using the whole-cell patch-clamp technique. Intracellular calcium concentration [Ca2+]i was measured using calcium-sensitive fluorescent dye (Fura-2 AM). UV-induced melanin formation and MMP-1 production were quantified in B16F10 melanoma cells and HaCaT cells, respectively. Our results indicate that nootkatol (90 μM) reduced TRPV1 current by 94% ± 2% at –60 mV and ORAI1 current by 97% ± 1% at –120 mV. Intracellular calcium signaling was significantly inhibited by nootkatol in response to ORAI1 activation in human primary melanocytes (51.6% ± 0.98% at 100 μM). Additionally, UV-induced melanin synthesis was reduced by 76.38% ± 5.90% in B16F10 melanoma cells, and UV-induced MMP-1 production was reduced by 59.33% ± 1.49% in HaCaT cells. In conclusion, nootkatol inhibits both TRPV1 and ORAI1 to prevent photoaging, and targeting ion channels may be a promising strategy for preventing photoaging.

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January, 2021
Vol.25 No.1

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