Publications by authors named "Ki Woo Kim"

128 Publications

Ultrastructure of phytoplasma-infected jujube leaves with witches' broom disease.

Micron 2021 09 29;148:103108. Epub 2021 Jun 29.

Department of Ecology and Environmental System, Kyungpook National University, Sangju, 37224, South Korea; Tree Diagnostic Center, Kyungpook National University, Sangju, 37224, South Korea. Electronic address:

The subcellular characteristics of phytoplasma-infected jujube (Ziziphus jujuba) leaves were investigated using transmission electron microscopy. Midrib fragments of witches' broom-diseased jujube leaves were collected from abnormally small leaves at an early stage of branch clustering. The diseased jujube leaves showed multivesicular bodies (MVBs) with vesicles and tubules in the phloem parenchyma cells and sieve elements. The MVBs were connected to the plasma membrane appressed to the cell wall. There were increased callose collars at the pore-plasmodesma unit ends of the sieve elements in the diseased leaves than in control leaves. The proliferation of MVBs in the diseased jujube leaves could be associated with endoplasmic reticulum stress-dependent exosome release. The phytoplasma produced pleomorphic cells in sieve elements. Several types of putative extracellular structures were observed on the phytoplasma cells: (i) fimbriae-like threads, (ii) pili-like projections, (iii) flagella-like appendages, and (iv) tube-like structures. This study provides novel insights into intracellular obligate cell wall-less prokaryotes and host phloem structures.
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http://dx.doi.org/10.1016/j.micron.2021.103108DOI Listing
September 2021

Hypothalamic primary cilium: A hub for metabolic homeostasis.

Exp Mol Med 2021 Jul 1;53(7):1109-1115. Epub 2021 Jul 1.

Departments of Oral Biology and Applied Biological Science, BK21 Four, Yonsei University College of Dentistry, Seoul, 03722, Korea.

Obesity is a global health problem that is associated with adverse consequences such as the development of metabolic disorders, including cardiovascular disease, neurodegenerative disorders, and type 2 diabetes. A major cause of obesity is metabolic imbalance, which results from insufficient physical activity and excess energy intake. Understanding the pathogenesis of obesity, as well as other metabolic disorders, is important in the development of methods for prevention and therapy. The coordination of energy balance takes place in the hypothalamus, a major brain region that maintains body homeostasis. The primary cilium is an organelle that has recently received attention because of its role in controlling energy balance in the hypothalamus. Defects in proteins required for ciliary function and formation, both in humans and in mice, have been shown to cause various metabolic disorders. In this review, we provide an overview of the critical functions of primary cilia, particularly in hypothalamic areas, and briefly summarize the studies on the primary roles of cilia in specific neurons relating to metabolic homeostasis.
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http://dx.doi.org/10.1038/s12276-021-00644-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333261PMC
July 2021

Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction.

Front Cell Dev Biol 2021 26;9:646803. Epub 2021 Mar 26.

Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.

The receptor activator of nuclear factor-kappa B ligand (RANKL) mediates osteoclast differentiation and functions by inducing Ca oscillations, activating mitogen-activated protein kinases (MAPKs), and activating nuclear factor of activated T-cells type c1 (NFATc1) via the RANK and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) interaction. Reactive oxygen species (ROS) also plays an important role during osteoclastogenesis and Sestrin2, an antioxidant, maintains cellular homeostasis upon stress injury via regulation of ROS, autophagy, and inflammation. However, the role of Sestrin2 in osteoclastogenesis remains unknown. In this study, we investigated the role of Sestrin2 in the RANKL-RANK-TRAF6 signaling pathway during osteoclast differentiation. Deletion of () increased bone mass and reduced the number of multinucleated osteoclasts on bone surfaces. RANKL-induced osteoclast differentiation and function decreased in knockout (KO) bone marrow-derived monocytes/macrophages (BMMs) due to inhibition of NFATc1 expression, but osteoblastogenesis was not affected. mRNA expression of RANKL-induced specific osteoclastogenic genes and MAPK protein expression were lower in KO BMMs than wild-type (WT) BMMs after RANKL treatment. However, the deletion did not affect ROS generation or intracellular Ca oscillations during osteoclastogenesis. In contrast, the interaction between TRAF6 and p62 was reduced during osteoclasts differentiation in KO BMMs. The reduction in the TRAF6/p62 interaction and TRAP activity in osteoclastogenesis in KO BMMs was recovered to the WT level upon expression of Flag- in KO BMMs. These results suggest that Sestrin2 has a novel role in bone homeostasis and osteoclasts differentiation through regulation of NFATc1 and the TRAF6/p62 interaction.
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http://dx.doi.org/10.3389/fcell.2021.646803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033026PMC
March 2021

Methanol fixation for scanning electron microscopy of plants.

Authors:
Ki Woo Kim

Appl Microsc 2020 May 25;50(1):10. Epub 2020 May 25.

School of Ecology and Environmental System, Kyungpook National University, Sangju, 37224, Republic of Korea.

Plant specimens for scanning electron microscopy (SEM) are commonly treated using standard protocols. Conventional fixatives consist of toxic chemicals such as glutaraldehyde, paraformaldehyde, and osmium tetroxide. In 1996, methanol fixation was reported as a rapid alternative to the standard protocols. If specimens are immersed in methanol for 30 s or longer and critical-point dried, they appear to be comparable in preservation quality to those treated with the chemical fixatives. A modified version that consists of methanol fixation and ethanol dehydration was effective at preserving the tissue morphology and dimensions. These solvent-based fixation and dehydration protocols are regarded as rapid and simple alternatives to standard protocols for SEM of plants.
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http://dx.doi.org/10.1186/s42649-020-00028-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818355PMC
May 2020

-Coumaric Acid Enhances Hypothalamic Leptin Signaling and Glucose Homeostasis in Mice via Differential Effects on AMPK Activation.

Int J Mol Sci 2021 Jan 31;22(3). Epub 2021 Jan 31.

School of Medicine, Tan Tao University, Duc Hoa 850000, Long An, Vietnam.

AMP-activated protein kinase (AMPK) plays a crucial role in the regulation of energy homeostasis in both peripheral metabolic organs and the central nervous system. Recent studies indicated that -Coumaric acid (CA), a hydroxycinnamic phenolic acid, potentially activated the peripheral AMPK pathway to exert beneficial effects on glucose metabolism in vitro. However, CA's actions on central AMPK activity and whole-body glucose homeostasis have not yet been investigated. Here, we reported that CA exhibited different effects on peripheral and central AMPK activation both in vitro and in vivo. Specifically, while CA treatment promoted hepatic AMPK activation, it showed an inhibitory effect on hypothalamic AMPK activity possibly by activating the S6 kinase. Furthermore, CA treatment enhanced hypothalamic leptin sensitivity, resulting in increased proopiomelanocortin (POMC) expression, decreased agouti-related peptide (AgRP) expression, and reduced daily food intake. Overall, CA treatment improved blood glucose control, glucose tolerance, and insulin sensitivity. Together, these results suggested that CA treatment enhanced hypothalamic leptin signaling and whole-body glucose homeostasis, possibly via its differential effects on AMPK activation.
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http://dx.doi.org/10.3390/ijms22031431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867021PMC
January 2021

Single- or double-membrane-bound vesicles and P, Ca, and Fe-containing granules in Xanthomonas citri cultured on a solid medium.

Micron 2021 04 27;143:103024. Epub 2021 Jan 27.

Department of Ecology and Environmental System, Kyungpook National University, Sangju, 37224, South Korea; Tree Diagnostic Center, Kyungpook National University, Sangju, 37224, South Korea. Electronic address:

The organelle-like structures of Xanthomonas citri, a bacterial pathogen that causes citrus canker, were investigated using an analytical transmission electron microscope. After high-pressure freezing, the bacteria were then freeze-substituted for imaging and element analysis. Miniscule electron-dense structures of varying shapes without a membrane enclosure were frequently observed near the cell poles in a 3-day culture. The bacteria formed cytoplasmic electron-dense spherical structures measuring approximately 50 nm in diameter. Furthermore, X. citri produced electron-dense or translucent ellipsoidal intracellular or extracellular granules. Single- or double-membrane-bound vesicles, including outer-inner membrane vesicles, were observed both inside and outside the cells. Most cells had been lysed in the 3-week X. citri culture, but they harbored one or two electron-dense spherical structures. Contrast-inverted scanning transmission electron microscopy images revealed distinct white spherical structures within the cytoplasm of X. citri. Likewise, energy-dispersive X-ray spectrometry showed the spatial heterogeneity and co-localization of phosphorus, oxygen, calcium, and iron only in the cytoplasmic electron-dense spherical structures, thus corroborating the nature of polyphosphate granules.
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http://dx.doi.org/10.1016/j.micron.2021.103024DOI Listing
April 2021

Morphology and surface characteristics of the anamorphic stage of powdery mildew Erysiphe australiana on crape myrtle leaves.

Authors:
Ki Woo Kim

Micron 2021 04 22;143:103013. Epub 2021 Jan 22.

School of Ecology and Environmental System, Kyungpook National University, Sangju, 37224, Republic of Korea; Tree Diagnostic Center, Kyungpook National University, Sangju, 37224, Republic of Korea. Electronic address:

The morphology and surface characteristics of the powdery mildew Erysiphe australiana growing on crape myrtle leaves were observed with field emission scanning electron microscopy. The powdery mildew infection caused distortion and withering of the leaves, and nearly all external parts such as flowers, petioles, and branches were covered by the whitish colonies. Hyphal proliferation was prevalent on the adaxial surface of the powdery mildew-infected leaves. Globose ascocarp initials with hyphal aggregations were frequently seen on the leaf surface. Collapsed conidia showed longitudinal striations or ridges on the surface and deep linear wrinkling. Foot-cells were straight and grew at right angles from the vegetative hyphae. The conidiophores had fragmented, cylindrical, non-chained conidia which were produced singly at the apex of the conidiophores. The germ tubes formed intercalary multi-lobed appressoria and the conidia produced filiform protrusions emerging from subterminal positions. This study visualized previously unknown structures of E. australiana such as the ascocarp initials, filiform protrusions on conidia, and multi-lobed appressoria on germ tubes. These observations will facilitate the identification and taxonomy of this fungus and its allied species.
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http://dx.doi.org/10.1016/j.micron.2021.103013DOI Listing
April 2021

β-Neoendorphin Enhances Wound Healing by Promoting Cell Migration in Keratinocyte.

Molecules 2020 Oct 12;25(20). Epub 2020 Oct 12.

Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Korea.

The skin is the largest and a remarkably plastic organ that serves as a protective barrier against environmental stimuli and injuries throughout life. Skin injuries are serious health problems, and wound healing is a critical process to replace devitalized cellular and tissue structures. Although some endogenous opioids are known to be involved in the modulation of wound healing, it remains to be determined whether the β-neoendorphin (β-NEP), an endogenous opioid, has beneficial effects on wound repair in human keratinocyte. In this study, we found that β-NEP accelerated wound repair through activation of mitogen-activated protein kinase (MAPK)/Erk1/2 signaling pathways in human keratinocytes. Moreover, the wound healing effect of β-NEP is mainly through the acceleration of keratinocyte migration without affecting cell proliferation. Therefore, our studies reveal that β-NEP plays an important role in the regulation of wound repair and suggest a therapeutic strategy to promote wound healing using β-NEP.
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http://dx.doi.org/10.3390/molecules25204640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587199PMC
October 2020

Ventromedial hypothalamic primary cilia control energy and skeletal homeostasis.

J Clin Invest 2021 01;131(1)

Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea.

Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH primary cilia are not yet known. In this study, we identify VMH primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88-KOSF-1) using steroidogenic factor 1-Cre (SF-1-Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone-density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function and was also associated with insulin and leptin resistance. The effect of bone-density accrual was independent of obesity, as it was caused by decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88-KOSF-1 and VMH primary cilia knockdown mice. Overall, our current study identifies VMH primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis.
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http://dx.doi.org/10.1172/JCI138107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773357PMC
January 2021

Epigallocatechin-3-Gallate (EGCG)-Inducible SMILE Inhibits STAT3-Mediated Hepcidin Gene Expression.

Antioxidants (Basel) 2020 Jun 11;9(6). Epub 2020 Jun 11.

Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Korea.

Hepatic peptide hormone hepcidin, a key regulator of iron metabolism, is induced by inflammatory cytokine interleukin-6 (IL-6) in the pathogenesis of anemia of inflammation or microbial infections. Small heterodimer partner-interacting leucine zipper protein (SMILE)/CREBZF is a transcriptional corepressor of nuclear receptors that control hepatic glucose and lipid metabolism. Here, we examined the role of SMILE in regulating iron metabolism by inflammatory signals. Overexpression of SMILE significantly decreased activation of the Janus kinase 2-signal transducer and activator of transcription 3 (STAT3)-mediated hepcidin production and secretion that is triggered by the IL-6 signal in human and mouse hepatocytes. Moreover, SMILE co-localized and physically interacted with STAT3 in the nucleus in the presence of IL-6, which significantly suppressed binding of STAT3 to the hepcidin gene promoter. Interestingly, epigallocatechin-3-gallate (EGCG), a major component of green tea, induced SMILE expression through forkhead box protein O1 (FoxO1), as demonstrated in FoxO1 knockout primary hepatocytes. In addition, EGCG inhibited IL-6-induced hepcidin expression, which was reversed by SMILE knockdown. Finally, EGCG significantly suppressed lipopolysaccharide-induced hepcidin secretion and hypoferremia through induction of SMILE expression in mice. These results reveal a previously unrecognized role of EGCG-inducible SMILE in the IL-6-dependent transcriptional regulation of iron metabolism.
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http://dx.doi.org/10.3390/antiox9060514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346121PMC
June 2020

Switching Enhancement via a Back-Channel Phase-Controlling Layer for p-Type Copper Oxide Thin-Film Transistors.

ACS Appl Mater Interfaces 2020 Jun 21;12(22):24929-24939. Epub 2020 May 21.

School of Electrical and Electronic Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.

P-type copper oxide (CuO) thin-film transistors (TFTs) with enhanced switching characteristics were fabricated by introducing a sputter-processed capping layer capable of controlling the back-channel phase (labeled as phase-controlling layer, PCL). By optimizing the processing conditions (the deposition power and postdeposition annealing parameters), the switching characteristics of the TFTs achieved a subthreshold swing of 0.11 V dec, an on/off current ratio (/) of 2.81 × 10, and a field-effect mobility (μ) of 0.75 cm V s, a considerable enhancement in performance compared to that of CuO TFTs without the PCL. Through optical/electrical analyses and technology computer-aided design simulations, we determined that the performance improvements were because of the CuO back-channel phase reconstruction through PCL deposition and subsequent annealing. The two factors that occurred during the process, sputtering damage and heat treatment, played key roles in creating the phase reconstruction by inducing a local phase transition that sharply reduced the off-current via controlling back-channel hole conduction. As a sample application, we fabricated a complementary metal oxide semiconductor inverter based on our optimized CuO TFT and an InGaZnO TFT that demonstrated a large inverter voltage gain of >14. The proposed approach opens up advancements in low-power circuit design by expanding the utilization range of oxide TFTs.
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http://dx.doi.org/10.1021/acsami.0c01530DOI Listing
June 2020

Neural regulation of energy and bone homeostasis by the synaptic adhesion molecule Calsyntenin-3.

Exp Mol Med 2020 05 7;52(5):793-803. Epub 2020 May 7.

Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Yonsei-ro 50-1, Seodaemun-gu, Seoul, 03722, Korea.

Neuronal regulation of energy and bone metabolism is important for body homeostasis. Many studies have emphasized the importance of synaptic adhesion molecules in the formation of synapses, but their roles in physiology still await further characterization. Here, we found that the synaptic adhesion molecule Calsyntenin-3 (CLSTN3) regulates energy and bone homeostasis. Clstn3 global knockout mice show reduced body mass with improved leptin sensitivity and increased energy expenditure compared to their wild-type littermates. In addition, Clstn3 knockout mice show reduced marrow volume and cortical bone mass without alteration of trabecular bone microarchitecture. This reduced bone mass is not bone cell-autonomous because neither osteoblast- nor osteoclast-specific Clstn3 knockout mice show bone defects; similarly, in vitro cultures of both Clstn3 knockout osteoblasts and osteoclasts do not show any defects. These reduced body and bone mass phenotypes can be attributed instead to neuronal CLSTN3 because they are recapitulated by pan-neuronal but not sympathetic neuron-specific deletion of Clstn3. This study reveals novel physiological functions of neuronal Clstn3 as a key regulator of energy and bone homeostasis.
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http://dx.doi.org/10.1038/s12276-020-0419-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272401PMC
May 2020

Publisher Correction: In vivo structure of the Legionella type II secretion system by electron cryotomography.

Nat Microbiol 2020 04;5(4):651

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41564-020-0693-1DOI Listing
April 2020

Composite cuticle with heterogeneous layers in the leaf epidermis of Ficus elastica.

Authors:
Ki Woo Kim

Appl Microsc 2019 Dec 24;49(1):19. Epub 2019 Dec 24.

School of Ecology and Environmental System, Kyungpook National University, Sangju, 37224, Republic of Korea.

Two distinct layers in terms of texture and electron density were observed in the leaf cuticle of Ficus elastica using transmission electron microscopy. As depicted in a model, an inner polysaccharide-rich layer and an outer cutin (or cutan)-rich layer may support the composite, heterogeneous concept of the leaf cuticle.
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http://dx.doi.org/10.1186/s42649-019-0022-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818372PMC
December 2019

In vivo structure of the Legionella type II secretion system by electron cryotomography.

Nat Microbiol 2019 12 21;4(12):2101-2108. Epub 2019 Nov 21.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

The type II secretion system (T2SS) is a multiprotein envelope-spanning assembly that translocates a wide range of virulence factors, enzymes and effectors through the outer membrane of many Gram-negative bacteria. Here, using electron cryotomography and subtomogram averaging methods, we reveal the in vivo structure of an intact T2SS imaged within the human pathogen Legionella pneumophila. Although the T2SS has only limited sequence and component homology with the evolutionarily related type IV pilus (T4P) system, we show that their overall architectures are remarkably similar. Despite similarities, there are also differences, including, for example, that the T2SS-ATPase complex is usually present but disengaged from the inner membrane, the T2SS has a much longer periplasmic vestibule and it has a short-lived flexible pseudopilus. Placing atomic models of the components into our electron cryotomography map produced a complete architectural model of the intact T2SS that provides insights into the structure and function of its components, its position within the cell envelope and the interactions between its different subcomplexes.
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http://dx.doi.org/10.1038/s41564-019-0603-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879910PMC
December 2019

Carvedilol improves glucose tolerance and insulin sensitivity in treatment of adrenergic overdrive in high fat diet-induced obesity in mice.

PLoS One 2019 4;14(11):e0224674. Epub 2019 Nov 4.

School of Medicine, Tan Tao University, Long An, Viet Nam.

Catecholamine excess reflecting an adrenergic overdrive of the sympathetic nervous system (SNS) has been proposed to link to hyperleptinemia in obesity and may contribute to the development of metabolic disorders. However, relationship between the catecholamine level and plasma leptin in obesity has not yet been investigated. Moreover, whether pharmacological blockade of the adrenergic overdrive in obesity by the third-generation beta-blocker agents such as carvedilol could help to prevent metabolic disorders is controversial and remains to be determined. Using the high fat diet (HFD)-induced obese mouse model, we found that basal plasma norepinephrine, the principal catecholamine as an index of SNS activity, was persistently elevated and highly correlated with plasma leptin concentration during obesity development. Targeting the adrenergic overdrive from this chronic norepinephrine excess in HFD-induced obesity with carvedilol, a third-generation beta-blocker with vasodilating action, blunted the HFD-induced hepatic glucose over-production by suppressing the induction of gluconeogenic enzymes, and enhanced the muscular insulin signaling pathway. Furthermore, carvedilol treatment in HFD-induced obese mice decreased the enlargement of white adipose tissue and improved the glucose tolerance and insulin sensitivity without affecting body weight and blood glucose levels. Our results suggested that catecholamine excess in obesity might directly link to the hyperleptinemic condition and the therapeutic targeting of chronic adrenergic overdrive in obesity with carvedilol might be helpful to attenuate obesity-related metabolic disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224674PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827914PMC
April 2020

Humanin suppresses receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation AMP-activated protein kinase activation.

Korean J Physiol Pharmacol 2019 Sep 26;23(5):411-417. Epub 2019 Aug 26.

Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 03722, Korea.

Humanin (HN) is a mitochondrial peptide that exhibits cytoprotective actions against various stresses and diseases. HN has been shown to induce the phosphorylation of AMP-activated protein kinase (AMPK), which is a negative regulator of receptor activator of nuclear factor-κB ligand (RANKL). However, the role of HN in osteoclastogenesis or other skeletal disorders remains unknown. Here, we examined whether HN regulates osteoclastogenesis via AMPK activation using bone marrow-derived macrophage (BMM) cultures. Our results show that HN inhibited RANKL-induced osteoclast formation and reduced the expression of genes involved in osteoclastogenesis, including nuclear factor of activated T-cells cytoplasmic 1, osteoclast-associated receptor, cathepsin K, and tartrate-resistant acid phosphatase. Moreover, HN increased the levels of phosphorylated AMPK protein; compound C, an AMPK inhibitor, recovered HN-induced osteoclast differentiation. In addition, we found that HN significantly decreased the levels of RANKL-induced reactive oxygen species in BMMs. Therefore, these results indicate that HN plays an important role in osteoclastogenesis and may function as an inhibitor of bone disorders via AMPK activation.
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http://dx.doi.org/10.4196/kjpp.2019.23.5.411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717796PMC
September 2019

Homer2 and Homer3 modulate RANKL-induced NFATc1 signaling in osteoclastogenesis and bone metabolism.

J Endocrinol 2019 09;242(3):241-249

Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea.

The receptor activator of nuclear factor-kappa B ligand (RANKL) induces osteoclastogenesis by induction of Ca2+ oscillation, calcineurin activation and translocation into the nucleus of nuclear factor of activated T cells type c1 (NFATc1). Homer proteins are scaffold proteins. They regulate Ca2+ signaling by modulating the activity of multiple Ca2+ signaling proteins. Homers 2 and 3, but not Homer1, also independently affect the interaction between NFATc1 and calcineurin. However, to date, whether and how the Homers are involved in osteoclastogenesis remains unknown. In the present study, we investigated Homer2 and Homer3 roles in Ca2+ signaling and NFATc1 function during osteoclast differentiation. Deletion of Homer2/Homer3 (Homer2/3) markedly decreased the bone density of the tibia, resulting in bone erosion. RANKL-induced osteoclast differentiation is greatly facilitated in Homer2/3 DKO bone marrow-derived monocytes/macrophages (BMMs) due to increased NFATc1 expression and nuclear translocation. However, these findings did not alter RANKL-induced Ca2+ oscillations. Of note, RANKL treatment inhibited Homer proteins interaction with NFATc1, but it was restored by cyclosporine A treatment to inhibit calcineurin. Finally, RANKL treatment of Homer2/3 DKO BMMs significantly increased the formation of multinucleated cells. These findings suggest a novel potent mode of bone homeostasis regulation through osteoclasts differentiation. Specifically, we found that Homer2 and Homer3 regulate NFATc1 function through its interaction with calcineurin to regulate RANKL-induced osteoclastogenesis and bone metabolism.
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http://dx.doi.org/10.1530/JOE-19-0123DOI Listing
September 2019

P110β in the ventromedial hypothalamus regulates glucose and energy metabolism.

Exp Mol Med 2019 04 26;51(4):1-9. Epub 2019 Apr 26.

Division of Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, 75390, USA.

Phosphoinositide 3-kinase (PI3K) signaling in hypothalamic neurons integrates peripheral metabolic cues, including leptin and insulin, to coordinate systemic glucose and energy homeostasis. PI3K is composed of different subunits, each of which has several unique isoforms. However, the role of the PI3K subunits and isoforms in the ventromedial hypothalamus (VMH), a prominent site for the regulation of glucose and energy homeostasis, is unclear. Here we investigated the role of subunit p110β in steroidogenic factor-1 (SF-1) neurons of the VMH in the regulation of metabolism. Our data demonstrate that the deletion of p110β in SF-1 neurons disrupts glucose metabolism, rendering the mice insulin resistant. In addition, the deletion of p110β in SF-1 neurons leads to the whitening of brown adipose tissues and increased susceptibility to diet-induced obesity due to blunted energy expenditure. These results highlight a critical role for p110β in the regulation of glucose and energy homeostasis via VMH neurons.
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http://dx.doi.org/10.1038/s12276-019-0249-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486607PMC
April 2019

Hypothalamic inflammation and obesity: a mechanistic review.

Arch Pharm Res 2019 May 5;42(5):383-392. Epub 2019 Mar 5.

Department of Oral Biology, Yonsei University College of Dentistry, BK21 PLUS, Seoul, 03722, Korea.

Obesity is one of the worldwide prevalent disease caused by the imbalance between food intake and energy expenditure. Over a 100 years of research demonstrate that hypothalamus is the critical brain region regulating energy homeostasis, and evidences suggest the participation of non-neuronal populations such as astrocytes and microglia in the regulation of energy homeostasis. Recently, fat-rich diet induced hypothalamic inflammation has been found to deregulate the energy homeostasis, leading to the insulin resistance, glucose intolerance, and obesity. Several underlying mechanisms have been proposed, yet compelling evidences require further elucidations. This review discusses the up to date proposed mechanisms by which fat-rich diet induces hypothalamic inflammation and obesity.
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http://dx.doi.org/10.1007/s12272-019-01138-9DOI Listing
May 2019

A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice.

FASEB J 2019 03 19;33(3):4314-4326. Epub 2018 Dec 19.

Department of Molecular Science and Technology, Ajou University, Suwon, South Korea.

The overactivity of cannabinoid 1 receptor (CB1R) is associated with obesity and type 2 diabetes. First-generation CB1R antagonists, such as rimonabant, offered therapeutic advantages for the control of obesity and related metabolic abnormalities, but their therapeutic potential was limited by undesirable neuropsychiatric side effects. Here, we evaluated AJ5012 as a novel potent peripheral CB1R antagonist and, using this antagonist, investigated the role of peripheral CB1R on adipose tissue inflammation in obese mouse models. AJ5012 had a high degree of CB1R and cannabinoid 2 receptor selectivity but a low brain:plasma concentration ratio without eliciting centrally mediated neurobehavioral effects. In diet-induced obese (DIO) mice, AJ5012 did not reduce food intake but did induce a significant weight loss, likely owing to an increased energy expenditure. It was as effective as rimonabant for the improvement of hormonal or metabolic abnormalities, glycemic control, and insulin sensitivity. The treatment of DIO and leptin receptor-deficient mice with AJ5012 also exhibited effects comparable to rimonabant for the prevention of macrophage infiltration, activation of the nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome, and production of proinflammatory cytokines, which resulted in the suppression of adipose tissue inflammation. In addition to macrophage, activation of CB1R in 3T3-L1 adipocytes induced the expression of proinflammatory genes, which was fully inhibited by AJ5012. Our findings identified AJ5012 as a novel peripheral CB1R antagonist and suggest that peripheral CB1R blockade might break the links between insulin resistance and adipose tissue inflammation.-Han, J. H., Shin, H., Park, J.-Y., Rho, J. G., Son, D. H., Kim, K. W., Seong, J. K., Yoon, S.-H., Kim, W. A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice.
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http://dx.doi.org/10.1096/fj.201801152RRDOI Listing
March 2019

FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase.

Metabolism 2019 02 27;91:43-52. Epub 2018 Nov 27.

Department of Oral Biology, BK21 PLUS, Yonsei University College of Dentistry, Seoul 03722, South Korea; Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, South Korea; Department of Wellness & Healthy Aging, Wonju College of Medicine, Yonsei University, Wonju 26426, South Korea. Electronic address:

Purpose: While leptin has been associated with various psycho-physiological functions, the molecular network in leptin-mediated mood regulation remains elusive.

Methods: Anxiolytic behaviors and tyrosine hydroxylase (TH) levels were examined after leptin administration. Functional roles of STAT3 and FoxO1 in regulation of TH expression were investigated using in vivo and in vitro systems. A series of animal behavioral tests using dopaminergic neuron-specific FoxO1 KO (FoxO1 KO) were performed and investigated the roles of FoxO1 in regulation of mood behaviors.

Results: Here, we show that administration of leptin induces anxiolytic-like phenotype through the activation of signal transducer and activator of transcription 3 (STAT3) and the inhibition of forkhead box protein O1 (FoxO1) in dopaminergic (DA) neurons of the midbrain. Specifically, STAT3 and FoxO1 directly bind to and exert opposing effects on tyrosine hydroxylase (TH) expression, where STAT3 acts as an enhancer and FoxO1 acts as a prominent repressor. Accordingly, suppression of the prominent suppressor FoxO1 by leptin strongly increased TH expression. Furthermore, our previous results showed that specific deletion of FoxO1 in DA neurons (FoxO1 KO) led to a profound elevation of TH activity and dopamine contents. Finally, FoxO1 KO mice exhibited enhanced leptin sensitivity as well as displayed reduced anxiety- and depression-like behaviors.

Conclusions: This work establishes a novel molecular mechanism of mood behavior regulation by leptin and suggests FoxO1 suppression by leptin might be a key for leptin-induced behavioral manifestation in DA neurons.
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http://dx.doi.org/10.1016/j.metabol.2018.11.013DOI Listing
February 2019

CCN5 knockout mice exhibit lipotoxic cardiomyopathy with mild obesity and diabetes.

PLoS One 2018 28;13(11):e0207228. Epub 2018 Nov 28.

College of Life Sciences, Gwangju Institute of Science and Technology, Buk-gu, Gwangju, Republic of Korea.

Obesity is associated with various human disorders, such as type 2 diabetes, cardiovascular diseases, hypertension, and cancers. In this study, we observed that knockout (KO) of CCN5, which encodes a matricellular protein, caused mild obesity in mice. The CCN5 KO mice also exhibited mild diabetes characterized by high fasting glucose levels and impaired insulin and glucose tolerances. Cardiac hypertrophy, ectopic lipid accumulation, and impaired lipid metabolism in hearts were observed in the CCN5 KO mice, as determined using histology, quantitative RT-PCR, and western blotting. Fibrosis was significantly greater in hearts from the CCN5 KO mice both in interstitial and perivascular regions, which was accompanied by higher expression of pro-fibrotic and pro-inflammatory genes. Both systolic and diastolic functions were significantly impaired in hearts from the CCN5 KO mice, as assessed using echocardiography. Taken together, these results indicate that CCN5 KO leads to lipotoxic cardiomyopathy with mild obesity and diabetes in mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261567PMC
April 2019

TRPM3/TRPV4 regulates Ca2+-mediated RANKL/NFATc1 expression in osteoblasts

J Mol Endocrinol 2018 10 15;61(4):207-218. Epub 2018 Oct 15.

Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea.

Mechanical stress plays an important role in the regulation of bone turnover. However, the mechanism underlying hypo-osmotic stress-induced cellular response in osteoblasts remains poorly understood. In this study, we investigated the effect of hypotonic stress on the expression of bone remodeling factors, including the receptor activator of nuclear factor-kappa B ligand (RANKL) and the nuclear factor of activated T cells type c1 (NFATc1) in primary mouse osteoblasts and MC3T3-E1 cells. Hypo-osmotic stress induced significant increases in RANKL mRNA expression and intracellular Ca2+ concentration ([Ca2+]i) from the extracellular space. Hypo-osmotic stress-induced effects on [Ca2+]i and RANKL and NFATc1 protein expression were decreased by antagonists of transient receptor potential melastatin 3 (TRPM3) and vanilloid 4 (TRPV4). Agonists of TRPM3 and TRPV4 activated [Ca2+]i and RANKL and NFATc1 protein expression. Furthermore, genetic suppression of Trpm3 and Trpv4 reduced hypo-osmotic stress-induced effects in mouse osteoblasts. These results suggest that hypo-osmotic stress induces increases in [Ca2+]i through TRPM3 and TRPV4 to regulate RANKL and NFATc1 expression in mouse osteoblastic cells and that mechanical stress-activated TRP channels may play a critical role in bone remodeling.
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http://dx.doi.org/10.1530/JME-18-0051DOI Listing
October 2018

Prokaryotic cytoskeletons: in situ and ex situ structures and cellular locations.

Authors:
Ki Woo Kim

Antonie Van Leeuwenhoek 2019 Feb 20;112(2):145-157. Epub 2018 Aug 20.

School of Ecology and Environmental System, Kyungpook National University, Sangju, 37224, Korea.

Cytoskeletons have long been perceived to be present only in eukaryotes. However, this notion changed drastically in the 1990s, with observations of cytoskeleton-like structures in several prokaryotes. Homologs of the main components of eukaryotic cytoskeletons, such as microtubules, microfilaments, and intermediate filaments, have been identified in bacteria and archaea. Tubulin homologs include filamenting temperature-sensitive mutant Z (FtsZ), bacterial tubulin A/B (BtubA/B), and tubulin/FtsZ-like protein (TubZ), whereas actin homologs comprise murein region B (MreB) and crenactin. Unlike other proteins, crescentin (CreS) is a homolog of intermediate filaments. Recent findings elucidated their localization, structural organization, and helical properties in prokaryotes, thus revising traditional models. FtsZ is involved in cell division, forming a bundle of overlapping filaments that cover the entire division plane. Cryogenic transmission electron microscopy identified tubular structures of BtubA/B that were not previously identified using conventional ultrathin plastic sections. TubZ generates two joint filaments to form a quadruplex structure. After a long debate, MreB, a cell shape determinant, was shown to form filament stretches that move circumferentially around rod-shaped bacteria. Initially characterized as single-stranded, crenactin was eventually identified as right-handed double-stranded helical filaments. CreS, another cell shape determinant, forms filament bundles located inside the inner membrane of the concave side of cells. These observations suggest that the use of in situ or ex situ microscopy in combination with structural analysis techniques will enable the elucidation and further understanding of the current models of prokaryotic cytoskeletons.
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http://dx.doi.org/10.1007/s10482-018-1142-5DOI Listing
February 2019

A Novel Peptide, Nicotinyl⁻Isoleucine⁻Valine⁻Histidine (NA⁻IVH), Promotes Antioxidant Gene Expression and Wound Healing in HaCaT Cells.

Mar Drugs 2018 Aug 1;16(8). Epub 2018 Aug 1.

Department of Oral Biology, BK21 PLUS, Yonsei University College of Dentistry, Seoul 03722, Korea.

Nicotinamide (NA), a water-soluble vitamin B₃, has been shown to exert cellular-protective effects against reactive oxygen species (ROS). In order to improve the cellular-protective effects of NA, we synthesized a novel compound, nicotinyl⁻isoleucine⁻valine⁻histidine (NA⁻IVH), by combining NA with jellyfish peptides' IVH. In the present study, we examined the cellular-protective effects of the novel synthetic nicotinyl-peptide, NA⁻IVH. We found that NA⁻IVH enhances the radical scavenging activity with a robust increase of the nuclear factor (erythroid-derived 2)-like factor (Nrf2) expression in human HaCaT keratinocytes. In addition, NA⁻IVH protected the cells from hydrogen peroxide (H₂O₂)-induced cell death. Interestingly, NA⁻IVH exhibited an improved wound-healing effect in a high glucose condition, possibly through the regulation of reactive oxygen species (ROS). Collectively, our results imply that a novel nicotinyl-peptide, NA⁻IVH, has a wound-healing effect in a hyperglycemic condition, possibly by modulating excessive ROS.
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http://dx.doi.org/10.3390/md16080262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117656PMC
August 2018

Peltate trichomes on biogenic silvery leaves of Elaeagnus umbellata.

Authors:
Ki Woo Kim

Microsc Res Tech 2018 Jul 20;81(7):789-795. Epub 2018 Apr 20.

School of Ecology and Environmental System, Kyungpook National University, Sangju 37224, Korea.

External and internal features of Elaeagnus umbellata leaves were investigated by optical and electron microscopy. The adaxial (upper) and abaxial (lower) leaf surfaces appeared green and silver in color, respectively. There were peltate trichomes on both the adaxial and abaxial leaf surfaces. The peltate trichomes were 200-300 μm in diameter and shield or umbrella-shaped. They had a central dome and 20-30 radiating rays that were fused to form a circular cap in the center and tapered at the end. The density of peltate trichomes was apparently higher on the abaxial leaf surface than on the adaxial leaf surface. At least two layers of peltate trichomes were commonly observed on the abaxial leaf surface. The epidermal cells on the abaxial leaf surface had convex lens-like shape in cross sections. No distinct chloroplasts were found in the cytoplasm of peltate trichomes. These results suggest that the silver coloration on the abaxial leaf surface is mostly due to structural coloration associated with the profuse overlapping peltate trichomes having a circular cap of radially fused rays. The shrub did not show any pigmentary cellular features associated with the silver coloration. With the silvery leaves as a reflective surface for shaded leaves in canopy, E. umbellata is likely to adapt to the harsh non-native light-demanding environments.
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http://dx.doi.org/10.1002/jemt.23037DOI Listing
July 2018

Electron microscopic observations of stomata, epicuticular waxes, and papillae in Chamaecyparis obtusa: Reconsidering the traditional concept of Y-shaped white stomatal bands.

Authors:
Ki Woo Kim

Microsc Res Tech 2018 Jul 6;81(7):716-723. Epub 2018 Apr 6.

School of Ecology and Environmental System, Kyungpook National University, Sangju, 37224, Korea.

The foliar morphological characters of hinoki (Chamaecyparis obtusa) were revisited using optical and scanning electron microscopy. In C. obtusa, typical Y-shaped white stomatal bands were evident on the abaxial leaf surfaces. Two facial leaves and two lateral leaves were observed at the same node. Waxy papillae and oval stomata were arranged in two or three rows with protuberant rims on the abaxial leaf surfaces. Higher magnifications revealed the deposition of epicuticular waxes (tubules) on the Y-shaped white stomatal bands. Given the absence of stomatal bands after dewaxing with organic solvents, the white stomatal bands in C. obtusa were related to the epicuticular waxes rather than the presence of aggregated stomata alone. In contrast to C. obtusa, a single median leaf and two lateral leaves were observed at the same node of oriental arborvitae (Platycladus koraiensis). Neither stomatal bands nor papillae were observed on P. koraiensis leaves. The stomatal density and epicuticular waxes in the stomatal regions of C. obtusa were higher than those of P. koraiensis. This study suggests that the traditional concept of Y-shaped white stomatal bands in C. obtusa should be revised to describe the arrangement of the aggregated waxy stomata that occur in rows.
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http://dx.doi.org/10.1002/jemt.23027DOI Listing
July 2018

Insulin Regulates Adrenal Steroidogenesis by Stabilizing SF-1 Activity.

Sci Rep 2018 03 22;8(1):5025. Epub 2018 Mar 22.

Departments of Pharmacology and Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju, 26426, Korea.

Development of metabolic syndrome is associated with hyperactivity of the HPA axis characterized by elevated levels of circulating adrenal hormones including cortisol and aldosterone. However, the molecular mechanism leading to the dysregulation of the HPA axis is not well elucidated. In this study, we found that insulin regulates adrenal steroidogenesis by increasing the expression and activity of steroidogenic factor 1 (SF-1) both in vitro and in vivo and this insulin effect was partly through inhibition of FoxO1. Specifically, insulin increased the protein and RNA levels of SF-1 and steroidogenic target genes. Further, adrenal SF-1 expression was significantly increased by hyperactivation of insulin signaling in mice. Together with the elevated SF-1 expression in adrenal glands, hyperactivation of insulin signaling led to increased aldosterone and corticosterone levels. On the other hand, suppressing the insulin signaling using streptozotocin markedly reduced the expression of adrenal SF-1 in mice. In addition, overexpression of FoxO1 significantly suppressed SF-1 and its steroidogenic target genes implying that the positive effect of insulin on SF-1 activity might be through suppression of FoxO1 in the adrenal gland. Taken together, these results indicate that insulin regulates adrenal steroidogenesis through coordinated control of SF-1 and FoxO1.
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http://dx.doi.org/10.1038/s41598-018-23298-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864882PMC
March 2018

Serum Fibroblast Growth Factor 21 and New-Onset Metabolic Syndrome: KoGES-ARIRANG Study.

Yonsei Med J 2018 Mar;59(2):287-293

Institute of Genomic Cohort, Yonsei University Wonju College of Medicine, Wonju, Korea.

Purpose: Fibroblast growth factor 21 (FGF21) is a crucial metabolic regulator, with multiple favorable effects on glucose homeostasis and lipid metabolism. Since serum FGF21 level has been implicated as a potential marker for the early identification of metabolic syndrome (MetS), we investigated the association between serum FGF21 level and the development of MetS in a population-based prospective study.

Materials And Methods: We conducted a prospective study of 221 randomly sampled adults without MetS from a general population-based cohort study who were examined from 2005-2008 (baseline) and from 2008-2011 (follow-up). Baseline serum FGF21 levels were analyzed using enzyme-linked immunosorbent assay.

Results: During the average 2.8-year follow-up period, 82 participants (36.6%) developed new-onset MetS. Serum FGF21 levels were significantly higher in patients with new-onset MetS than in those without MetS (209.56±226.80 vs. 110.09±81.10, p<0.01). In multivariate adjusted models, the odds for MetS development were greater in patients with serum FGF21 levels in the highest quartile, compared to those in the lowest quartile (3.84, 95% confidence interval: 1.59-9.28).

Conclusion: Serum FGF21 level was an independent predictor for new-onset MetS in a population-based prospective study.
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http://dx.doi.org/10.3349/ymj.2018.59.2.287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823832PMC
March 2018
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