Tomohide Takaya

Shinshu University | Shindai · Faculty of Agriculture

Cancer cachexia is characterized by irreversible muscle loss which is a critical factor in the prognosis of cancer patients. Myoblasts are myogenic precursor cells that are required to maintain skeletal muscle tissue. Previous studies reported that cancer-released factors deteriorate myoblast differentiation, which is one of the causes of cachexia-...

Embryonal rhabdomyosarcoma (ERMS) is the muscle-derived tumor retaining myogenic ability. iSN04 and AS1411, which are myogenetic oligodeoxynucleotides (myoDNs) serving as anti-nucleolin aptamers, have been reported to inhibit the proliferation and induce the differentiation of myoblasts. The present study investigated the effects of iSN04 and AS141...

Abstract An 18-base myogenetic oligodeoxynucleotide (myoDN), iSN04, acts as an anti-nucleolin aptamer and induces myogenic differentiation of skeletal muscle myoblasts. This study investigated the effect of iSN04 on murine embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). In the undifferentiated state, iSN04 inhibited the prol...

A myogenetic oligodeoxynucleotide (myoDN), iSN04 (5′-AGA TTA GGG TGA GGG TGA-3′), is a single-stranded 18-base telomeric DNA that serves as an anti-nucleolin aptamer and induces myogenic differentiation, which is expected to be a nucleic acid drug for the prevention of disease-associated muscle wasting. To improve the drug efficacy and synthesis co...

De-differentiation and subsequent increased proliferation and inflammation of vascular smooth muscle cells (VSMCs) is one of the mechanisms of atherogenesis. Maintaining VSMCs in a contractile differentiated state is therefore a promising therapeutic strategy for atherosclerosis. We have reported the 18-base myogenetic oligodeoxynucleotide, iSN04,...

De-differentiation and subsequent increased proliferation and inflammation of vascular smooth muscle cells (VSMCs) is one of the mechanisms of atherogenesis. Maintaining VSMCs in a contractile differentiated state is therefore a promising therapeutic strategy for atherosclerosis. We have reported the 18-base myogenetic oligodeoxynucleotide, iSN04,...

A myogenetic oligodeoxynucleotide (myoDN), iSN04 (5’-AGA TTA GGG TGA GGG TGA-3’), is a single-stranded 18-base telomeric DNA that serves as an anti-nucleolin aptamer and induces myogenic differentiation, which is expected to be a nucleic acid drug for the prevention of disease-associated muscle wasting. To improve the drug efficacy and synthesis co...

Supplementary Video S1. Beating cardiomyocytes spontaneously differentiated from miPSCs. Undifferentiated 20D17 cells were seeded on gelatin-coated dishes and induced spontaneous differentiation in DM for 11 days.

Supplementary Video S2. Beating cardiomyocytes differentiated from miPSCs treated with iSN04. Undifferentiated 20D17 cells were seeded on gelatin-coated dishes and induced spontaneous differentiation in DM for 11 days. The cells were treated with 10 μM iSN04 from day 5 to day 9.

An 18-base myogenetic oligodeoxynucleotide (myoDN), iSN04, acts an anti-nucleolin aptamer and induces myogenic differentiation of skeletal muscle myoblasts. This study investigated the effect of iSN04 on murine embryonic stem cells (ESCs) and induced pluripotent stem cells (iP-SCs). In the undifferentiated state, iSN04 inhibited the proliferation o...

A myogenetic oligodeoxynucleotide, iSN04, is the 18-base single-stranded DNA that acts as an anti-nucleolin aptamer. iSN04 has been reported to restore myogenic differentiation by suppressing inflammatory responses in myoblasts isolated from patients with diabetes or healthy myoblasts exposed to cancer-releasing factors. Thus, iSN04 is expected to...

A myogenetic oligodeoxynucleotide, iSN04, is the 18-base single-stranded DNA that acts as an anti-nucleolin aptamer. iSN04 has been reported to restore myogenic differentiation by suppressing inflammatory responses in myoblasts isolated from patients with diabetes or healthy myoblasts exposed to cancer-releasing factors. Thus, iSN04 is expected to...

Objectives: Chicken meat and egg are one of the most excellent animal proteins. Mass production of poultry meat or eggs have been raising chickens. However, poultry husbandry raising chickens is always at risk of infectious diseases, such as the avian flu. To overcome these problem, experimental challenges has been conducted producing chicken meat...

Objectives: Chicken meat and eggs are highly nutritious and are widely eaten all over the world as an excellent foodstuffs. Also, chick embryos are useful as a material for developmental biology. Improving embryogenesis is extremely important in the production of individual chickens. However, chicken embryogenesis is blocked from the outside by egg...

Dysfunction of bone-forming cells, osteoblasts, is one of the causes of osteoporosis. Accumulating evidence has indicated that oligodeoxynucleotides (ODNs) designed from genome sequences have the potential to regulate osteogenic cell fate. Such osteogenetic ODNs (osteoDNs) targeting and activating osteoblasts can be the candidates of nucleic acid d...

In a previous study, the three-dimensional structures of mitochondria in type I and type IIb muscle fibers of chicken were analyzed. The study reported differences in the shape of the mitochondria and the distribution of lipid droplets. In this study, we three-dimensionally analyzed mitochondria and lipid droplets of type II muscle fiber subtypes I...

Recent studies have revealed that oligodeoxynucleotides (ODNs) designed from genome sequences have the potential to regulate cell fate. Currently, ODNs that conduct cell differentiation are nanomolecular drug candidates for regenerative medicine. Herein, we demonstrate that iSN40, an 18-base ODN derived from the Lacticaseibacillus rhamnosus GG geno...

Avian stem cells derived from stage X chick embryos were found to be pluripotent to differentiate into soma and germline. Genome editing in the stem cells using CRISPR/Cas9 for ovomucoid was successfully conducted. The manipulated stem cells were used to generate germline chimeras. The eggs from the genome-edited chickens could reduce allergy. Avia...

Cancer cachexia is characterized by irreversible muscle loss which is a critical factor in the prognosis of cancer patients. Myoblasts are myogenic precursor cells that are required to maintain skeletal muscle tissue. Previous studies have reported that cancer-released factors deteriorate myoblast differentiation, which is one of the causes of cach...

Background Embryonal rhabdomyosarcoma (ERMS) is the muscle-derived tumor retaining myogenic ability. iSN04 and AS1411, which are myogenetic oligodeoxynucleotides (myoDNs) serving as anti-nucleolin aptamers, have been reported to inhibit the proliferation and induce the differentiation of myoblasts. The present study investigated the effects of iSN0...

Myoblasts are myogenic precursors that develop into myotubes during muscle formation. Improving efficiency of myoblast differentiation is important for advancing meat production by domestic animals. We recently identified novel oligodeoxynucleotides (ODNs) termed myogenetic ODNs (myoDNs) that promote the differentiation of mammalian myoblasts. An i...

細菌ゲノム由来のオリゴDNAはTLRリガンドとして免疫応答を調節するが，一部のオリゴDNAは幹細胞の分化にも影響することがわかってきた．核酸医薬のシーズとして期待される新しいタイプのオリゴDNAについて紹介する． Bacterial genome-derived oligodeoxynucleotides regulate not only immune responses but also stem cell differentiation. These type of oligonucleotides can be seeds for novel nucleic acid drugs.

Skeletal muscle wasting in patients with diabetes mellitus (DM) is a complication of decreased muscle mass and strength, and is a serious risk factor that may result in mortality. Deteriorated differentiation of muscle precursor cells, called myoblasts, in DM patients is considered to be one of the causes of muscle wasting. We recently developed my...

Skeletal muscle myoblasts are myogenic precursor cells that generate myofibers during muscle development and growth. We recently reported that broiler myoblasts, compared to layer myoblasts, proliferate and differentiate more actively and promptly into myocytes, which corresponds well with the muscle phenotype of broilers. Furthermore, RNA sequenci...

Sarcopenic obesity is a complication of decreased muscle mass and strength associated with obesity, and sarcopenia associated with diabetes mellitus (DM) is a serious risk factor that may result in mortality. Deteriorated differentiation of muscle precursor cells, called myoblasts, in DM patients is considered to be one of the causes of muscle atro...

Herein we report that the 18-base telomeric oligodeoxynucleotides (ODNs) designed from the Lactobacillus rhamnosus GG genome promote differentiation of skeletal muscle myoblasts which are myogenic precursor cells. We termed these myogenetic ODNs (myoDNs). The activity of one of the myoDNs, iSN04, was independent of Toll-like receptors, but dependen...

Skeletal muscle myoblasts are myogenic precursors that develop into myofibers during muscle formation. Improvement of myoblast differentiation is important for advancing meat production by domestic animals. We recently identified novel oligodeoxynucleotides (ODNs) termed myogenetic ODNs (myoDNs) that promote the differentiation of mammalian myoblas...

Herein we report that the 18-base telomeric oligodeoxynucleotides (ODNs) designed from the Lactobacillus rhamnosus GG genome promote differentiation of skeletal muscle myoblasts which are myogenic precursor cells. We termed these myogenetic ODNs (myoDNs). The activity of one of the myoDNs, iSN04, was independent of Toll-like receptors, but dependen...

Wooden breast syndrome (WB) constitutes an emerging myopathy in the pectoralis major muscle (PM) of broiler chickens, characterized by myofiber hypertrophy and degeneration along with severe fibrosis. WB pathogenesis has been considered to involve hypoxia induced by rapid growth of the PM. In this study, we focused on mitochondrial morphology and d...

A natural isoquinoline alkaloid, berberine, has been known to exhibit anti-tumor activity in various cancer cells via inducing cell cycle arrest. However, it has not been investigated whether berberine and its analogs inhibit the growth of rhabdomyosarcoma (RMS), which is the most frequent soft tissue tumor in children. The present study examined t...

Myoblasts play a central role during skeletal muscle formation and growth. Precise understanding of myoblast properties is thus indispensable for meat production. Herein, we report the cellular characteristics and gene expression profiles of primary-cultured myoblasts of layer and broiler chickens. Broiler myoblasts actively proliferated and prompt...

We recently identified that iSN04, an 18-nt oligodeoxynucleotide with telomere sequence, strongly promotes skeletal muscle differentiation. Since iSN04 is incorporated into cytoplasm and works depending on its molecular structure, iSN04 is considered to induce myogenic differentiation by interacting with its target protein(s) within the cells. Prot...

Muscle atrophy is a severe problem for the motor function of elderly people and for the prognosis of the patients with cancer or heart failure. Homeostasis of skeletal muscle tissue is maintained by myogenic precursor cells called myoblasts. After several rounds of cell divisions, myoblasts differentiate into contractile myocytes in order to regene...

Homeostasis of skeletal muscle is maintained by myogenic progenitors called myoblasts. We recently identified a telomeric 18 nt-oligodeoxynucleotide, myoDN, which intensively facilitates myogenic differentiation. myoDN induces differentiation of myoblasts, rhabdomyosarcoma, and pluripotent stem cells in a structure-dependent manner. In this study,...

Genetic selection has promoted muscle development of broiler chickens. Multinuclear muscle myofibers grow through the fusion of myogenic precursor cells, myoblasts. Understanding of myoblast properties is thus indispensable for meat production. Herein, we report the cellular characteristics and gene expression profiles of primary-cultured myoblasts...

Toll-like receptors (TLRs) are a group of sensory receptors which are capable of recognizing a microbial invasion and activating innate immune system responses, including inflammatory responses, in both immune and non-immune cells. However, TLR functions in chick myoblasts, which are myogenic precursor cells contributing to skeletal muscle developm...

Glucose spike is a set of acute increase and decrease in blood glucose level. Glucose spike is a risk factor for metabolic and cardiovascular disorders which occasionally lead muscle atrophy. However, it has not been reported the effect of glucose spike on myoblasts, which are myogenic progenitor cells maintaining skeletal muscle tissue. We invest...

Summary: Toll-like receptors (TLRs) are essential for innate immune system. However, it has not been reported whether TLRs initiate inflammatory responses in chick skeletal muscle myoblasts which are myogenic precursor cells. Here, we confirmed the distinct expression patterns of TLR genes between broiler and layer myoblasts. We also found that TLR...

Summary: Generation of mouse-chicken chimeras was challenged. The manipulated chimeric embryos were sampled and fluorescence signals derived from ES cells were observed. A novel stretegy for avian reproductive assist technology, AART, has been developed. Materials & Methods: GFP-ES cells were injected into chicken blastoderm and the embryos were e...

Summary: We identified that a telomeric DNA aptamer, myoDN, potently promotes differentiation of myogenic precursor cells into myotubes. The activity of myoDN is markedly enhanced by forming complex with berberine (Ber), an alkaloid from Phellodendron amurense. myoDN-Ber complex will be useful to promote skeletal muscle development for meat product...

Summary: Glucose spike is a set of acute increase and decrease in blood glucose level which occurs within 2 hours after meal. Recent studies revealed that glucose spike is a risk factor for diabetes, dementia, and myocardial and cerebral infarctions. However, the impact of glucose spike on skeletal muscle myoblasts has not been reported. In this st...

In association with an increase of world population, the total amount of meat consumption has been increasing in this half century. To improve efficiency of meat production, broiler chickens with well-developed muscle have been established by selective breeding. Skeletal muscle tissue is composed of numerous myofibers that are multinuclear contract...

Adipose tissues in obese individuals are characterized by a state of chronic low-grade inflammation. Pre-adipocytes and adipocytes in this state secrete pro-inflammatory adipokines, such as interleukin 6 (IL-6), which induce insulin resistance and hyperglycemia. Theophylline (1,3-dimethylxanthine) exerts anti-inflammatory effects, but its effects o...

Background: Genetic selection has promoted muscle development of broiler chickens. Multinuclear muscle myofibers grow through the fusion of myogenic precursor cells, myoblasts. Recently, the inflammation in well-developed broiler breast muscles is increasingly reported but the reason of this serious disorder has been still unclear. Toll-like recept...

Skeletal muscle, which generates a great power for active behaviors, is the largest tissue in human. However, muscle strength and mass gradually decrease with aging. To improve quality of life, muscle atrophy should be prevented in aging societies. Skeletal muscle regeneration is maintained by somatic stem cells existing on myofibers, called satell...

Cell-cell fusion has been a great technology to generate valuable hybrid cells and organisms such as hybridomas. In this study, skeletal muscle myoblasts were utilized to establish a novel method for autonomous xenogenic cell fusion. Myoblasts are mononuclear myogenic precursor cells and fuse mutually to form multinuclear myotubes. We generated mur...

Summary: Cell-cell fusion has been a great technology to generate valuable hybrid cells such as hybridomas. We utilized skeletal muscle myoblasts to establish a novel method for cell fusion. Myoblasts are mononuclear myogenic precursor cells but fuse mutually to form multinuclear myotubes. We found that murine and chick myoblasts spontaneously and...

Summary: Genetic selection enabled to promote skeletal muscle development as meat yield in broiler chickens than in other chickens. Muscle myofibers develop through the fusion of myoblasts, which are mononuclear myogenic precursor cells. We presumed that difference of muscle development among chicken breeds is attributed to gene expression profiles...

Summary: In chick ex ovo culture system, most of the embryos can be dead basket during a few days just before hatching. If the embryo development to hatching could be assisted by avian reproductive technologies, progress could be contributed for avian biotechnology. In the present studies, a novel method of avian assisted reproductive technology; A...

Summary: We recently found that the oligodeoxynucleotide, involved in the genome of Lactobacillus rhamnosus GG, intensively promotes myogenic differentiation of skeletal muscle myoblasts. This oligonucleotide named "myoDN" induced differentiation of myoblasts but did not have any effects on fibroblasts. It is anticipated that such specific action o...

Skeletal muscle, which generates a great power for active behaviors, is the largest tissue in animals and also important for us as meat. Muscle tissue is composed of numerous myofibers that are multinuclear contractile cells. During development, myofibers are formed by fusion of myogenic progenitor cells called myoblasts. After birth, myofibers gro...

Aim: Smoking induces vascular inflammation and increases the risk of cardiovascular events. Lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that is induced by oxidative stress and is associated with atherosclerotic plaque formation and destabilization. LOX-1 interacts with C-reactive protein (CRP) and plays a...

Background: The mechanisms that lead from obesity to atherosclerotic disease are not fully understood. Obesity involves angiogenesis in which vascular endothelial growth factor-A (VEGF-A) plays a key role. Vascular endothelial growth factor-C (VEGF-C), a homologue of the VEGF family, plays a pivotal role in lymphangiogenesis. Circulating levels of...

As drug therapy is of limited efficacy in the treatment of heart diseases related to loss of cardiomyocytes, which have very poor division potential, regenerative medicine is expected to be a new strategy to address regenerative treatment in cardiac diseases. To achieve myocardial regeneration, elucidation of the mechanism of myocardial differentia...

OBJECTIVE It has recently been highlighted that proinflammatory (M1) macrophages predominate over anti-inflammatory (M2) macrophages in obesity, thereby contributing to obesity-induced adipose inflammation and insulin resistance. A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA) reduces the incidence of major coronar...

Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor, induced by oxidative stress, and suggested to be associated with atherosclerotic plaque destabilization. Soluble LOX-1 (sLOX-1) is known as a biomarker of acute coronary syndrome. It is reported that the LOX index, represented by multiplication of L...

Oxidized LDL (oxLDL) is implicated in atherogenesis through receptor-mediated action which causes vascular cell dysfunction leading to inflammatory responses and lipid accumulation resulting in foam cell formation. Although a huge number of studies have been reported on characterization oxLDL receptors, there have been no reports on endogenous inhi...

The mechanisms that lead from obesity to atherosclerotic disease are not fully understood. Obesity involves angiogenesis in which vascular endothelial growth factor-A (VEGF-A) plays a key role. On the other hand, vascular endothelial growth factor-C (VEGF-C) plays a pivotal role in lymphangiogenesis. Circulating levels of VEGF-A and VEGF-C are elev...

Background: We found that curcumin, a p300 histone acetyltransferase (HAT) inhibitor, prevents deterioration of the systolic function in rat heart failure models in vivo. To clinically apply this novel therapy to humans, it should be clarified whether or not curcumin has additional effects on conventional heart failure therapy comprising angiotensi...

Hemodynamic overload in the heart can trigger maladaptive hypertrophy of cardiomyocytes, which eventually leads to systolic dysfunction or decompensated heart failure. We have clarified that a histone acetyltransferase (HAT), p300, mediates nuclear acetylation during this process. HAT activity of p300 is required for the development of left ventric...

LOX-1 is an endothelial receptor for oxidized low-density lipoprotein (oxLDL), a key molecule in the pathogenesis of atherosclerosis.The basal expression of LOX-1 is low but highly induced under the influence of proinflammatory and prooxidative stimuli in vascular endothelial cells, smooth muscle cells, macrophages, platelets and cardiomyocytes. Mu...

A natural p300-specific histone acetyltransferase (HAT) inhibitor, curcumin, may have therapeutic potential for heart failure. However, it is unclear whether curcumin exhibits beneficial additive or synergistic effects on conventional therapy with angiotensin-converting enzyme inhibitors (ACEIs). Rats were subjected to a sham operation or left coro...

MicroRNAs (miRNAs), small noncoding RNAs, are negative regulators of gene expression and play important roles in gene regulation in the heart. To examine the role of miRNAs in the expression of the two isoforms of the cardiac myosin heavy chain (MHC) gene, α- and β-MHC, which regulate cardiac contractility, endogenous miRNAs were downregulated in n...

The treatment of ES cells with trichostatin A (TSA), an HDAC inhibitor, induces the acetylation of GATA4 as well as histones, and facilitates their differentiation into cardiomyocytes. Recently, we demonstrated that cyclin-dependent kinase 9 (Cdk9), a core component of positive elongation factor-b, is a novel GATA4-binding partner. The present stud...

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is a receptor for oxidized LDL, and is strongly expressed in endothelial cells at an early stage of atherosclerosis. LOX-1 expression in adipocytes is induced by PPARγ ligands and appears to be involved in adipocyte cholesterol metabolism. However, the role of adipose tissue LOX-...

Background: The adipocytokine adiponectin is regulated by visceral fat accumulation and is decreased in sera of patients with obesity-linked diseases. In a general population, the adiponectin level is inversely associated with left ventricular hypertrophy (LVH). In contrast, levels of adiponectin increase in proportion to the severity of heart fail...

Mouse and human fibroblasts can be directly reprogrammed to pluripotency by the ectopic expression of four transcription factors (Oct3/4, Sox2, Klf4, and c-Myc) to yield induced pluripotent stem (iPS) cells. iPS cells can be generated even without the expression of c-Myc. The present study examined patterns of differentiation of mouse iPS cells int...

Purpose: Signals activated by increased hemodynamic overload to the heart finally reach nuclei of cardiac myocytes, change patterns of gene expression and cause their maladaptive hypertrophy. Nuclear acetylation controlled by histone deacetylases and an intrinsic histone acetyltransferase (HAT), p300, is a critical event during this process. Recent...

During embryogenesis, cell type-specific gene expression plays a pivotal role in the determination of cell fate, including differentiation, proliferation, and apoptosis. In contrast to other cell types, cardiac muscle cells are highly organized and their developmental processes require a number of cell type-specific transcription factors. One of HA...

Background: Vascular endothelial growth factor-C (VEGF-C) plays a key role in lymphangiogenesis through binding to VEGF receptor-3 (VEGFR-3). A recent report demonstrated that naturally occurring soluble VEGFR-2 (sVEGFR-2) acts as a VEGF-C antagonist, while we reported that serum sVEGFR-2 levels are increased in patients with metabolic syndrome (Me...

Background: Placental growth factor (PlGF) is a homologue of vacular endothelial growth factor-A (VEGF-A) which is essential for angiogenesis and adipogenesis in obesity. PlGF plays an important role in pathological, but not in physiological, angiogenesis, and its inactivation impairs adipose tissue development in a murine model of diet-induced obe...

Background: Human induced pluripotent stem (iPS) cells are potential sources of cardiovascular cells to be transplanted in patients with end-stage heart failure. The identification and purification of cardiovascular progenitor cells in primate ES/iPS cells in critical to apply human iPS cells for cardiovascular regenerative therapy in the clinical...

Introduction: An intrinsic histone acetyltransferase (HAT), p300 is required for acetylation and the transcriptional activity of GATA4 as well as for cardiomyocyte hypertrophy and the development of heart failure in vivo. By mass spectrometric analyses, we identified SNF5/INI1, a component of the human SWI/SNF chromatin remodeling complex, as a nov...

Introduction: A zinc finger protein GATA4 is one of the hypertrophy-responsive transcription factors, and increases its DNA-binding and transcriptional activities in response to hypertrophic stimuli in cardiac myocytes. By tandem affinity purification and mass spectrometric analyses, we identified that retinoblastoma binding proteins, RbAp46 and Rb...

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is a receptor for oxidized LDL, and is strongly expressed in endothelial cells at an early stage of atherosclerosis. LOX-1 expression in adipocytes is induced by PPARgamma (ligands and appears to be involved in adipocyte cholesterol metabolism. However, the role of adipose tissue...

While myocardial regeneration therapy is an important approach for end-staged heart failure, clinical application of embryonic stem (ES) cells may be hindered because of the ethical issue surrounding the manipulation of oocytes and immune rejection. Recent technologies to create induced pluripotent stem (iPS) cells from mouse and human fibroblasts...

Although myocardial regeneration therapy emerged as an important approach for end-staged heart failure, there remain several clinical problems regarding the application of embryonic stem (ES) because of the ethical issue surrounding the manipulation of oocytes and immune rejection. Recent studies have shown that mouse and human somatic cells can be...

A zinc finger protein GATA4 is one of the hypertrophy-responsive transcription factors and forms a complex with an intrinsic histone acetyltransferase, p300. Disruption of this complex results in the inhibition of cardiomyocyte hypertrophy and heart failure in vivo. By tandem affinity purification and mass spectrometric analyses, we identified cycl...