Role of agmatine in the application of neural progenitor cell in central nervous system diseases: therapeutic potentials and effects / 대한해부학회지

Agmatine, the primary decarboxylation product of L-arginine, generated from arginine decarboxylase. Since the discovery of agmatine in the mammalian brain in the 1990s, an increasing number of agmatine-mediated effects have been discovered, demonstrating the benefits of agmatine on ischemic strokes, traumatic brain injury and numerous psychological disorders such as depression, anxiety, and stress. Agmatine also has cellular protective effects and contributes to cell proliferation and differentiation in the central nervous system (CNS). Neural progenitor cells are an important component in the recovery and repair of many neurological disorders due to their ability to differentiate into functional adult neurons. Recent data has revealed that agmatine can regulate and increase proliferation and the fate of progenitor cells in the adult hippocampus. This review aims to summarise and discuss the role of agmatine in the CNS; specifically, the effects and relationship between agmatine and neural progenitor cells and how these ideas can be applied to potential therapeutic application.

Role of agmatine in the application of neural progenitor cell in central nervous system diseases: therapeutic potentials and effects / 대한해부학회지

Agmatine, the primary decarboxylation product of L-arginine, generated from arginine decarboxylase. Since the discovery of agmatine in the mammalian brain in the 1990s, an increasing number of agmatine-mediated effects have been discovered, demonstrating the benefits of agmatine on ischemic strokes, traumatic brain injury and numerous psychological disorders such as depression, anxiety, and stress. Agmatine also has cellular protective effects and contributes to cell proliferation and differentiation in the central nervous system (CNS). Neural progenitor cells are an important component in the recovery and repair of many neurological disorders due to their ability to differentiate into functional adult neurons. Recent data has revealed that agmatine can regulate and increase proliferation and the fate of progenitor cells in the adult hippocampus. This review aims to summarise and discuss the role of agmatine in the CNS; specifically, the effects and relationship between agmatine and neural progenitor cells and how these ideas can be applied to potential therapeutic application.

Restorative Mechanism of Neural Progenitor Cells Overexpressing Arginine Decarboxylase Genes Following Ischemic Injury

Cell replacement therapy using neural progenitor cells (NPCs) following ischemic stroke is a promising potential therapeutic strategy, but lacks efficacy for human central nervous system (CNS) therapeutics. In a previous in vitro study, we reported that the overexpression of human arginine decarboxylase (ADC) genes by a retroviral plasmid vector promoted the neuronal differentiation of mouse NPCs. In the present study, we focused on the cellular mechanism underlying cell proliferation and differentiation following ischemic injury, and the therapeutic feasibility of NPCs overexpressing ADC genes (ADC-NPCs) following ischemic stroke. To mimic cerebral ischemia in vitro , we subjected the NPCs to oxygen-glucose deprivation (OGD). The overexpressing ADC-NPCs were differentiated by neural lineage, which was related to excessive intracellular calcium-mediated cell cycle arrest and phosphorylation in the ERK1/2, CREB, and STAT1 signaling cascade following ischemic injury. Moreover, the ADC-NPCs were able to resist mitochondrial membrane potential collapse in the increasingly excessive intracellular calcium environment. Subsequently, transplanted ADC-NPCs suppressed infarct volume, and promoted neural differentiation, synapse formation, and motor behavior performance in an in vivo tMCAO rat model. The results suggest that ADC-NPCs are potentially useful for cell replacement therapy following ischemic stroke.

Role of Agmatine on Neuroglia in Central Nervous System Injury

Recovery from central nervous system (CNS) injury, such as stroke or spinal cord injury (SCI), largely depends on axonal regeneration, and the neuronal and glial cells plasticity in the lesioned tissue. The lesioned tissue following CNS injury forms a scar that is composed of astrocytes and mixed with connective tissues. At the glial scar, the regenerating axon forms dystrophic endbulbs which do not regenerate and grow beyond the glial scar without a suitable environment. Along with the astrocytes, microglia are also suspected of being involved in necrotic and apoptotic neuronal cell death and the early response to axonal damage in CNS injury. The inflammatory response, a major component of secondary injury and controlled by the microglia, plays a pivotal role in nerve injury and control the regenerative response. As a result, it is very important to control the glial cell function in order to assure the recovery of the CNS injury. Studies have suggested that agmatine, a L-arginine derived primary amine, is a potential modulator of glial cell function after CNS injuries. Agmatine was found to possess anti-inflammatory and neuroprotective characteristics that benefited the rehabilitation process following CNS injury. In this review, we will discuss the effect of agmatine on glial cells in the process of recovery after CNS injury.

Assessment of Cognitive Impairment in a Mouse Model of High-Fat Diet-Induced Metabolic Stress with Touchscreen-Based Automated Battery System

Obesity-related metabolic disorders can affect not only systemic health but also brain function. Recent studies have elucidated that amyloid beta deposition cannot satisfactorily explain the development of Alzheimer's disease (AD) and that dysregulation of glucose metabolism is a critical factor for the sporadic onset of non-genetic AD. Identifying the pathophysiology of AD due to changes in brain metabolism is crucial; however, it is limited in measuring changes in brain cognitive function due to metabolic changes in animal models. The touchscreen-based automated battery system, which is more accurate and less invasive than conventional behavioral test tools, is used to assess the cognition of mice with dysregulated metabolism. This system was introduced in humans to evaluate cognitive function and was recently back-translated in monkeys and rodents. We used outbred ICR mice fed on high-fat diet (HFD) and performed the paired associates learning (PAL) test to detect their visual memory and new learning ability loss as well as to assess memory impairment. The behavioral performance of the HFD mice was weaker than that of normal mice in the training but was not significantly associated with motivation. In the PAL test, the average number of trials completed and proportion of correct touches was significantly lower in HFD mice than in normal diet-fed mice. Our results reveal that HFD-induced metabolic dysregulation has detrimental effects on operant learning according to the percentage of correct responses in PAL. These findings establish that HFD-induced metabolic stress may have an effect in accelerating AD-like pathogenesis.

M2 Phenotype Microglia-derived Cytokine Stimulates Proliferation and Neuronal Differentiation of Endogenous Stem Cells in Ischemic Brain

Microglia play a key role in the immune response and inflammatory reaction that occurs in response to ischemic stroke. Activated microglia promote neuronal damage or protection in injured brain tissue. Extracellular signals polarize the microglia towards the M1/M2 phenotype. The M1/M2 phenotype microglia released pro- and anti-inflammatory cytokines which induce the activation of neural stem/progenitor cells (NSPCs). In this study, we investigated how the cytokines released by microglia affect the activation of NSPCs. First, we treated BV2 cells with a lipopolysaccharide (LPS; 20 ng/ml) for M1 phenotype microglia and interleukin-4 (IL-4; 20 ng/ml) for M2 phenotype microglia in BV2 cells. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 1 h. In ex vivo, brain sections containing the subventricular zone (SVZ) were cultured in conditioned media of M1 and M2 phenotype-conditioned media for 3 d. We measured the expression of cytokines in the conditioned media by RT-PCR and ELISA. The M2 phenotype microglia-conditioned media led to the proliferation and neural differentiation of NSPCs in the ipsilateral SVZ after ischemic stroke. The RT-PCR and ELISA results showed that the expression of TGF-α mRNA was significantly higher in the M2 phenotype microglia-conditioned media. These data support that M2 phenotype microglia-derived TGF-α is one of the key factors to enhance proliferation and neural differntiation of NSPCs after ischemic stroke.

NOX Inhibitors - A Promising Avenue for Ischemic Stroke

NADPH-oxidase (NOX) mediated superoxide originally found on leukocytes, but now recognized in several types of cells in the brain. It has been shown to play an important role in the progression of stroke and related cerebrovascular disease. NOX is a multisubunit complex consisting of 2 membrane-associated and 4 cytosolic subunits. NOX activation occurs when cytosolic subunits translocate to the membrane, leading to transport electrons to oxygen, thus producing superoxide. Superoxide produced by NOX is thought to function in long-term potentiation and intercellular signaling, but excessive production is damaging and has been implicated to play an important role in the progression of ischemic brain. Thus, inhibition of NOX activity may prove to be a promising treatment for ischemic brain as well as an adjunctive agent to prevent its secondary complications. There is mounting evidence that NOX inhibition in the ischemic brain is neuroprotective, and targeting NOX in circulating immune cells will also improve outcome. This review will focus on therapeutic effects of NOX assembly inhibitors in brain ischemia and stroke. However, the lack of specificity and toxicities of existing inhibitors are clear hurdles that will need to be overcome before this class of compounds could be translated clinically.

Suppression of MicroRNA let-7a Expression by Agmatine Regulates Neural Stem Cell Differentiation

PURPOSE: Neural stem cells (NSCs) effectively reverse some severe central nervous system (CNS) disorders, due to their ability to differentiate into neurons. Agmatine, a biogenic amine, has cellular protective effects and contributes to cellular proliferation and differentiation in the CNS. Recent studies have elucidated the function of microRNA let-7a (let-7a) as a regulator of cell differentiation with roles in regulating genes associated with CNS neurogenesis. MATERIALS AND METHODS: This study aimed to investigate whether agmatine modulates the expression of crucial regulators of NSC differentiation including DCX, TLX, c-Myc, and ERK by controlling let-7a expression. RESULTS: Our data suggest that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated expression of TLX and increased expression of ERK by negatively regulating let-7a. CONCLUSION: Our study therefore enhances the present understanding of the therapeutic potential of NSCs in CNS disorders.

Suppression of MicroRNA let-7a Expression by Agmatine Regulates Neural Stem Cell Differentiation

PURPOSE: Neural stem cells (NSCs) effectively reverse some severe central nervous system (CNS) disorders, due to their ability to differentiate into neurons. Agmatine, a biogenic amine, has cellular protective effects and contributes to cellular proliferation and differentiation in the CNS. Recent studies have elucidated the function of microRNA let-7a (let-7a) as a regulator of cell differentiation with roles in regulating genes associated with CNS neurogenesis. MATERIALS AND METHODS: This study aimed to investigate whether agmatine modulates the expression of crucial regulators of NSC differentiation including DCX, TLX, c-Myc, and ERK by controlling let-7a expression. RESULTS: Our data suggest that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated expression of TLX and increased expression of ERK by negatively regulating let-7a. CONCLUSION: Our study therefore enhances the present understanding of the therapeutic potential of NSCs in CNS disorders.

Inflammation after Ischemic Stroke: The Role of Leukocytes and Glial Cells

The immune response after stroke is known to play a major role in ischemic brain pathobiology. The inflammatory signals released by immune mediators activated by brain injury sets off a complex series of biochemical and molecular events which have been increasingly recognized as a key contributor to neuronal cell death. The primary immune mediators involved are glial cells and infiltrating leukocytes, including neutrophils, monocytes and lymphocyte. After ischemic stroke, activation of glial cells and subsequent release of pro- and anti-inflammatory signals are important for modulating both neuronal cell damage and wound healing. Infiltrated leukocytes release inflammatory mediators into the site of the lesion, thereby exacerbating brain injury. This review describes how the roles of glial cells and circulating leukocytes are a double-edged sword for neuroinflammation by focusing on their detrimental and protective effects in ischemic stroke. Here, we will focus on underlying characterize of glial cells and leukocytes under inflammation after ischemic stroke.

Biocompatability of carbon nanotubes with stem cells to treat CNS injuries / 대한해부학회지

Cases reporting traumatic injuries to the brain and spinal cord are extended range of disorders that affect a large percentage of the world's population. But, there are only few effective treatments available for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. The use of stem cell therapy in regenerative medicine has been extensively examined to replace lost cells during CNS injuries. But, given the complexity of CNS injuries oxidative stress, toxic byproducts, which prevails in the microenvironment during the diseased condition, may limit the survival of the transplanted stem cells affecting tissue regeneration and even longevity. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine for the prevention, diagnosis and therapy of certain diseases, including CNS diseases. In particular, the use of CNTs as substrates/scaffolds for supporting the stem cell differentiation has been an area of active research. Single-walled and multi-walled CNT's have been increasingly used as scaffolds for neuronal growth and more recently for neural stem cell growth and differentiation. This review summarizes recent research on the application of CNT-based materials to direct the differentiation of progenitor and stem cells toward specific neurons and to enhance axon regeneration and synaptogenesis for the effective treatment of CNS injuries. Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in neurological research.

The immune modulating properties of the heat shock proteins after brain injury / 대한해부학회지

Inflammation within the central nervous system often accompanies ischemia, trauma, infection, and other neuronal injuries. The immune system is now recognized to play a major role in neuronal cell death due to microglial activation, leukocyte recruitment, and cytokine secretion. The participation of heat shock proteins (Hsps) in the immune response following in brain injury can be seen as an attempt to correct the inflammatory condition. The Hsps comprise various families on the basis of molecular size. One of the most studied is Hsp70. Hsp70 is thought to act as a molecular chaperone that is present in almost intracellular compartments, and function by refolding misfolded or aggregated proteins. Hsps have recently been studied in inflammatory conditions. Hsp70 can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. In this review, we will focus on underlying inflammatory mechanisms and Hsp70 in acute neurological injury.

Heat Treatment Suppressed the Expression and Activity of Matrix Metalloproteinases in the Primary Cultured Astrocytes / 대한해부학회지

Matrix metalloproteinases (MMPs), which is a kind of Zn-dependent enzyme, are a family of proteolytic enzymes that can degrade the extracellular matrix and then play important roles in the pathophysiology of ischemia/reperfusion, especially MMP-2 and MMP-9. This study was aimed to demonstrate how heat treatment and Hsp70 regulate expression of MMP-2 and MMP-9. The expression and regulation of MMPs after ischemic-like injury with and without heat treatment were investigated in the astrocytes expressing Hsp70 or LacZ and mock infected cells. Primary astrocyte cultures were prepared from ICR mice and infected with retroviral vectors overexpressed Hsp70 or LacZ. After heat treatment, expression of MMP-2 mRNAs was not remarkably changed in heat moc cells. Otherwise, expression of MMP-9 mRNAs was significantly reduced by heat treatment. Expression of MMP-2 and MMP-9 in astrocytes, which were treated with ischemic injury after heat treatment, was obviously decreased than in untreated Moc cells. Moreover, Hsp70s were significantly synthesized in response to heat treatment. Compared to amount of protein expression of MMP-2 and MMP-9, the expression of MMP-2 in astrocytes expressing Hsp70, LacZ and mock infected were decreased after heat treatment, especially pro-form of protein expression of MMP-2. However, the expression of MMP-9 were decreased only in the astrocytes expressing Hsp70 by heat treatment and OGD injury after heat treatment, not shown a big change in the LacZ cells and mock infected cells. The results of activity study with MMPs protein were that MMP-2 protein activity was reduced but not in condition of ischemic injury after heat treatment. On the other hand, the activity of MMP-9 after heat treatment was similar to the results of activity of MMP-9 adding ischemic injury. In this study, we shown that Hsp70 overexpression following heat treatment reduced the expression of proMMP-2, proMMP-9 and processed MMP-2, especially. This findings can suggest a possible role of Hsp70 induced by heat treatment for regulation of MMPs and neuroprotection in ischemic injury.

Exfoliative Dermatitis and Toxic Hepatitis Associated with Occupational Exposure to Trichloroethylene / 대한산업의학회지

A 28-year-old male began working as a degreaser. The solvent used in the degreasing operation was trichloroethylene. Over the next month the man experienced fever, chills, and an erythematous skin rash and itching. At that time he had a marked elevation in his liver enzyme, with cholestasis. Over the next few days the rash persisted then peeled. There was an elevation of Ig E, and a positive patch test reaction to trichloroethylene. His dermatitis and hepatitis were considered to be mediated by a hypersensitivity mechanism.

Generalized Erythema Multiforme-like Eruption is the Novel Cutaneous Manifestation of Vibrio Vulnificus Septicemia

Cutaneous manifestations of Vibrio vulnificus septicemia are bullae, vesicles, necrotic ulcers, localized swelling, cyanosis, and gangrene, which begin to occur mostly on the legs. The characteristic cutaneous lesions associated with pain often give an informative clue for the suspicion of Vibrio vulnificus infection in endemic area. We report a case of Vibrio vulnificus septicemia with atypical cutaneous manifestation of generalized erythema multiforme-like eruption in a Korean man, who died within 9 hours following hospitalization in spite of the intensive therapy. We suggest EM-like eruption of V. vulnificus septicemia is the novel cutaneous manifestation and may indicate poor prognosis.

Reconstruction of the Nose with Local Flaps / 대한피부과학회지

BACKGROUND: Reconstructive procedures are required to repair the defects following removal of the malignant tumors on the nose. Local flaps of the nose require careful preoperative planning and meticulous surgical technique because of unique anatomic features and cosmetically central location in the face. OBJECTIVE: The purpose of this study was to investigate the preferred local flap modalities used to reconstruct the defects occurred after removing skin tumors on the nose. METHOD: From January 1995 to June 2001, thirty-nine patients reconstructed with local flaps to repair surgical defects of the nose following excision for the treatment of malignant skin tumors were included in this study. RESULTS: It was clear that the choice of flap is depended on the location of the defect. Defects on the upper two thirds were repaired differently than were defects on the lower one third. Of the thirty-nine patients, twenty-three patients had a tumor on the upper two thirds of the nose and sixteen patients had a tumor on the lower one third of the nose. Used local flap modalities were as follows. Upper two thirds of the nose - transposition flap(56.5%), rotation flap(26.1%), advancement flap(8.7%), subcutaneous island pedicle flap(4.35%) and combining flap(4.35%). Lower one third of the nose - transposition flap(81.25%), rotation flap(12.5%) and subcutaneous island pedicle flap(6.25%). CONCLUSION: Transposition flaps including rhombic and nasolabial flaps were the most useful of all flaps for each subunit.

A Case of Sporotrichoid Fish Tank Granuloma / 대한피부과학회지

Mycobacterium marinum, group I photochromogen, is an atypical mycobacterium living in an aquatic environment including swimming pools, lagoon, lake, or fish tanks. Infections with M. marinum are not common, so only three cases have been reported in Korea. In general, skin lesions evolve as a solitary nodule or pustule but occasionally sporotrichoid spreading along the course of lymphatic vessels occurs. A 46-year-old woman visited our department with 2X1.5cm sized erythmatous ulcerated nodule on her right hand dorsum and several rice-sized subcutaneous nodules along the ascending course of lymphatic vessels on her right forearm. She had cleaned fish tank two months before the skin lesion developed. A AFB-positive microorganism was isolated by culture of the tissue specimen, which grew slowly at 30degrees C and those colonies showed yellowish color after light exposure on Ogawa medium. This microorganism was confirmed as M. marinum by polymerase chain reaction and restriction enzyme analysis. To the best of our knowledge, this is the first case of sporotrichoid granuloma due to M marinum infection occurred in association with fish tank in Korea.

Expression of Fas and Fas ligand on Ultraviolet B-irradiated Skin / 대한피부과학회지

BACKGROUND: It is well known that ultraviolet-induced cell death is mediated by p53 and Fas in the skin. Elimination of DNA-damaged cells after ultraviolet radiation(UVR) through sunburn cell(apoptotic keratinocyte) formation is thought to be pivotal for the removal of precancerous skin cells. Sunburn cell formation was found to be dependent on Fas ligand(FasL), a pro-apoptotic protein induced by DNA damage. OBJECTIVE: This study was aimed to evaluate the relationship between changes of Fas/FasL expression and sunburn cell formation by ultraviolet B(UVB) irradiation in rat skin. METHOD: Expression of Fas and FasL induced by UVB was evaluated by western blotting and direct immunofluorescence test. In addition, sunburn cells were counted in the epidermal sections from UVB irradiated rat skin. RESULTS: Fas and FasL expression were increased from 3 and 12 hours as time lapsed after UVB irradiation, respectively. UVB irradiation caused sunburn cell formation from 6 hours after irradiation, and then peaked at 24 hours after irradiation. This result revealed FasL expression is closely related to sunburn cell formation in view of time after irradiation. CONCLUSION: FasL-mediated apoptosis is important for skin homeostasis. Further studies on the roles of Fas/FasL in the UVB-irradiated skin should be performed to understand the response of the skin to ultraviolet irradiation.

Expression of Fas and Fas ligand on Ultraviolet B-irradiated Skin / 대한피부과학회지

BACKGROUND: It is well known that ultraviolet-induced cell death is mediated by p53 and Fas in the skin. Elimination of DNA-damaged cells after ultraviolet radiation(UVR) through sunburn cell(apoptotic keratinocyte) formation is thought to be pivotal for the removal of precancerous skin cells. Sunburn cell formation was found to be dependent on Fas ligand(FasL), a pro-apoptotic protein induced by DNA damage. OBJECTIVE: This study was aimed to evaluate the relationship between changes of Fas/FasL expression and sunburn cell formation by ultraviolet B(UVB) irradiation in rat skin. METHOD: Expression of Fas and FasL induced by UVB was evaluated by western blotting and direct immunofluorescence test. In addition, sunburn cells were counted in the epidermal sections from UVB irradiated rat skin. RESULTS: Fas and FasL expression were increased from 3 and 12 hours as time lapsed after UVB irradiation, respectively. UVB irradiation caused sunburn cell formation from 6 hours after irradiation, and then peaked at 24 hours after irradiation. This result revealed FasL expression is closely related to sunburn cell formation in view of time after irradiation. CONCLUSION: FasL-mediated apoptosis is important for skin homeostasis. Further studies on the roles of Fas/FasL in the UVB-irradiated skin should be performed to understand the response of the skin to ultraviolet irradiation.

A Case of Klippel-Trenaunay Syndrome with Lymphangioma Circumscriptum / 대한피부과학회지

Klippel-Trenaunay Syndrome(KTS) is a rare clinical syndrome of children and young adults characterized by port-wine stain, varicose veins and venous malformations, and hypertrophy of soft tissue and bone of the extremity which are involved usually unilateral but occasionally bilateral. Additional variants and complicating features include varicose pulmonary veins, cutaneous lymphangiomas, hemihypertrophy of the face, hyperhidrosis, hypertrichosis, cellulitis, paresthesias, syndactyly, macrodactyly, spina bifida, and decalcification of involved bone. We report a 14-year-old girl with port-wine stain on her both flank and left thigh associated with hypertrophy of left lower extremity. She also has lymphangioma circumscriptum on left thigh, macrodactyly, and syndactyly . To the best of our knowledge, this is the first reported case of KTS with lymphagioma circumscriptum in Korea.