Minnesota Multiphasic Personality Inventory-Adolescent-Restructured Form (MMPI-A-RF) characteristics of ADHD in a Korean psychiatric sample.

Global rates of attention-deficit/hyperactivity disorder (ADHD) have risen. In Korea, ADHD is associated with functional impairments and comorbidity with other psychological disorders. This study examined the correlates of ADHD in a psychiatric sample of Korean adolescents on the Minnesota Multiphasic Personality Inventory-Adolescent-Restructured Form (MMPI-A-RF). In a clinical sample of 247 adolescents, MMPI-A-RF scores from 46 patients diagnosed with ADHD were compared to the remainder of the clinical sample and to the Korean MMPI-A-RF norms. Results demonstrated significantly different scores for the ADHD group on scales indicating externalizing concerns and behavior dysfunction compared with the clinical group with other disorders and to a normative sample. Notable differences were also observed between clinical groups on scales reflecting interpersonal functioning. Relative risk ratio analyses demonstrated that an MMPI-A-RF T-score of 55 was generally most effective for predicting risk for an ADHD diagnosis in the clinical sample.

Effects of equine-assisted activities on attention and quality of life in children with cerebral palsy in a randomized trial: examining the comorbidity with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention problems and decreased quality of life are frequently accompanied in Cerebral Palsy (CP), which can negatively affect rehabilitation of physical disability. However, the majority of affected children remain untreated in the aspects of attention or psychosocial factors. Equine-Assisted Activities and Therapies (EAAT) use horse as a therapeutic modality including grooming as well as mounted riding activities in which patients exercise and experience mounted stimulation. It is known to help improve attention in children with ADHD, so that it can be an exercise therapy that is expected to improvement of attention as well as rehabilitating effects in CP patients. EAA may be a promising strategy to address the unmet need for CP patients. This study aims to investigate the efficacy of EAA for children with CP, those with both CP and ADHD and confirm the comorbidity between CP and ADHD. METHODS: Forty-six children with cerebral palsy participated in this study. For the exercise group, they participated in a 40-min session twice a week for a 16-week period, while the control group engaged in daily life without any special treatments. Each children individually were assessed on attention and psychological wellbeing at baseline and post-treatment. Comorbidity were identified based on the Diagnostic and Statistical Manual of Mental Disorder 5th edition (DSM-5) and confirmed by Korean Kiddie-Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL). RESULTS: Perseveration rated using the Conner's Performance Test (CPT) showed a significant decrease only in the exercise group (p < .024). However, no significant improvement in children's quality of life was observed after EAA program compared with control group. Among the total participants, fifteen children (31.91%) were diagnosed with ADHD. When conducting an additional analysis with the subsample of CP patients diagnosed with ADHD, the d', commission error and perseveration showed a significant decrease only in the exercise group. Children with CP and ADHD reported an improvement in quality of life both in exercise and control group, but only in the exercise group social functioning exhibited a significant difference. CONCLUSION: The positive effects of the EAA on attention and quality of life were confirmed. Children with CP in the exercise group were more capable to sustain their attention longer. Those with CP and ADHD showed an increase in attention and perceived to have better social skills after receiving 16 weeks of EAA compared to those in the control group. Considering high comorbidity of CP and ADHD, it seems that the EAA program could be the better alternative treatment for CP with attentional problem. The results of this study will contribute to growing evidence for the efficacy of EAA in children especially with CP and ADHD. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov ( NCT03870893 ). Registered 26 July 2017.

Evaluating the Measurement Invariance of MMPI-2-RF Restructured Clinical Scale 4 (Antisocial Behavior) between American and Korean Clinical Samples: Exploring Cultural and Translation Issues Affecting Item Responding.

Establishing the cross-cultural measurement invariance of psychometric scales is considered an essential step before scale means are compared across cultures. Although the MMPI instruments have been extensively researched, few studies have examined the measurement equivalence of MMPI scales in cross-cultural research. This study examined the measurement invariance of MMPI-2-RF Restructured Clinical Scale 4 (RC4; Antisocial Behavior) using multi-group confirmatory factor analysis with American and Korean clinical samples by (a) comparing a rationally-derived four-factor model (School Problems, Substance Abuse, Family Problems, and Violation of Social Norms) with a one-factor model, and (b) examining the measurement invariance of the RC4 four-factor model. After adjusting for age and gender, partial scalar invariance was achieved, and six non-invariant items were identified, most of which centered around substance abuse. Results support the generalizability of the four factors across cultures; however, special attention is needed when using substance abuse items with Korean clinical populations. Plausible sources of item non-invariance were explored in the context of translation challenges and observed patterns of relationship with external measures.

Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51.

BACKGROUND: Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. METHODS: Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. RESULTS: Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. CONCLUSIONS: Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.

Differences in anxiety sensitivity factors between anxiety and depressive disorders.

BACKGROUND: Anxiety sensitivity (AS) refers to the tendency to fear physical sensations associated with anxiety due to concerns about potential physical, social, or cognitive consequences. Many previous studies were limited by the use of the anxiety sensitivity index (ASI) or the ASI-revised (ASI-R), which are both measurements with unitary or unstable structures. No recent study that has utilized the ASI-3 examined the relations between AS dimensions and depression. Thus, we examined multiple relationships between AS and anxiety disorders and depression using the ASI-3. METHODS: The total sample consisted of 667 outpatients, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth text revision as assessed by a structured clinical interview. There were eight patient groups: multiple anxiety disorder, major depressive disorder (MDD), panic disorder (PD), social phobia (SP), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and anxiety disorder not otherwise specified (AD NOS). We conducted one-way analysis of variances and post hoc tests to compare the ASI-3 total and subscale scores across the groups. RESULTS: The physical concern score was higher in patients with PD than patients with MDD, SP, OCD, or GAD. The social concern score was higher in the SP group than those with MDD, PD, GAD, and AD NOS. Patients with GAD and PTSD showed higher cognitive concern scores than the patients with PD. CONCLUSION: Results partially replicated the relationship between PD and physical concern, between SP and social concern, and between GAD and cognitive concern examining the relationships between AS dimensions and anxiety disorders.

A comparative evaluation of Korean MMPI-A and MMPI-A-RF Substance Abuse Scales.

OBJECTIVE: The purpose of the present study was to compare psychometric properties of the Substance Abuse (SUB) Scale on the Korean Minnesota Multiphasic Personality Inventory-Adolescent-Restructured Form (MMPI-A-RF) with those on the Korean MMPI-A (the Alcohol/Drug Problem Acknowledgment Scale [ACK]), the Alcohol/Drug Problem Proneness Scale [PRO], and the MacAndrew Alcoholism Scale-Revised Scale [MAC-R]). METHOD: Participants consisted of 237 Korean adolescent psychiatric patients whose scores on these measures were compared in terms of internal consistency and predictive validity. RESULTS: Scores on SUB exhibited superior internal consistency to that of the MMPI-A substance abuse scales. Further, scores on SUB predicted substance abuse more accurately than did the optimal combination of scores on the MMPI-A substance abuse scales. CONCLUSION: Results provide strong support for the use of the Korean MMPI-A-RF SUB scale when assessing substance abuse in Korean youth.

Identification of a rare homozygous c.790C>T variation in the TFB2M gene in Korean patients with autism spectrum disorder.

Mitochondrial dysfunction and subsequent enhanced oxidative stress is implicated in the pathogenesis of autism spectrum disorder (ASD). Mitochondrial transcription factor B2 (TFB2M) is an essential protein in mitochondrial gene expression. No reports have described TFB2M mutations and variations involved in any human diseases. We identified a rare homozygous c.790C>T (His264Tyr) variation in TFB2M gene in two Korean siblings with ASD by whole-exome sequencing. The roles of the TFB2M variation in the pathogenesis of ASD were investigated. Patient fibroblasts revealed increased transcription of mitochondrial genes and mitochondrial function in terms of ATP, membrane potential, oxygen consumption, and reactive oxygen species (ROS). Overexpression of the TFB2M variant in primary-cultured fibroblasts demonstrated significantly increased transcription of mitochondrial genes and mitochondrial function compared with overexpression of wild-type TFB2M. Molecular dynamics simulation of the TFB2M variant protein suggested an increase in the rigidity of the hinge region, which may cause alterations in loading and/or unloading of TFB2M on target DNA. Our results suggest that augmentation of mitochondrial gene expression and subsequent enhancement of mitochondrial function may be associated with the pathogenesis of ASD in Korean patients.

Validation Study for the Korean Version of Fear of Cancer Recurrence Inventory.

Fear of cancer recurrence (FCR) is one of the most prevalent unmet psychosocial needs. This study aimed to confirm the cultural equivalence, reliability, and validity of the Korean version of Fear of Cancer Recurrence Inventory (K-FCRI). We conducted a forward-backward translation of the English version FCRI to Korean version through meticulous process including transcultural equivalence test. The psychometric property of the K-FCRI was then validated in 444 survivors from cancers at various sites. The Korean translation was accepted well by participants. There was a good cultural equivalence between the Korean version and the English version of FCRI. Confirmatory factor analysis supported the original seven-factor structure with slightly insufficient level of goodness-of-fit indices (comparative fit index = 0.900, non-normed fit index = 0.893, root mean square error of approximation = 0.060). The K-FCRI had high internal consistency (α = 0.85 for total scale and α = 0.77-0.87 for subscales) and test-retest reliability (r = 0.90 for total scale and r = 0.54-0.84 for subscales). The K-FCRI had significant correlations with the Korean version of Fear of Progression Questionnaire, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0, Hospital Anxiety and Depression Scale, and Fatigue Severity Score, supporting the good construct validity and psychometric properties of K-FCRI. The K-FCRI was confirmed as a valid and reliable psychometric test for measuring FCR of Korean survivors from cancers at various sites.

Investigation of the clinical utility of the hypomania checklist 32 (HCL-32) for the screening of bipolar disorders in the non-clinical adult population.

BACKGROUND: The hypomania checklist-32 (HCL-32) is a widely used questionnaire developed for identifying hypomanic components in patients with a depressive episode. Measuring and screening previous hypomanic symptoms in individuals without any definite history of depressive episode would also be needed for early detection of bipolar disorders (BDs). This study aimed at testing the clinical utility of the HCL-32 for screening of BDs in the non-clinical population. METHODS: Lifetime history of hypomanic symptoms was evaluated by using the HCL-32 in 220 patients with BDs and 313 non-clinical individuals. Sensitivity, specificity, and the area under the curve (AUC) of the Receiver Operating Characteristic (ROC) were evaluated for assessing the discriminatory power of the scale and its two sub-domains in screening BDs. RESULTS: The mean HCL-32 total score was significantly higher in the Bipolar II disorder group compared to the non-clinical group (P < 0.001). Most of the items (10/12) of the irritable/risk-taking factor showed higher positive responses in patient groups. Items of active/elated factor showed mixed results. The HCL-32 total score and the active/elated factor score were not adequate for both BDs and its subgroups with AUC values of less than 0.7. The irritable/risk-taking factor score showed higher discrimination power, i.e. AUC for BDs, Bipolar I disorder, and Bipolar II disorder was 0.71, 0.67, and 0.75, respectively. CONCLUSIONS: The HCL-32 could not adequately distinguish BD patients from the non-clinical adult population. However, the current study identified items of irritable/risk-taking factor of the scale that could be useful in screening BDs in the general population.

E3 ubiquitin ligase, WWP1, interacts with AMPKα2 and down-regulates its expression in skeletal muscle C2C12 cells.

It is known that the activity of AMP-activated protein kinase (AMPKα2) was depressed under high glucose conditions. However, whether protein expression of AMPKα2 is also down-regulated or not remains unclear. In this study, we showed that the expression of AMPKα2 was down-regulated in cells cultured under high glucose conditions. Treatment of proteasome inhibitor, MG132, blocked high glucose-induced AMPKα2 down-regulation. Endogenous AMPKα2 ubiquitination was detected by immunoprecipitation of AMPKα2 followed by immunoblotting detection of ubiquitin. The yeast-two hybrid (YTH) approach identified WWP1, an E3 ubiquitin ligase, as the AMPKα2-interacting protein in skeletal muscle cells. Interaction between AMPKα2 and WWP1 was validated by co-immunoprecipitation. Knockdown of WWP1 blocked high glucose-induced AMPKα2 down-regulation. The overexpression of WWP1 down-regulated AMPKα2. In addition, the expression of WWP1 is increased under high glucose culture conditions in both mRNA and protein levels. The level of AMPKα2 was down-regulated in the quadriceps muscle of diabetic animal model db/db mice. Expression of WWP1 blocked metformin-induced glucose uptake. Taken together, our results demonstrated that WWP1 down-regulated AMPKα2 under high glucose culture conditions via the ubiquitin-proteasome pathway.

Improvement in subjective and objective neurocognitive functions in patients with major depressive disorder: a 12-week, multicenter, randomized trial of tianeptine versus escitalopram, the CAMPION study.

Although many patients with major depressive disorder (MDD) complain of neurocognitive impairment, the effects of antidepressant medications on neurocognitive functions remain unclear. This study compares neurocognitive effects of tianeptine and escitalopram in MDD. Patients with MDD (N = 164) were randomly assigned in a 1:1 ratio to either tianeptine (37.5 mg/d) or escitalopram (10 mg/d) for 12 weeks. Outcome measures included clinical improvement, subjective cognitive impairment on memory and concentration, the Mini-Mental State Examination, the Continuous Performance Test, the Verbal Learning Test, and the Raven Progressive Matrices, assessed every 4 weeks. After 12 weeks, the tianeptine group showed significant improvement in commission errors (P = 0.002), verbal immediate memory (P < 0.0001), Mini-Mental State Examination (P < 0.0001), delayed memory (P < 0.0001), and reasoning ability (P = 0.0010), whereas the escitalopram group improved in delayed memory and reasoning ability but not in the other measures. Both groups significantly improved in subjective cognitive impairment in memory (P < 0.0001) and concentration (P < 0.0001). Mixed effects model repeated measures analyses revealed that the tianeptine group had a significant improvement in scores of commission errors (F = 6.64, P = 0.011) and verbal immediate memory (F = 4.39, P = 0.038) from baseline to 12 weeks, compared with the escitalopram group, after controlling for age, sex, education years, baseline scores, and changes of depression severity. The treatment of MDD with tianeptine led to more improvements in neurocognitive functions, especially in commission errors and verbal immediate memory, compared with escitalopram, after controlling for changes in depression severity. Both drugs improved subjective cognitive impairment of memory and concentration.

Diagnostic utility of worry and rumination: a comparison between generalized anxiety disorder and major depressive disorder.

AIM: Although previous reports have addressed worry and rumination as prominent cognitive processes in generalized anxiety disorder (GAD) and major depressive disorder (MDD) and their distinct correlation with anxious and depressive symptoms, the differential association of worry and rumination with the diagnosis of GAD and MDD remains unclear. The purpose of this study was to investigate the distinct features of worry and rumination in factor structure and their predictive validity for the diagnosis of GAD and MDD. METHODS: Four hundred and sixty-eight patients with GAD (n = 148) and MDD (n = 320) were enrolled and the diagnoses were confirmed with the Structured Clinical Interview for DSM-IV. Participants completed the Penn State Worry Questionnaire and Ruminative Response Scale and the severity of anxiety and depressive symptoms was assessed via clinician ratings. RESULTS: In joint factor analysis using the Penn State Worry Questionnaire and Ruminative Response Scale items, worry and rumination emerged as distinct factors. In logistic regression analyses, worry contributed to a higher probability of the diagnosis of GAD than rumination, as rumination did in MDD than worry. CONCLUSION: This is the first comprehensive study investigating the diagnostic utility of worry and rumination in a well-defined clinical sample of both GAD and MDD. Our results suggest that worry and rumination are distinct cognitive processes and play a differential role in the diagnosis of GAD and MDD, distinguishing them at the cognitive level.

IL-7-primed bystander CD8 tumor-infiltrating lymphocytes optimize the antitumor efficacy of T cell engager immunotherapy.

Bispecific T cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, enhancing the efficacy of TCE immunotherapy. rhIL-7-hyFc induces a dramatic increase in CD8 tumor-infiltrating lymphocytes (TILs) in various solid tumors, but the majority of these cells are PD-1-negative tumor non-responsive bystander T cells. However, they are non-exhausted and central memory-phenotype CD8 T cells with high T cell receptor (TCR)-recall capacity that can be triggered by tumor antigen-specific TCEs to acquire tumoricidal activity. Single-cell transcriptome analysis reveals that rhIL-7-hyFc-induced bystander CD8 TILs transform into cycling transitional T cells by TCE redirection with decreased memory markers and increased cytotoxic molecules. Notably, TCE treatment has no major effect on tumor-reactive CD8 TILs. Our results suggest that rhIL-7-hyFc treatment promotes the antitumor efficacy of TCE immunotherapy by increasing TCE-sensitive bystander CD8 TILs in solid tumors.

Metformin regulates glucose transporter 4 (GLUT4) translocation through AMP-activated protein kinase (AMPK)-mediated Cbl/CAP signaling in 3T3-L1 preadipocyte cells.

Metformin is a leading oral anti-diabetes mellitus medication and is known to stimulate GLUT4 translocation. However, the mechanism by which metformin acts is still largely unknown. Here, we showed that short time treatment with metformin rapidly increased phosphorylation of Cbl in an AMP-activated protein kinase (AMPK)-dependent fashion in 3T3-L1 preadipocytes. Metformin also increased phosphorylation of Src in an AMPK-dependent manner. Src inhibition blocked metformin-mediated Cbl phosphorylation, suggesting that metformin stimulates AMPK-Src-Cbl axis pathway. In addition, long term treatment with metformin stimulated the expression of Cbl-associated protein (CAP) mRNA and protein. Long term treatment with metformin stimulated phosphorylation of c-Jun N-terminal kinase (JNK) and its downstream molecule c-Jun, which is a critical molecule for CAP transcription. Knockdown of AMPK and JNK blocked metformin-induced expression of CAP, implying that metformin stimulates AMPK-JNK-CAP axis pathway. Moreover, AMPK knockdown attenuated metformin-induced Cbl/CAP multicomplex formation, which is critical for GLUT4 translocation. A colorimetric absorbance assay demonstrated that metformin-induced translocation of GLUT4 was suppressed in CAP or Cbl knockdown cells. Furthermore, the promoter activity of CAP was increased by metformin in an AMPK/JNK-dependent fashion. In summary, these results demonstrate that metformin modulates GLUT4 translocation by regulating Cbl and CAP signals via AMPK.

Caspase-1 level in synovial fluid is high in patients with spondyloarthropathy but not in patients with gout.

Activation of caspase-1 by NALP3 inflammasomes has been shown to be important in initiating acute gouty arthritis. The objectives of this study were to measure the levels of caspase-1 in synovial fluid in gout and various arthritides, and to elucidate the clinical significance of caspase-1 levels in synovial fluid. Caspase-1, IL-1ß, IL-18, and uric acid were measured in synovial fluid from 112 patients with gout and other arthritides, such as rheumatoid arthritis, osteoarthritis, and spondyloarthropathy. Caspase-1 in synovial fluid from patients with crystal-induced arthritis, inflammatory arthritis, osteoarthritis, and spondyloarthropathy was 35.9 ± 86.7, 49.7 ± 107.7, 2.1 ± 7.0, and 152.6 ± 155.7 pg/mL, respectively. The mean level and the frequency of high levels (≥125 pg/mL) of caspase-1 in spondyloarthropathy were significantly higher than those in the other arthritides including gout. Caspase-1 was detectible in the synovial fluid of patients with the various arthritides. Contrary to our hypothesis, the caspase-1 level in the synovial fluid of patients with gout was not higher than in that of other arthritides. High levels of caspase-1 may be helpful in differentiating spondyloarthropathy from other arthritides.

The effect of the neurac sling exercise on postural balance adjustment and muscular response patterns in chronic low back pain patients.

[Purpose] This study aimed to examine the effects of the Neurac sling exercise on postural balance adjustment and muscular response patterns in chronic low back pain (CLBP) patients. [Subjects and Methods] Sixteen CLBP patients participated in this study. They were randomly and equally assigned to group I, whose members received ordinary physical therapy (40 minutes per time, four times per week), and group II, whose members performed a lumbar stabilization exercise using the Neurac sling after ordinary physical therapy (40 minutes per time, four times per week). The visual analogue scale (VAS) and Oswestry Disability Index (ODI) were used to evaluate exercise effects. BioRescue and electromyography were utilized for the measurement of changes in postural balance adjustment and muscular response patterns, respectively. [Results] Both groups saw their VAS and ODI decrease significantly. There were significant decreases in both groups in posturography as well, but group II recorded a greater decrease. There were significant increases in the flexion-relaxation ratio in both groups, and there were significant increases in the extension-flexion ratio in the left L1-2 of group I and in all elements of group II. [Conclusion] Lumbar stabilization exercise using the Neurac sling is effective in decreasing pain, improving damaged postural balance adjustment, and normalizing muscle response patterns of CLBP patients.

An Updated Meta-Analysis for Safety Evaluation of Alirocumab and Evolocumab as PCSK9 Inhibitors.

Background: Alirocumab and evolocumab, as protein convertase subtilisin kexin type 9 (PCSK9) inhibitors, have been reported to reduce cardiovascular risk. This meta-analysis is aimed at updating the safety data of PCSK9 inhibitors. Methods: We assessed the relative risk for all treatment-related adverse events, serious adverse events, diabetes-related adverse events, and neurocognitive and neurologic adverse events with PCSK9 inhibitors compared to controls (placebo or ezetimibe). In addition, we conducted a meta-analysis to quantitatively integrate and estimate the adverse event rates in long-term studies. Results: There were no significant differences between PCSK9 inhibitors and controls in the relative risk analysis. In a subgroup analysis of each PCSK9 inhibitor, alirocumab treatment significantly reduced the risk of serious adverse events compared to control treatment (risk ratio (RR) = 0.937; 95% confidence interval (CI), 0.896-0.980), but no significant difference was observed with evolocumab treatment (RR = 1.003; 95% CI, 0.963-1.054). Moreover, alirocumab treatment afforded a significant reduction in the risk of diabetes-related adverse events compared to control treatment (RR = 0.9137; 95% CI, 0.845-0.987). The overall incidence (event rate) of long-term adverse events was 75.1% (95% CI, 71.2%-78.7%), and the incidence of serious long-term event rate was 16.2% (95% CI, 11.6%-22.3%). Conclusions: We suggest that alirocumab and evolocumab are generally safe and well tolerated and that their addition to background lipid-lowering therapy is not associated with an increased risk of adverse events or toxicity.

The glutamate agonist homocysteine sulfinic acid stimulates glucose uptake through the calcium-dependent AMPK-p38 MAPK-protein kinase C zeta pathway in skeletal muscle cells.

Homocysteine sulfinic acid (HCSA) is a homologue of the amino acid cysteine and a selective metabotropic glutamate receptor (mGluR) agonist. However, the metabolic role of HCSA is poorly understood. In this study, we showed that HCSA and glutamate stimulated glucose uptake in C2C12 mouse myoblast cells and increased AMP-activated protein kinase (AMPK) phosphorylation. RT-PCR and Western blot analysis revealed that C2C12 expresses mGluR5. HCSA transiently increased the intracellular calcium concentration. Although α-methyl-4-carboxyphenylglycine, a metabotropic glutamate receptor antagonist, blocked the action of HCSA in intracellular calcium response and AMPK phosphorylation, 6-cyano-7-nitroquinoxaline-2,3-dione, an AMPA antagonist, did not exhibit such effects. Knockdown of mGluR5 with siRNA blocked HCSA-induced AMPK phosphorylation. Pretreatment of cells with STO-609, a calmodulin-dependent protein kinase kinase (CaMKK) inhibitor, blocked HCSA-induced AMPK phosphorylation, and knockdown of CaMKK blocked HCSA-induced AMPK phosphorylation. In addition, HCSA activated p38 mitogen-activated protein kinase (MAPK). Expression of dominant-negative AMPK suppressed HCSA-mediated phosphorylation of p38 MAPK, and inhibition of AMPK and p38 MAPK blocked HCSA-induced glucose uptake. Phosphorylation of protein kinase C ζ (PKCζ) was also increased by HCSA. Pharmacologic inhibition or knockdown of p38 MAPK blocked HCSA-induced PKCζ phosphorylation, and knockdown of PKCζ suppressed the HCSA-induced increase of cell surface GLUT4. The stimulatory effect of HCSA on cell surface GLUT4 was impaired in FITC-conjugated PKCζ siRNA-transfected cells. Together, the above results suggest that HCSA may have a beneficial role in glucose metabolism in skeletal muscle cells via stimulation of AMPK.

Streptococcus mutans GS-5 antigen I/II stimulates cell survival in serum deprived-cultures through PI3K/Akt pathways.

The antigen I/II (AgI/II) protein is a major surface protein that mediates the attachment of Streptococcus mutans (S. mutans) to the saliva-coated pellicle. Numerous studies have investigated not only the mechanisms by which AgI/II signaling is transduced within cells, but have also attempted to use AgI/II-specific antibodies to treat dental caries and host immune responses. However, little information is available about the effects of AgI/II on basic cellular events in bone cells. In this study, we examined the effects of the His-tagged recombinant N-terminal half of the AgI/II protein (rAgI/II-N) generated from S. mutans GS-5 on the viability, proliferation, and cell cycle progression of primary calvarial osteoblasts. We also investigated the mechanisms involved in the rAgI/II-N-mediated survival of serum-starved osteoblasts. We found that rAgI/II treatment attenuated the serum deprivation-induced decrease in cell viability and proliferation of osteoblasts. rAgI/II-N also prevented the loss of mitochondrial membrane potential (MMP), alterations in levels of two key mitochondrial Bcl-2 family proteins, and the accumulation of numerous cells into the sub-G(1) phase that were observed in serum-starved osteoblasts. Pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), but not of extracellular signal-regulated kinase or Ras, blocked the rAgI/II-N-mediated protection against serum deprivation-induced cell death. Additional experiments revealed that the integrin α5ß1-mediated PI3K pathway is required for rAgI/II-N-mediated Akt phosphorylation in osteoblasts. Collectively, these results suggest that rAgI/II-N induces survival signals in serum-starved osteoblasts through integrin-induced PI3K/Akt signaling pathways.

Psychological characteristics of early remitters in patients with panic disorder.

We aimed to examine whether anxiety sensitivity and agoraphobic fear could affect the time taken to remission after 24 weeks of open-label escitalopram treatment of patients with panic disorder (PD). We recruited 158 patients, and 101 patients completed the study. Clinical severity and psychological characteristics were assessed at baseline and 4, 12, and 24 weeks after the treatment, using the Clinical Global Impression-Severity (CGI-S), the Hamilton Rating Scales for Anxiety and Depression, the Anxiety Sensitivity Index-Revised (ASI-R), the Albany Panic and Phobia Questionnaire (APPQ), and the Panic Disorder Severity Scale (PDSS). Remission was defined as the absence of full panic attacks and PDSS scores of 7 or less. Completing patients were stratified according to the time taken to remit: early (n=20) and late (n=58) remission and non-remission groups (n=23). There were no significant differences among the three groups at baseline on the CGI-S and the PDSS mean scores. However, early remitters had significantly lower scores than late remitters and non-remitters on the ASI-R and APPQ. In conclusion, anxiety sensitivity and agoraphobic fear can affect the time to remission after pharmacotherapy, and clinicians should consider the psychological characteristics of PD patients in order to achieve an optimal response to pharmacotherapy.