Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and ... more Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer, is among the most serious health problems. Increased monoamine oxidase (MAO) activity has been observed in the adipose tissue of obese humans and animals. Although previous studies have already demonstrated the potential of MAO-B inhibitors as a treatment for this condition, the mechanism of their effect has been insufficiently elucidated. In this study, we investigated the anti-obesity effect of selegiline, a selective MAO-B inhibitor, using in vivo animal models. The effect was evaluated through an assessment of body energy homeostasis, glucose tolerance tests, and biochemical analysis. Pharmacological inhibition of MAO-B by selegiline was observed to reduce body weight and fat accumulation, and improved glucose metabolism without a corresponding change in food intake, in HFD-fed obese mice. We also observed that both the expression of adipogenenic markers, including C/EBPα and...
Stress management is necessary for vertebrate survival. Chronic stress drives depression by excit... more Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic l-amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivit...
Obesity is considered a health hazard in part due to the associated multiple diseases. As rates o... more Obesity is considered a health hazard in part due to the associated multiple diseases. As rates of obesity continue to increase, a new strategy for its prevention and treatment is required. Compound-K, an active ingredient in ginseng, possesses antioxidant, anti-inflammatory, and anti-cancer properties. Although ginseng has used as various therapeutics, its potential ability to alleviate metabolic diseases by regulating adipocyte differentiation is still unknown. In this study, we found that CK treatment significantly inhibited lipid droplet and adipogenesis by downregulating the mRNA expression of C/ebpα, Ppar-γ, Fabp4, Srebp1, and adiponectin as well as protein levels of C/EBPα, PPAR-γ, and FABP4. CK also decreased the production of reactive oxygen species (ROS), while it increased endogeneous antioxidant enzymes such as catalase, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) 3 and SOD2. We observed that CK treatment suppressed the expression...
Alzheimer's disease (AD) is a common neurodegenerative disease that lacks biomarkers for diag... more Alzheimer's disease (AD) is a common neurodegenerative disease that lacks biomarkers for diagnosis. Biomarkers for accurate detection of AD are required for potential therapeutic approaches. Recent studies in mammalian cells have demonstrated an association between the expression of cell cycle proteins and AD occurrence. Therefore, we aimed to identify a potent biomarker among relevant cell cycle-regulating proteins such as cyclin-dependent kinases (CDKs) for the diagnosis of AD. We also developed a multiplex-PCR-based diagnostic method, which showed the rapid and accurate detection of AD biomarkers. Genome-wide association study (GWAS) results showed increased gene expression of CDKs in an AD mouse model. Based on genomic analysis, our multiplex-PCR method, which contained optimized primer sets and PCR conditions targeting genes of CDKs, accurately matched RT-PCR results in the AD mouse model. Interestingly, validation by in silico meta-analysis for the expression of each CDK gene showed significant expression in moderate and severe groups of AD patients. Accordingly, clinical applications relying on the diagnosis of AD using our results may shed light on AD therapeutics.
Localized drug-delivery systems (LDDSs) are a promising approach for cancer treatment because the... more Localized drug-delivery systems (LDDSs) are a promising approach for cancer treatment because they decrease systematic toxicity and enhance the therapeutic effect of the drugs via site-specific delivery of active compounds and possible gradual release. However, the development of LDDS with rationally controlled drug release and intelligent functionality holds great challenge. To this end, we have developed a tailorable fibrous site-specific drug-delivery platform functionalized with pH- and near-infrared (NIR)-responsive polypyrrole (PPy), with the aim of cancer treatment via a combination of photothermal ablation and chemotherapy. First, a paclitaxel (PTX)-loaded polycaprolactone (PCL) (PCL-PTX) mat was prepared by electrospinning and subsequently in situ membrane surface-functionalized with different concentrations of PPy. The obtained PPy-functionalized mats exhibited excellent photostability and heating property in response to NIR exposure. PPy-coated mats exhibited enhanced PTX...
Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional... more Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional status. This plasticity at hypothalamic synapses contributes to the control of food intake and body weight. Here we show that genetic ablation of leptin receptor gene expression in pro-opiomelanocortin (POMC) neurons (POMC: Lepr−/− GFP) induces alterations at synapses on POMC neurons in the arcuate nucleus of the hypothalamus. Our studies reveal that POMC: Lepr−/− GFP mice have decreased frequency of spontaneous GABAergic, but not glutamatergic, postsynaptic currents at synapses on POMC neurons. The decay time course of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) onto POMC neurons in POMC: Lepr−/− GFP mice is significantly slower than that of sIPSCs in control animals. While analysis of individual miniature IPSCs shows lowered baseline activity, this tonic decrease is associated with an increased amplitude and slow decay of mini-IPSCs onto POMC neurons in POMC: Lepr−...
Powder-based 3D printing is an excellent technique for the fabrication of complex structural shap... more Powder-based 3D printing is an excellent technique for the fabrication of complex structural shapes. The outstanding bone remodeling capacity of calcium phosphate bioceramics is a desirable characteristic for such fabrication. Whitlockite (WH) is a calcium phosphate-based ceramic that contains Mg ions and possesses good mechanical properties, rapid resorbability, and promotes osteogenesis. The aim of this study was to fabricate 3D-printed scaffolds using marine plankton-derived WH (MP-WH) powder. The surface morphology and composition of the fabricated scaffolds were characterized by scanning electron microscopy and X-ray diffraction. The biocompatibility and osteogenic effects were evaluated using human mesenchymal stem cells. We successfully obtained a 3D porous scaffold using MP-WH. The MP-WH 3D scaffold showed improved compressive strength compared to the tricalcium phosphate (TCP) 3D scaffold. The in vitro results showed that compared with TCP 3D scaffolds, MP-WH 3D scaffolds w...
Hypoxia is one of key characteristics of microenvironments of solid tumors, and evaluation of hyp... more Hypoxia is one of key characteristics of microenvironments of solid tumors, and evaluation of hypoxia status in solid tumors is important to determine cancer stage and appropriate treatment. In the present study, novel, multivalent, near-infrared (NIR) fluorescent imaging agents were developed to measure tumor hypoxia. These agents were synthesized using an amino acid as a backbone to connect mono-, bis-, or tris-2-nitroimidazole as a hypoxia-sensitive moiety to enhance uptake by the tumor and to attach sulfo-Cyanine 5.5 as an NIR fluorophore to visualize tumor accumulation. Studies of physical characteristics demonstrated that the novel NIR imaging agents showed suitable optical properties for in vitro and in vivo imaging and were stable in serum. In vitro cellular uptake studies in SK-N-BE(2) and SW620 cell lines demonstrated that NIR imaging agents bearing 2-nitroimidazole structures showed significantly higher tumor uptake in hypoxic cells than in normoxic cells. Moreover, in vivo optical imaging studies using SK-N-BE(2) and SW620 xenografted mice demonstrated that novel, multivalent, 2-nitroimadazole NIR imaging agents with two or three 2-nitroimidazole moieties showed higher uptake in tumor than the control agents with only one 2-nitroimidazole. These observations suggest that novel, multivalent, NIR agents could serve as potential optical imaging agents for evaluating tumor hypoxia.
Stress management is a prerequisite for the survival of vertebrates because chronic stress may ca... more Stress management is a prerequisite for the survival of vertebrates because chronic stress may cause depression and is known to negatively modulate the dopaminergic reward system. Enhanced excitability of neurons in the lateral habenula (LHb) induced by chronic stress is essential for silencing dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neurons in the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on the LHb-RMTg-VTA pathway is unknown. Here, we show that both aromatic L-amino acid decarboxylase (AADC)-expressing neurons (D-neurons) in the LHb and dopaminergic neurons in the VTA are activated by acute stress, whereas GABAergic neurons in the RMTg are not. Selective stimulation of LHb D-neurons and AADC knockdown of these neurons reverse-regulate the RMTg-VTA pathway. Circuit tracing and electrophysiology data demonstrate that trace aminergic signalling by LHb D-neurons directly suppresses RMTg GABAergic neurons. Furthermore, lo...
Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and ... more Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer, is among the most serious health problems. Increased monoamine oxidase (MAO) activity has been observed in the adipose tissue of obese humans and animals. Although previous studies have already demonstrated the potential of MAO-B inhibitors as a treatment for this condition, the mechanism of their effect has been insufficiently elucidated. In this study, we investigated the anti-obesity effect of selegiline, a selective MAO-B inhibitor, using in vivo animal models. The effect was evaluated through an assessment of body energy homeostasis, glucose tolerance tests, and biochemical analysis. Pharmacological inhibition of MAO-B by selegiline was observed to reduce body weight and fat accumulation, and improved glucose metabolism without a corresponding change in food intake, in HFD-fed obese mice. We also observed that both the expression of adipogenenic markers, including C/EBPα and...
Stress management is necessary for vertebrate survival. Chronic stress drives depression by excit... more Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic l-amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivit...
Obesity is considered a health hazard in part due to the associated multiple diseases. As rates o... more Obesity is considered a health hazard in part due to the associated multiple diseases. As rates of obesity continue to increase, a new strategy for its prevention and treatment is required. Compound-K, an active ingredient in ginseng, possesses antioxidant, anti-inflammatory, and anti-cancer properties. Although ginseng has used as various therapeutics, its potential ability to alleviate metabolic diseases by regulating adipocyte differentiation is still unknown. In this study, we found that CK treatment significantly inhibited lipid droplet and adipogenesis by downregulating the mRNA expression of C/ebpα, Ppar-γ, Fabp4, Srebp1, and adiponectin as well as protein levels of C/EBPα, PPAR-γ, and FABP4. CK also decreased the production of reactive oxygen species (ROS), while it increased endogeneous antioxidant enzymes such as catalase, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) 3 and SOD2. We observed that CK treatment suppressed the expression...
Alzheimer's disease (AD) is a common neurodegenerative disease that lacks biomarkers for diag... more Alzheimer's disease (AD) is a common neurodegenerative disease that lacks biomarkers for diagnosis. Biomarkers for accurate detection of AD are required for potential therapeutic approaches. Recent studies in mammalian cells have demonstrated an association between the expression of cell cycle proteins and AD occurrence. Therefore, we aimed to identify a potent biomarker among relevant cell cycle-regulating proteins such as cyclin-dependent kinases (CDKs) for the diagnosis of AD. We also developed a multiplex-PCR-based diagnostic method, which showed the rapid and accurate detection of AD biomarkers. Genome-wide association study (GWAS) results showed increased gene expression of CDKs in an AD mouse model. Based on genomic analysis, our multiplex-PCR method, which contained optimized primer sets and PCR conditions targeting genes of CDKs, accurately matched RT-PCR results in the AD mouse model. Interestingly, validation by in silico meta-analysis for the expression of each CDK gene showed significant expression in moderate and severe groups of AD patients. Accordingly, clinical applications relying on the diagnosis of AD using our results may shed light on AD therapeutics.
Localized drug-delivery systems (LDDSs) are a promising approach for cancer treatment because the... more Localized drug-delivery systems (LDDSs) are a promising approach for cancer treatment because they decrease systematic toxicity and enhance the therapeutic effect of the drugs via site-specific delivery of active compounds and possible gradual release. However, the development of LDDS with rationally controlled drug release and intelligent functionality holds great challenge. To this end, we have developed a tailorable fibrous site-specific drug-delivery platform functionalized with pH- and near-infrared (NIR)-responsive polypyrrole (PPy), with the aim of cancer treatment via a combination of photothermal ablation and chemotherapy. First, a paclitaxel (PTX)-loaded polycaprolactone (PCL) (PCL-PTX) mat was prepared by electrospinning and subsequently in situ membrane surface-functionalized with different concentrations of PPy. The obtained PPy-functionalized mats exhibited excellent photostability and heating property in response to NIR exposure. PPy-coated mats exhibited enhanced PTX...
Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional... more Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional status. This plasticity at hypothalamic synapses contributes to the control of food intake and body weight. Here we show that genetic ablation of leptin receptor gene expression in pro-opiomelanocortin (POMC) neurons (POMC: Lepr−/− GFP) induces alterations at synapses on POMC neurons in the arcuate nucleus of the hypothalamus. Our studies reveal that POMC: Lepr−/− GFP mice have decreased frequency of spontaneous GABAergic, but not glutamatergic, postsynaptic currents at synapses on POMC neurons. The decay time course of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) onto POMC neurons in POMC: Lepr−/− GFP mice is significantly slower than that of sIPSCs in control animals. While analysis of individual miniature IPSCs shows lowered baseline activity, this tonic decrease is associated with an increased amplitude and slow decay of mini-IPSCs onto POMC neurons in POMC: Lepr−...
Powder-based 3D printing is an excellent technique for the fabrication of complex structural shap... more Powder-based 3D printing is an excellent technique for the fabrication of complex structural shapes. The outstanding bone remodeling capacity of calcium phosphate bioceramics is a desirable characteristic for such fabrication. Whitlockite (WH) is a calcium phosphate-based ceramic that contains Mg ions and possesses good mechanical properties, rapid resorbability, and promotes osteogenesis. The aim of this study was to fabricate 3D-printed scaffolds using marine plankton-derived WH (MP-WH) powder. The surface morphology and composition of the fabricated scaffolds were characterized by scanning electron microscopy and X-ray diffraction. The biocompatibility and osteogenic effects were evaluated using human mesenchymal stem cells. We successfully obtained a 3D porous scaffold using MP-WH. The MP-WH 3D scaffold showed improved compressive strength compared to the tricalcium phosphate (TCP) 3D scaffold. The in vitro results showed that compared with TCP 3D scaffolds, MP-WH 3D scaffolds w...
Hypoxia is one of key characteristics of microenvironments of solid tumors, and evaluation of hyp... more Hypoxia is one of key characteristics of microenvironments of solid tumors, and evaluation of hypoxia status in solid tumors is important to determine cancer stage and appropriate treatment. In the present study, novel, multivalent, near-infrared (NIR) fluorescent imaging agents were developed to measure tumor hypoxia. These agents were synthesized using an amino acid as a backbone to connect mono-, bis-, or tris-2-nitroimidazole as a hypoxia-sensitive moiety to enhance uptake by the tumor and to attach sulfo-Cyanine 5.5 as an NIR fluorophore to visualize tumor accumulation. Studies of physical characteristics demonstrated that the novel NIR imaging agents showed suitable optical properties for in vitro and in vivo imaging and were stable in serum. In vitro cellular uptake studies in SK-N-BE(2) and SW620 cell lines demonstrated that NIR imaging agents bearing 2-nitroimidazole structures showed significantly higher tumor uptake in hypoxic cells than in normoxic cells. Moreover, in vivo optical imaging studies using SK-N-BE(2) and SW620 xenografted mice demonstrated that novel, multivalent, 2-nitroimadazole NIR imaging agents with two or three 2-nitroimidazole moieties showed higher uptake in tumor than the control agents with only one 2-nitroimidazole. These observations suggest that novel, multivalent, NIR agents could serve as potential optical imaging agents for evaluating tumor hypoxia.
Stress management is a prerequisite for the survival of vertebrates because chronic stress may ca... more Stress management is a prerequisite for the survival of vertebrates because chronic stress may cause depression and is known to negatively modulate the dopaminergic reward system. Enhanced excitability of neurons in the lateral habenula (LHb) induced by chronic stress is essential for silencing dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neurons in the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on the LHb-RMTg-VTA pathway is unknown. Here, we show that both aromatic L-amino acid decarboxylase (AADC)-expressing neurons (D-neurons) in the LHb and dopaminergic neurons in the VTA are activated by acute stress, whereas GABAergic neurons in the RMTg are not. Selective stimulation of LHb D-neurons and AADC knockdown of these neurons reverse-regulate the RMTg-VTA pathway. Circuit tracing and electrophysiology data demonstrate that trace aminergic signalling by LHb D-neurons directly suppresses RMTg GABAergic neurons. Furthermore, lo...
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