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Rapid Assessment of Microbiota Changes in Individuals with Autism Spectrum Disorder Using Bacteria-derived Membrane Vesicles in Urine.

Yunjin LEE ; Jin Young PARK ; Eun Hwa LEE ; Jinho YANG ; Bo Ri JEONG ; Yoon Keun KIM ; Ju Young SEOH ; SoHyun LEE ; Pyung Lim HAN ; Eui Jung KIM

Experimental Neurobiology.2017;26(5):307-317. doi:10.5607/en.2017.26.5.307

Individuals with autism spectrum disorder (ASD) have altered gut microbiota, which appears to regulate ASD symptoms via gut microbiota-brain interactions. Rapid assessment of gut microbiota profiles in ASD individuals in varying physiological contexts is important to understanding the role of the microbiota in regulating ASD symptoms. Microbiomes secrete extracellular membrane vesicles (EVs) to communicate with host cells and secreted EVs are widely distributed throughout the body including the blood and urine. In the present study, we investigated whether bacteria-derived EVs in urine are useful for the metagenome analysis of microbiota in ASD individuals. To address this, bacterial DNA was isolated from bacteria-derived EVs in the urine of ASD individuals. Subsequent metagenome analysis indicated markedly altered microbiota profiles at the levels of the phylum, class, order, family, and genus in ASD individuals relative to control subjects. Microbiota identified from urine EVs included gut microbiota reported in previous studies and their up- and down-regulation in ASD individuals were partially consistent with microbiota profiles previously assessed from ASD fecal samples. However, overall microbiota profiles identified in the present study represented a distinctive microbiota landscape for ASD. Particularly, the occupancy of g_Pseudomonas, g_Sphingomonas, g_Agrobacterium, g_Achromobacter, and g_Roseateles decreased in ASD, whereas g_Streptococcus, g_Akkermansia, g_Rhodococcus, and g_Halomonas increased. These results demonstrate distinctively altered gut microbiota profiles in ASD, and validate the utilization of urine EVs for the rapid assessment of microbiota in ASD.
Autism Spectrum Disorder* ; Autistic Disorder* ; DNA, Bacterial ; Down-Regulation ; Gastrointestinal Microbiome ; Humans ; Membranes* ; Metagenome ; Microbiota*

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Inhibition of HIF1α and PDK Induces Cell Death of Glioblastoma Multiforme.

Jiwon Esther HAN ; Pyung Won LIM ; Chul Min NA ; You Sik CHOI ; Joo Young LEE ; Yona KIM ; Hyung Woo PARK ; Hyo Eun MOON ; Man Seung HEO ; Hye Ran PARK ; Dong Gyu KIM ; Sun Ha PAEK

Experimental Neurobiology.2017;26(5):295-306. doi:10.5607/en.2017.26.5.295

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. GBMs, like other tumors, rely relatively less on mitochondrial oxidative phosphorylation (OXPHOS) and utilize more aerobic glycolysis, and this metabolic shift becomes augmented under hypoxia. In the present study, we investigated the physiological significance of altered glucose metabolism and hypoxic adaptation in the GBM cell line U251 and two newly established primary GBMs (GBM28 and GBM37). We found that these three GBMs exhibited differential growth rates under hypoxia compared to those under normoxia. Under normoxia, the basal expressions of HIF1α and the glycolysis-associated genes, PDK1, PDK3, and GLUT1, were relatively low in U251 and GBM28, while their basal expressions were high in GBM37. Under hypoxia, the expressions of these genes were enhanced further in all three GBMs. Treatment with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), induced cell death in GBM28 and GBM37 maintained under normoxia, whereas DCA effects disappeared under hypoxia, suggesting that hypoxic adaptation dominated DCA effects in these GBMs. In contrast, the inhibition of HIF1α with chrysin suppressed the expression of PDK1, PDK3, and GLUT1 and markedly promoted cell death of all GBMs under both normoxia and hypoxia. Interestingly, however, GBMs treated with chrysin under hypoxia still sustained higher viability than those under normoxia, and chrysin and DCA co-treatment was unable to eliminate this hypoxia-dependent resistance. Together, these results suggest that hypoxic adaptation is critical for maintaining viability of GBMs, and targeting hypoxic adaptation can be an important treatment option for GBMs.
Anoxia ; Brain Neoplasms ; Cell Death* ; Cell Line ; Dichloroacetic Acid ; Glioblastoma* ; Glucose ; Glycolysis ; Metabolism ; Oxidative Phosphorylation ; Oxidoreductases ; Phosphotransferases ; Pyruvic Acid

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Structural and Functional Alterations at Pre-Epileptic Stage Are Closely Associated with Epileptogenesis in Pilocarpine-induced Epilepsy Model.

Hani KIM ; Yunsook CHOI ; Hye Young JOUNG ; Yun Seo CHOI ; Hyeon Jin KIM ; Yohan JOO ; Jin Hwan OH ; Hoo Jae HANN ; Zang Hee CHO ; Hyang Woon LEE

Experimental Neurobiology.2017;26(5):287-294. doi:10.5607/en.2017.26.5.287

Pilocarpine-induced rat epilepsy model is an established animal model that mimics medial temporal lobe epilepsy in humans. The purpose of this study was to investigate neuroimaging abnormalities in various stages of epileptogenesis and to correlate them with seizure severity in pilocarpine-induced rat epilepsy model. Fifty male Sprague-Dawley rats were subject to continuous video and electroencephalographic monitoring after inducing status epilepticus (SE) and seizure severity was estimated by frequency and total durations of class 3 to 5 spontaneous recurrent seizures (SRS) by modified Racine's classification. The 7.0 Tesla magnetic resonance imaging (MRI) with high resolution flurodeoxyglucose positron emission tomography (FDG-PET) was performed at 3 hours, 1, 3, 7 days and 4 weeks after the initial insult. The initial SRS was observed 9.7±1.3 days after the pilocarpine injection. MRI revealed an abnormal T2 signal change with swelling in both hippocampi and amygdala in acute (day 1 after injection) and latent phases (days 3 and 7), in association with PET hypometabolism in these areas. Interestingly, the mean frequency of class 3 to 5 SRS was positively correlated with abnormal T2 signals in hippocampal area at 3 days. SRS duration became longer with more decreased glucose metabolism in both hippocampi and amygdala at 7 days after pilocarpine injection. This study indicates that development and severity of SRS at chronic phase could be closely related with structural and functional changes in hippocampus during the latent period, a pre-epileptic stage.
Amygdala ; Animals ; Classification ; Epilepsy* ; Epilepsy, Temporal Lobe ; Glucose ; Hippocampus ; Humans ; Magnetic Resonance Imaging ; Male ; Metabolism ; Models, Animal ; Neuroimaging ; Pilocarpine ; Positron-Emission Tomography ; Rats ; Rats, Sprague-Dawley ; Seizures ; Status Epilepticus

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Agmatine Modulates the Phenotype of Macrophage Acute Phase after Spinal Cord Injury in Rats.

Jae Hwan KIM ; Jae Young KIM ; Chin Hee MUN ; Minah SUH ; Jong Eun LEE

Experimental Neurobiology.2017;26(5):278-286. doi:10.5607/en.2017.26.5.278

Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206+ & ED1+ cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype.
Agmatine* ; Animals ; Arginine ; Contusions ; Immunohistochemistry ; Interleukin-10 ; Macrophages* ; N-Methylaspartate ; Neuralgia ; Neuroprotection ; Neuroprotective Agents ; Nitric Oxide Synthase ; Phenotype* ; Rats* ; RNA, Messenger ; Spinal Cord Injuries* ; Spinal Cord*

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Beneficial Effects of Silibinin Against Kainic Acid-induced Neurotoxicity in the Hippocampus in vivo.

Sehwan KIM ; Un Ju JUNG ; Yong Seok OH ; Min Tae JEON ; Hyung Jun KIM ; Won Ho SHIN ; Jungwan HONG ; Sang Ryong KIM

Experimental Neurobiology.2017;26(5):266-277. doi:10.5607/en.2017.26.5.266

Silibinin, an active constituent of silymarin extracted from milk thistle, has been previously reported to confer protection to the adult brain against neurodegeneration. However, its effects against epileptic seizures have not been examined yet. In order to investigate the effects of silibinin against epileptic seizures, we used a relevant mouse model in which seizures are manifested as status epilepticus, induced by kainic acid (KA) treatment. Silibinin was injected intraperitoneally, starting 1 day before an intrahippocampal KA injection and continued daily until analysis of each experiment. Our results indicated that silibinin-treatment could reduce seizure susceptibility and frequency of spontaneous recurrent seizures (SRS) induced by KA administration, and attenuate granule cell dispersion (GCD), a morphological alteration characteristic of the dentate gyrus (DG) in temporal lobe epilepsy (TLE). Moreover, its treatment significantly reduced the aberrant levels of apoptotic, autophagic and pro-inflammatory molecules induced by KA administration, resulting in neuroprotection in the hippocampus. Thus, these results suggest that silibinin may be a beneficial natural compound for preventing epileptic events.
Adult ; Animals ; Brain ; Dentate Gyrus ; Epilepsy ; Epilepsy, Temporal Lobe ; Hippocampus* ; Humans ; Kainic Acid ; Mice ; Milk Thistle ; Neuroprotection ; Seizures ; Silymarin ; Status Epilepticus

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Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development.

Ki Chan KIM ; Chang Soon CHOI ; Edson Luck T GONZALES ; Darine Froy N MABUNGA ; Sung Hoon LEE ; Se Jin JEON ; Ram HWANGBO ; Minha HONG ; Jong Hoon RYU ; Seol Heui HAN ; Geon Ho BAHN ; Chan Young SHIN

Experimental Neurobiology.2017;26(5):252-265. doi:10.5607/en.2017.26.5.252

The valproic acid (VPA)-induced animal model is one of the most widely utilized environmental risk factor models of autism. Autism spectrum disorder (ASD) remains an insurmountable challenge among neurodevelopmental disorders due to its heterogeneity, unresolved pathological pathways and lack of treatment. We previously reported that VPA-exposed rats and cultured rat primary neurons have increased Pax6 expression during post-midterm embryonic development which led to the sequential upregulation of glutamatergic neuronal markers. In this study, we provide experimental evidence that telomerase reverse transcriptase (TERT), a protein component of ribonucleoproteins complex of telomerase, is involved in the abnormal components caused by VPA in addition to Pax6 and its downstream signals. In embryonic rat brains and cultured rat primary neural progenitor cells (NPCs), VPA induced the increased expression of TERT as revealed by Western blot, RT-PCR, and immunostainings. The HDAC inhibitor property of VPA is responsible for the TERT upregulation. Chromatin immunoprecipitation revealed that VPA increased the histone acetylation but blocked the HDAC1 binding to both Pax6 and Tert genes. Interestingly, the VPA-induced TERT overexpression resulted to sequential upregulations of glutamatergic markers such as Ngn2 and NeuroD1, and inter-synaptic markers such as PSD-95, α-CaMKII, vGluT1 and synaptophysin. Transfection of Tert siRNA reversed the effects of VPA in cultured NPCs confirming the direct involvement of TERT in the expression of those markers. This study suggests the involvement of TERT in the VPA-induced autistic phenotypes and has important implications for the role of TERT as a modulator of balanced neuronal development and transmission in the brain.
Acetylation ; Animals ; Autism Spectrum Disorder ; Autistic Disorder ; Blotting, Western ; Brain ; Chromatin Immunoprecipitation ; Embryonic Development ; Female ; Histones ; Models, Animal ; Neurodevelopmental Disorders ; Neurons ; Phenotype ; Population Characteristics ; Pregnancy ; Rats ; Ribonucleoproteins ; Risk Factors ; RNA, Small Interfering ; Stem Cells ; Synaptophysin ; Telomerase* ; Transfection ; Up-Regulation ; Valproic Acid*

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Modulating the Voltage-sensitivity of a Genetically Encoded Voltage Indicator.

Arong JUNG ; Dhanarajan RAJAKUMAR ; Bong June YOON ; Bradley J BAKER

Experimental Neurobiology.2017;26(5):241-251. doi:10.5607/en.2017.26.5.241

Saturation mutagenesis was performed on a single position in the voltage-sensing domain (VSD) of a genetically encoded voltage indicator (GEVI). The VSD consists of four transmembrane helixes designated S1-S4. The V220 position located near the plasma membrane/extracellular interface had previously been shown to affect the voltage range of the optical signal. Introduction of polar amino acids at this position reduced the voltage-dependent optical signal of the GEVI. Negatively charged amino acids slightly reduced the optical signal by 33 percent while positively charge amino acids at this position reduced the optical signal by 80%. Surprisingly, the range of V220D was similar to that of V220K with shifted optical responses towards negative potentials. In contrast, the V220E mutant mirrored the responses of the V220R mutation suggesting that the length of the side chain plays in role in determining the voltage range of the GEVI. Charged mutations at the 219 position all behaved similarly slightly shifting the optical response to more negative potentials. Charged mutations to the 221 position behaved erratically suggesting interactions with the plasma membrane and/or other amino acids in the VSD. Introduction of bulky amino acids at the V220 position increased the range of the optical response to include hyperpolarizing signals. Combining The V220W mutant with the R217Q mutation resulted in a probe that reduced the depolarizing signal and enhanced the hyperpolarizing signal which may lead to GEVIs that only report neuronal inhibition.
Amino Acids ; Cell Membrane ; Fluorescence ; Mutagenesis ; Neurons ; Plasma

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Balo's Concentric Sclerosis Mimicking Cerebral Tuberculoma.

Yoo Ri SON ; Hyeran YANG ; Sehoon LEE ; Jee Young KIM ; Suk Geun HAN ; Kyung Seok PARK

Experimental Neurobiology.2015;24(2):169-172. doi:10.5607/en.2015.24.2.169

Balo's concentric sclerosis (BCS) is considered a rare variant of multiple sclerosis, which often mimics an intracranial neoplasm or abscess. We report the case of a 21-year-old woman presenting with BCS while undergoing treatment for pulmonary tuberculosis. Initial brain magnetic resonance imaging (MRI) findings were similar to those for cerebral tuberculoma, multiple metastases, or abscesses. However, the pathognomonic concentric sclerosis characteristic of BCS was seen on MRI. The antemortem confirmatory diagnosis of BCS was made by follow-up MRI and a brain biopsy. It is suggested that BCS should be included in the differential diagnosis of cerebral tuberculoma, especially in developing countries with a high prevalence of tuberculosis.
Abscess ; Adrenal Cortex Hormones ; Biopsy ; Brain ; Brain Neoplasms ; Developing Countries ; Diagnosis ; Diagnosis, Differential ; Diffuse Cerebral Sclerosis of Schilder* ; Female ; Follow-Up Studies ; Humans ; Magnetic Resonance Imaging ; Multiple Sclerosis ; Neoplasm Metastasis ; Prevalence ; Sclerosis ; Tuberculoma* ; Tuberculosis ; Tuberculosis, Pulmonary ; Young Adult

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Chronic Antidepressant Treatment in Normal Mice Induces Anxiety and Impairs Stress-coping Ability.

In Sun BAEK ; Jin Young PARK ; Pyung Lim HAN

Experimental Neurobiology.2015;24(2):156-168. doi:10.5607/en.2015.24.2.156

Antidepressants are clinically used for patients with major depression. Antidepressant treatments in certain groups of patients are effective for relieving depression as well as anxiety disorder. However, it is not clearly known whether the use of current antidepressants in healthy persons is beneficial for upcoming depression- and anxiety-inducing life events. To address this question, normal mice were intraperitoneally administered with imipramine or fluoxetine for more than 2 weeks, and behaviors related to anxiety and depression were evaluated. Mice treated with imipramine or fluoxetine for more than 14 days exhibited significantly decreased immobility time in the forced swim test and tail suspension test, but these mice exhibited enhanced anxiety in several behavioral tests. Furthermore, chronic antidepressant treatments followed by sub-threshold level of stress in normal mice profoundly aggravated antidepressant-induced anxiety-like behaviors without further affecting depression-related behaviors. Chronic antidepressant treatments followed by sub-threshold level of stress produced swollen vesicles and ulcerations on the lips as well as a watery and inflammatory nose. Mice given chronic antidepressant treatments displayed intestinal abnormalities evidenced by a highly enlarged and inflamed small intestine full of defecation materials. These results suggest that chronic antidepressant treatment in normal mice provokes anxiety-like behaviors and impairs their stress-coping ability.
Animals ; Antidepressive Agents ; Anxiety Disorders ; Anxiety* ; Defecation ; Depression ; Fluoxetine ; Hindlimb Suspension ; Humans ; Imipramine ; Intestine, Small ; Lip ; Mice* ; Nose ; Ulcer

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Relapsing Polychondritis Presented with Encephalitis Followed by Brain Atrophy.

Suk Won AHN ; Moo Seok PARK ; Hae Bong JEONG ; Oh Sang KWON ; Byung Nam YOON ; Hee Sung KIM ; Sang Tae CHOI

Experimental Neurobiology.2017;26(1):66-69. doi:10.5607/en.2017.26.1.66

Relapsing polychondritis (RP) is a rare autoimmune disease that is characterized by inflammatory reaction of unknown etiology and destruction of cartilaginous structures. Characteristic symptoms of this disease include cartilage inflammation of the ear, nose, larynx, trachea, bronchi, joints, eyes, heart and skin. Concomitance with neurologic symptom is very rare in RP, and the detailed underlying mechanism of neurological involvement associated with RP is not fully understood. We herein described an unusual recurrent case of inflammatory brain lesions associated with RP, with attention to clinical manifestations, autoimmune disease involvement, and therapeutic effects.
Atrophy* ; Autoimmune Diseases ; Brain* ; Bronchi ; Cartilage ; Ear ; Encephalitis* ; Heart ; Inflammation ; Joints ; Larynx ; Multiple Sclerosis ; Neurologic Manifestations ; Neuromyelitis Optica ; Nose ; Polychondritis, Relapsing* ; Skin ; Therapeutic Uses ; Trachea

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