RESUMO
The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excretion of uric acid. However, the mechanisms driving cholesterol impacts on uric acid transporters have been unknown. Here, we show that cholesterol metabolite 27-hydroxycholesterol (27HC) upregulates the uric acid reabsorption transporter URAT1 encoded by SLC22A12 via estrogen receptors (ER). Transcriptional motif analysis showed that the SLC22A12 gene promoter has more estrogen response elements (EREs) than other uric acid reabsorption transporters such as SLC22A11 and SLC22A13, and 27HC-activated SLC22A12 gene promoter via ER through EREs. Furthermore, 27HC increased SLC22A12 gene expression in human kidney organoids. Our results suggest that in hypercholesterolemic conditions, elevated levels of 27HC derived from cholesterol induce URAT1/SLC22A12 expression to increase uric acid reabsorption, and thereby, could increase serum uric acid levels.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxicolesteróis/farmacologia , Rim/metabolismo , Transportadores de Ânions Orgânicos/biossíntese , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Receptores de Estrogênio/metabolismo , Humanos , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Organoides/metabolismo , Receptores de Estrogênio/genéticaRESUMO
The anticancer agent 5-fluorouracil (5-FU) is cytotoxic and often used to treat various cancers. 5-FU is thought to inhibit the enzyme thymidylate synthase, which plays a role in nucleotide synthesis and has been found to induce single- and double-strand DNA breaks. ATR Ser/Thr kinase (ATR) is a principal kinase in the DNA damage response and is activated in response to UV- and chemotherapeutic drug-induced DNA replication stress, but its role in cellular responses to 5-FU is unclear. In this study, we examined the effect of ATR inhibition on 5-FU sensitivity of mammalian cells. Using immunoblotting, we found that 5-FU treatment dose-dependently induced the phosphorylation of ATR at the autophosphorylation site Thr-1989 and thereby activated its kinase. Administration of 5-FU with a specific ATR inhibitor remarkably decreased cell survival, compared with 5-FU treatment combined with other major DNA repair kinase inhibitors. Of note, the ATR inhibition enhanced induction of DNA double-strand breaks and apoptosis in 5-FU-treated cells. Using gene expression analysis, we found that 5-FU induced the activation of the intra-S cell-cycle checkpoint. Cells lacking BRCA2 were sensitive to 5-FU in the presence of ATR inhibitor. Moreover, ATR inhibition enhanced the efficacy of the 5-FU treatment, independently of the nonhomologous end-joining and homologous recombination repair pathways. These findings suggest that ATR could be a potential therapeutic target in 5-FU-based chemotherapy.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Reparo de DNA por Recombinação/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular Tumoral , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Raios UltravioletaAssuntos
Dermatite de Contato , Dermatite , Fator Regulador 3 de Interferon , Humanos , Imunidade Inata , Inflamação , PeleRESUMO
Tumors developed in 2 old women presented with pathological findings similar to seborrheic keratosis, although the clinical feature of tumor showed typical keratoacanthoma. In addition to these two cases, we compared the pathological findings of a total of four cases, one case each of keratoacanthoma and seborrheic keratosis, which were clinically and histopathological typical. These two cases and the typical keratoacanthoma showed cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and infiltration of cytotoxic T cells. The keratoacanthoma in the decompensated stage may be histologically similar to seborrheic keratosis. TUNEL staining can help in the diagnosis of fading keratoacanthoma.
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Proline:arginine (PR) poly-dipeptides from the GGGGCC repeat expansion in C9orf72 have cytotoxicity and bind intermediate filaments (IFs). However, it remains unknown how PR poly-dipeptides affect cytoskeletal organization and focal adhesion (FA) formation. Here, we show that changes to the cytoskeleton and FA by PR poly-dipeptides result in the alteration of cell stiffness and mechanical stress response. PR poly-dipeptides increased the junctions and branches of the IF network and increased cell stiffness. They also changed the distribution of actin filaments and increased the size of FA and intracellular calcium concentration. PR poly-dipeptides or an inhibitor of IF organization prevented cell detachment. Furthermore, PR poly-dipeptides induced upregulation of mechanical stress response factors and led to a maladaptive response to cyclic stretch. These results suggest that the effects of PR poly-dipeptides on mechanical properties and mechanical stress response may serve as a pathogenesis of C9orf72-related neurodegeneration.
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Ischemic stroke is one of the most common neurological diseases. However, the impact of ischemic stroke on human cerebral tissue remains largely unknown due to a lack of ischemic human brain samples. In this study, we applied cerebral organoids derived from human induced pluripotent stem cells to evaluate the effect of oxygen-glucose deprivation/reoxygenation (OGD/R). Pathway analysis showed the relationships between vitamin digestion and absorption, fat digestion and absorption, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and complement and coagulation cascades. Combinational verification with transcriptome and gene expression analysis of different cell types revealed fatty acids-related PPAR signaling pathway and pyruvate kinase isoform M2 (PKM2) as key markers of neuronal cells in response to OGD/R. These findings suggest that, although there remain some limitations to be improved, our ischemic stroke model using human cerebral organoids would be a potentially useful tool when combined with other conventional two-dimensional (2D) mono-culture systems.
RESUMO
Nuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-ß2 (Kapß2) at 1:1 ratio. The nuclear magnetic resonances of Kapß2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapß2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration.
Assuntos
Transporte Ativo do Núcleo Celular/genética , Proteína C9orf72/química , Peptídeos/química , beta Carioferinas/química , Sítios de Ligação , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Clonagem Molecular , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células HeLa , Humanos , Modelos Moleculares , Sinais de Localização Nuclear/genética , Sinais de Localização Nuclear/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Transição de Fase , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , beta Carioferinas/antagonistas & inibidores , beta Carioferinas/genética , beta Carioferinas/metabolismoRESUMO
The brainstem is a posterior region of the brain, composed of three parts, midbrain, pons, and medulla oblongata. It is critical in controlling heartbeat, blood pressure, and respiration, all of which are life-sustaining functions, and therefore, damages to or disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells (hPSCs) recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models are limited in the extent hPSCs recapitulate human brain development and hence are not able to fully elucidate the diseases affecting various components of the brain such as brainstem. Here, we developed a method to generate human brainstem organoids (hBSOs), containing midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, dopaminergic neurons, and neural crest lineage cells. Single-cell RNA sequence (scRNA-seq) analysis, together with evidence from proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem, which raises the possibility of making use of hBSOs in investigating central nervous system disorders affecting brainstem and in efficient drug screenings.
Assuntos
COVID-19 , Dermatomiosite , Humanos , Vacinas contra COVID-19/efeitos adversos , Dermatomiosite/diagnóstico , Dermatomiosite/tratamento farmacológico , COVID-19/prevenção & controle , Imunossupressores , Vacinação , Helicase IFIH1 Induzida por Interferon , Autoanticorpos , Prognóstico , Estudos RetrospectivosRESUMO
In recent years, the number of patients receiving in vitro fertilization (IVF) has been increasing, though the rate of successful implantations has remained at 10-20%. A major goal of this procedure is to afford the ability to select embryos with the most potential for implantation and development. Previous studies claimed to have detected soluble HLA-G (sHLA-G) protein in culture supernatant from 2 to 3-day embryos using ELISA methods, and concluded that sHLA-G protein levels were associated with successful implantation. This result, if substantiated could provide an important tool for IVF. In this study, we have re-examined these experiments by attempting to detect sHLA-G in the medium from 2 to 3-day embryos (84 samples) and 4 to 6-day embryos (25 samples) in which a part of blastocyst has started to differentiate into trophoblasts. Using a highly specific and sensitive ELISA, no sHLA-G protein was detectable in any sample, despite the fact that 27 of the 109 samples were from successfully implanted embryos. These results indicate that 2-6-day embryos do not secrete sHLA-G detectable by ELISA, and therefore that sHLA-G in culture medium is not a useful for successful implantation at this stage of development.
Assuntos
Embrião de Mamíferos/imunologia , Ensaio de Imunoadsorção Enzimática , Antígenos HLA/análise , Antígenos de Histocompatibilidade Classe I/análise , Meios de Cultura/análise , Técnicas de Cultura Embrionária , Implantação do Embrião , Desenvolvimento Embrionário , Feminino , Fertilização in vitro , Antígenos HLA/isolamento & purificação , Antígenos HLA-G , Antígenos de Histocompatibilidade Classe I/isolamento & purificação , Humanos , Gravidez , Sensibilidade e EspecificidadeRESUMO
To verify the extent of contribution of spontaneous DNA lesions to spontaneous mutagenesis, we have developed a new genetic system to examine simultaneously both forward mutations and recombination events occurring within about 600 base pairs of a transgenic rpsL target sequence located on Escherichia coli chromosome. In a wild-type strain, the recombination events were occurring at a frequency comparable to that of point mutations within the rpsL sequence. When the cells were UV-irradiated, the recombination events were induced much more sharply than point mutations. In a recA null mutant, no recombination event was observed. These data suggest that the blockage of DNA replication, probably caused by spontaneous DNA lesions, occurs often in normally growing E. coli cells and is mainly processed by cellular functions requiring the RecA protein. However, the recA mutant strain showed elevated frequencies of single-base frameshifts and large deletions, implying a novel mutator action of this strain. A similar mutator action of the recA mutant was also observed with a plasmid-based rpsL mutation assay. Therefore, if the recombinogenic problems in DNA replication are not properly processed by the RecA function, these would be a potential source for mutagenesis leading to single-base frameshift and large deletion in E. coli. Furthermore, the single-base frameshifts induced in the recA-deficient cells appeared to be efficiently suppressed by the mutS-dependent mismatch repair system. Thus, it seems likely that the single-base frameshifts are derived from slippage errors that are not directly caused by DNA lesions but made indirectly during some kind of error-prone DNA synthesis in the recA mutant cells.
Assuntos
Escherichia coli/genética , Mutagênese/fisiologia , Recombinases Rec A/fisiologia , Sequência de Bases , Cromossomos Bacterianos , Proteínas de Escherichia coli , Modelos Biológicos , Dados de Sequência Molecular , Mutagênese/genética , Mutação de Sentido Incorreto , Organismos Geneticamente Modificados , Fenótipo , Recombinases Rec A/genética , Proteína S9 Ribossômica , Proteínas Ribossômicas/genéticaRESUMO
BACKGROUND: Major depressive disorder (MDD) is often resistant to treatment with usual approaches. Patients with MDD have shown hypofunction of the frontotemporal cortex in verbal fluency test (VFT)-related near-infrared spectroscopy (NIRS). METHODS: We examined whether the reactions to drug treatment in treatment-naive patients with MDD could be predicted by NIRS outcomes at the initial investigation. All subjects underwent psychological testing to determine levels of anxiety and depression. VFT was used to examine the functioning of the frontotemporal lobes. We administered selective serotonin reuptake inhibitors (SSRIs) for 12 weeks. Subjects included 28 patients with MDD with response to SSRIs (Response group), 19 with no response (Non-Response group), and 63 age-, sex-, and education years-matched healthy controls (HC). RESULTS: We found in the frontotemporal region that hemodynamic responses were significantly smaller in patients with Response and Non-Response groups than in HC before treatment. We also found in the medial frontal region that hemodynamic responses were significantly larger in patients with Response groups than in patients with Non-Response group before treatment. Patients with MDD scored significantly higher anxiety and depressive states than those in HC on several measures. The Response and Non-Response groups also had higher scores in future denial, threat prediction, self-denial, past denial, and interpersonal threat sections of Anxiety Cognition Scale (DACS). According to the stepwise regression analysis, one variable was determined as independent predictors of response: confusion (Post-POMS). LIMITATIONS: The number of patients and healthy controls was relatively small, and we will increase the number of participants in future studies. NIRS has reduced spatial resolution, which confuses the identification of the measurement position when using NIRS alone. CONCLUSION: Cognitive vulnerabilities are associated with predictors of SSRI treatment response. Different hemodynamic activities in the frontotemporal cortex predict response to SSRI treatment in MDD.
Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto , Cognição/fisiologia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
INTRODUCTION: Obsessive-compulsive personality disorder (OCPD) has a pervasive pattern of preoccupation with orderliness, perfection, and mental and interpersonal control at the expense of flexibility, openness, and efficiency. The aims of the present study were to explore the relationship between OCPD and psychological stress and psychological tests. METHODS: We evaluated 63 OCPD patients and 107 healthy controls (HCs). We collected saliva samples from patients and controls before and after a social stress procedure, the Trier Social Stress Test (TSST), to measure the concentrations of salivary alpha-amylase (sAA) and salivary cortisol. The Childhood Trauma Questionnaire (CTQ), Profile of Mood State (POMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Social Adaptation Self-Evaluation Scale (SASS), and Depression and Anxiety Cognition Scale (DACS) were administered to patients and HCs. RESULTS: Following TSST exposure, the salivary amylase and cortisol levels were significantly decreased in male patients compared with controls. Additionally, OCPD patients had higher CTQ, POMS, STAI, and BDI scores than HCs and exhibited significantly higher anxiety and depressive states. OCPD patients scored higher on future denial and threat prediction as per the DACS tool. According to a stepwise regression analysis, STAI, POMS, and salivary cortisol responses were independent predictors of OCPD. CONCLUSIONS: Our results suggested that attenuated sympathetic and parasympathetic reactivity in male OCPD patients occurs along with attenuated salivary amylase and cortisol responses to the TSST. In addition, there was a significant difference between OCPD patients and HCs in child trauma, mood, anxiety, and cognition. The finding support the modeling role of cortisol (20min) on the relationships between STAI trait and depression among OCPD.
Assuntos
Hidrocortisona/metabolismo , Transtorno Obsessivo-Compulsivo/metabolismo , alfa-Amilases Salivares/metabolismo , Estresse Psicológico/metabolismo , Pensamento , Adulto , Ansiedade/complicações , Ansiedade/metabolismo , Estudos de Casos e Controles , Cognição , Depressão/complicações , Depressão/metabolismo , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/complicações , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Saliva/metabolismo , Caracteres Sexuais , Estresse Psicológico/complicaçõesRESUMO
BACKGROUND: In Japan, the effects of reduced water, such as hydrogen-rich electrolyzed reduced water and natural reduced water, like Hita Tenryosui water®, have been examined. The purpose of the present study was to identify the role of natural reduced water in anxiety and blood biochemical analysis. MATERIALS AND METHODS: Natural reduced water and distilled water were administered to rats for 180 consecutive days, and their effect on anxiety-like behavior and depression was examined by using elevated plus maze, light/dark, forced swimming, and conditioned fear tests. Before and after administration of natural reduced or distilled water, we performed blood and urine analyses. RESULTS: Natural reduced water exhibited anxiolytic-like effects in the conditioned fear and elevated plus maze tests. The mean levels of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the natural reduced water were significantly lower than the distilled water group. Natural reduced water group also showed decrease in blood-urea nitrogen levels compared with the distilled water group. CONCLUSION: These results indicate that natural reduced water may decrease anxiety-related behaviors and prevent heightened oxidative stress.
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Therapeutic peptides and small molecules, rationally designed to trigger cell death have attracted strong attention. Cell death inducible peptides were screened from amino acid sequence of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Using Fmoc solid phase synthesis, cellulose membrane-bound octameric peptide library of TRAIL scan was prepared and cell viability assay was directly performed on peptide disk with Jurkat cells. Six peptide sequences that could induce cell death were found. Peptide sequence with RNSCWSKD (TRAIL(227-234)) that exist in the zinc-binding site revealed high cell death inducible activity. Apoptotic cell death was observed when cells were treated with soluble synthesized peptide.
Assuntos
Proteínas Reguladoras de Apoptose/farmacologia , Apoptose/efeitos dos fármacos , Glicoproteínas de Membrana/farmacologia , Oligopeptídeos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Sequência de Aminoácidos , Proteínas Reguladoras de Apoptose/química , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Células Jurkat , Glicoproteínas de Membrana/química , Dados de Sequência Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Biblioteca de Peptídeos , Ligante Indutor de Apoptose Relacionado a TNF , Fator de Necrose Tumoral alfa/químicaRESUMO
HLA-F has recently only begun to be studied in earnest, and has been thought not to be expressed on the cell surface. However, in our previous report, we demonstrated surface expression of HLA-F on extravillous trophoblasts (EVTs) invading the decidua in term placental tissues. To better understand its function, we attempted to determine when surface expression of HLA-F begins during normal pregnancy, and whether there is a difference in expression between normal and preeclamptic placentas, by comparing the expression of HLA-G and -E by immunohistochemical staining with anti-HLA-E, -F and -G antibodies (3D12, 3D11 and 87G, respectively). In EVTs, HLA-F was expressed only in the cytoplasm weakly during the first trimester, after which expression increased and moved to the cell surface with the progression of pregnancy from the second trimester, which was confirmed by the results of double-labeled immunofluorescence staining with anti-HLA-F and anti-HLA-G antibodies, and by flow cytometry using trophoblasts isolated from the decidua. HLA-E showed similar expression as HLA-F, though it was expressed on the cell surface from the first trimester, while HLA-G was expressed strongly in the cytoplasm and on the cell surface during all stages of pregnancy. The expressions of HLA-E, -F and -G in preeclamptic placentas were not different from those in normal placentas, though there were a greater number of necrotic EVTs in preeclampsia. The increase in expression of HLA-E and HLA-F from the second trimester to full term was coincident with the timing of rapid growth of the fetus. Our results suggest that these may function together to prepare an environment that supports fetal growth.
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Decídua/imunologia , Antígenos HLA/análise , Antígenos de Histocompatibilidade Classe I/análise , Segundo Trimestre da Gravidez/imunologia , Terceiro Trimestre da Gravidez/imunologia , Trofoblastos/imunologia , Adulto , Membrana Celular/imunologia , Decídua/citologia , Feminino , Antígenos HLA-G , Humanos , Imuno-Histoquímica , Pré-Eclâmpsia/imunologia , Gravidez , Antígenos HLA-ERESUMO
In the field of in vitro fertilization (IVF), useful markers for the prediction of successful implantation for oocyte or embryo selection are essential. It has been reported that sHLA-G (sHLA-G1/HLA-G5) could be detected in the supernatant of the fertilized embryo and in follicular fluid samples (FFs), and that the presence of sHLA-G was related to successful implantation. If sHLA-G could be used as a marker of oocyte selection from multiple FFs, oocytes could be selected without physical contact, thus reducing the likelihood of damage. To investigate the potential for sHLA-G as a marker of oocyte selection from multiple FFs in one patient, protein levels of total protein, sHLA-G, and sHLA-I (sHLA-A, B, and C) were examined in FFs. The variation among multiple FFs in total protein level and sHLA-G level was not related to successful pregnancy. The average sHLA-I levels did not differ in the successful implantation and unsuccessful implantation groups, indicating that sHLA-I levels were not related to successful pregnancy. Furthermore, sHLA-G in FFs was not detected by western blotting, despite being detected by ELISA, while sHLA-I was detected by both ELISA and western blot. These data suggest that sHLA-G in FF might not be a useful marker for oocyte selection as measurements of sHLA-G were inconsistent and there was no association with successful pregnancy. Further, more rigorously tested ELISA systems for detecting sHLA-G in body fluids are necessary before the utility of sHLA-G for diagnosis can be established.
Assuntos
Implantação do Embrião/imunologia , Embrião de Mamíferos/imunologia , Líquido Folicular/imunologia , Antígenos HLA-G/imunologia , Gravidez/imunologia , Adulto , Feminino , Fertilização in vitro , HumanosRESUMO
BACKGROUND: Patients with social anxiety disorder (SAD) experience unusual fear in normal social situations. The verbal fluency task (VFT) was administered while subjects were undergoing near-infrared spectroscopy (NIRS) scanning. The purpose of VFT was to examine the functions of the frontal and temporal lobes. METHODS: Subjects included 145 drug-naïve patients with SAD and 152 healthy controls (HCs). All subjects underwent psychological testing to determine levels of anxiety and depression and to evaluate cognition. RESULTS: The scores of patients with SAD indicated significantly higher anxiety and depressive states than those in HCs on several measures: Leibowitz Social Anxiety Scale (LSAS), Profile of Mood States (POMS), Spielberger Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and Social Adaptation Self-evaluation Scale (SASS). The patients with SAD also had higher scores on the future denial, threat prediction, self-denial, past denial, and interpersonal threat sections of the Depression and Anxiety Cognition Scale (DACS). NIRS scanning revealed hyperactivity in the left frontal cortex of patients with SAD. Threat prediction scores on DACS were negatively correlated with oxy-Hb responses in the right frontal cortex. LIMITATIONS: Further studies with a larger sample size are required to verify our findings. CONCLUSIONS: The results of this study demonstrate the different mechanisms of the right and left frontal cortex in situations of social anxiety disorder.