Core clinical symptoms and suicidal ideation in patients with obsessive-compulsive disorder: A network analysis.

INTRODUCTION: Suicidality in obsessive-compulsive disorder (OCD) is underestimated and it is important for clinicians to understand the factors that contribute to suicidal ideation. The present study aimed to estimate a network of the core clinical symptoms of OCD including obsessions, compulsions, and obsessive-compulsive (OC) symptom dimensions, depressive symptoms, and psychological traits, and to examine which symptoms contribute to suicidal ideation in patients with a primary diagnosis of obsessive-compulsive disorder. METHODS: A total of 444 patients with OCD were assessed with the Yale-Brown Obsessive-Compulsive Scale, the Montgomery-Asberg Depression Rating Scale, and various other measures. Network analysis was conducted to estimate the network of obsessive-compulsive and depressive symptoms, psychological traits including alexithymia and impulsivity, and demographic covariates. Symptoms directly related to suicidal ideation in the network were examined for their relative contribution to suicidal ideation. RESULTS: Suicidal ideation was directly related to degree of control over compulsive behaviors, distress associated with compulsive behaviors, time spent performing compulsive behaviors, and unacceptable thoughts, along with depressive symptoms and alexithymia. In the network of OC and depressive symptoms the most central symptoms among the former were interference due to compulsive behaviors and interference due to obsessive thoughts, and among the latter were pessimistic thoughts and reported sadness. CONCLUSION: The findings suggest that along with depressive symptoms and alexithymia, compulsions and unacceptable thoughts dimension may contribute to suicidality, and thus, should be carefully monitored in patients with OCD.

Microbiome analysis of circulating bacterial extracellular vesicles in obsessive-compulsive disorder.

AIM: The present study examined the microbiome abundance and composition of drug-naive or drug-free patients with obsessive-compulsive disorder (OCD) compared with healthy controls. In addition, in the OCD group, the microbiome composition was compared between early-onset and late-onset OCD. METHODS: Serum samples were collected from 89 patients with OCD and 107 age- and sex-matched healthy controls. Bacterial DNA was isolated from bacteria-derived extracellular vesicles in serum and then amplified and quantified using primers specific to the V3-V4 hypervariable region of the 16S ribosomal RNA gene. The 16S ribosomal DNA gene amplicon sequencing was performed. RESULTS: The pooled estimate showed that α-diversity was significantly reduced in patients with OCD compared with that in healthy controls (PShannon = 0.00015). In addition, a statistically significant difference was observed in ß-diversity between patients with OCD and healthy controls at the order (P = 0.012), family (P = 0.003), genus (P < 0.001), and species (P = 0.005) levels. In the microbiome composition, Pseudomonas, Caulobacteraceae (f), Streptococcus, Novosphingobium, and Enhydrobacter at the genus level were significantly less prevalent in patients with OCD than in controls. In addition, among patients with OCD, the microbial composition in the early-onset versus late-onset types was significantly different with respect to the genera Corynebacterium and Pelomonas. CONCLUSION: The present study showed an aberrant microbiome in patients with OCD, suggesting a role of the microbiota-brain interaction in the pathophysiology of OCD. Further longitudinal studies with larger sample sizes adjusting for various confounders are warranted.

Dysfunctional coronavirus anxiety in nonpsychotic psychiatric outpatients during the COVID-19 pandemic: A network analysis.

BACKGROUND: The 2019 coronavirus disease (COVID-19) pandemic has had a profound impact on the mental health of people worldwide. This study examined dysfunctional coronavirus anxiety in nonpsychotic psychiatric outpatients during the pandemic using the coronavirus anxiety scale (CAS) and examined the relationship between coronavirus anxiety and clinical symptoms using network analysis. METHODS: In this cross-sectional study, 192 patients who first visited the psychiatric outpatient clinic of Severance Hospital during the COVID-19 pandemic with chief complaints of depressed mood, anxiety, somatic symptoms, or insomnia were included. We compared the clinical characteristics of patients with and without dysfunctional coronavirus anxiety. Network analysis was conducted to estimate the network of coronavirus anxiety and depressive, anxious, and hypochondriacal psychopathology. RESULTS: The results showed that 7.8% of patients exhibited dysfunctional coronavirus anxiety (CAS ≥ 5). Patients with dysfunctional coronavirus anxiety showed higher levels of health worry, somatic preoccupation, and subjective anxiety compared to patients without dysfunctional coronavirus anxiety. In the network analysis, the health worry node (Item 6 of the WI) showed the greatest number of connections with coronavirus anxiety nodes. CONCLUSIONS: These findings suggest that health worry may be an important bridge symptom that connects coronavirus anxiety and other clinical psychopathology. Patients with elevated health worries should be carefully monitored during the COVID-19 pandemic for exacerbation of previous symptoms and COVID-19-related psychopathology. Understanding the psychological factors in the face of the pandemic and their relationships with clinical psychiatric symptoms would help people prevent and overcome mental health problems during the pandemic.

Alterations of cellular aging markers in obsessive- compulsive disorder: mitochondrial DNA copy number and telomere length.

BACKGROUND: The present study examined whether mitochondrial DNA copy number (mtDNAcn) and telomere length - key markers of cellular aging - were altered in male and female participants with obsessive-compulsive disorder (OCD) compared to healthy controls. We also tested for associations between these alterations and OCD-related clinical features and inflammatory index. METHODS: A total of 235 patients with OCD (38.7% female) and 234 healthy controls (41.5% female) were included. We quantified whole-blood mtDNAcn and leukocyte telomere length using quantitative polymerase chain reaction. We also calculated the neutrophil-to-lymphocyte ratio from complete blood cell counts. RESULTS: Multivariate analysis of covariance showed that OCD status had a significant overall effect on cellular aging markers in men (Wilks λ = 0.889, F2,275 = 17.13, p < 0.001) and women (Wilks λ = 0.742, F2,182 = 31.61, p < 0.001) after controlling for age, body mass index and childhood trauma. In post-hoc comparisons, men with OCD had lower mtDNAcn than controls (p < 0.001), but we found no between-group difference for telomere length (p = 0.55). Women with OCD had a significantly lower mtDNAcn (p < 0.001) and shortened telomere length (p = 0.023) compared to controls. Moreover, the lower mtDNAcn shown in the OCD group was significantly correlated with an increase in systemic inflammation for both sexes, as measured by neutrophil-to-lymphocyte ratio. LIMITATIONS: The present cross-sectional design did not allow us to infer a causal relationship between OCD disease status and cellular aging markers. CONCLUSION: The present study is, to our knowledge, the first to demonstrate alterations in mtDNAcn and telomere shortening in OCD. These results suggest that aging-associated molecular mechanisms may be important in the pathophysiology of OCD.

Serial mediating effects of childhood trauma and conduct behaviors on the impact of family history among patients with alcohol use disorder.

Family history (FH) of alcoholism increases the risk of alcohol use disorder (AUD); however, the contribution of childhood trauma (CT) in this respect remains unclear. This study investigated the relationship between FH and AUD-related clinical characteristics (social onset, antisocial tendency, and severity of problematic alcohol consumption) through the mediating effects of childhood trauma (CT) and conduct behaviors (CB) in a Korean male population with AUD. A total of 304 patients hospitalized for AUD at 16 psychiatric hospitals completed standardized questionnaires, including self-rated scales. Mediation analyses were performed using the SPSS macro PROCESS. Individuals with positive FH (133, 44%) had greater CT and CB and more severe AUD-related clinical characteristics than those without FH (171, 56%). In the present serial mediation model, FH had significant direct and indirect effects on AUD-related clinical characteristics through CT and CB. Indirect effects were 21.3% for social onset, 46.3%, antisocial tendency, and 37.9% for problematic drinking. FH directly contributed to AUD-related clinical characteristics, and CT and CB played mediating roles. This highlights the importance of careful intervention and surveillance of adverse childhood experiences and conduct disorder to prevent and mitigate alcohol-related problems in individuals with FH of AUD.

COVID-19 pandemic's impact on networks of depression and anxiety in naturalistic transdiagnostic sample of outpatients with non-psychotic mental illness.

Background: The 2019 coronavirus disease (COVID-19) pandemic has caused an unprecedented disruption of daily lives and a mental health crisis. The present study examined how the depression and anxiety symptom network changed during the COVID-19 pandemic in a naturalistic transdiagnostic sample with non-psychotic mental illness. Materials and methods: A total of 224 psychiatric outpatients before the pandemic and 167 outpatients during the pandemic were included in the study and were assessed for the Patient Health Questionnaire and the Beck Anxiety Inventory. The network of depression and anxiety symptoms before and during the pandemic were estimated separately and were assessed differences. Results: The network comparison analysis showed a significant structural difference between the networks before and during the pandemic. Before the pandemic, the most central symptom in the network was feelings of worthlessness, while in the during pandemic network, somatic anxiety emerged as the most central node. Somatic anxiety, which showed the highest strength centrality during the pandemic, showed significantly increased correlation with suicidal ideation during the pandemic. Limitations: The two cross-sectional network analyses of individuals at one point in time cannot demonstrate causal relationships among measured variables and cannot be assumed to generalize to the intraindividual level. Conclusion: The findings indicate that the pandemic has brought a significant change in the depression and anxiety network and somatic anxiety may serve as a target for psychiatric intervention in the era of the pandemic.

Sex-dependent association of DNA methylation of HPA axis-related gene FKBP5 with obsessive-compulsive disorder.

AIMS: Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation in obsessive-compulsive disorder (OCD) has been reported, epigenetic changes in HPA axis-related genes have not been well studied in OCD. The present study investigated whether the epigenetic regulation of FK506-binding protein 51 gene (FKBP5) intron 7 is associated with OCD status in each sex. In addition, relationships among the DNA methylation levels of FKBP5 intron 7, OCD status and early-life trauma were explored. METHODS: A total of 267 patients with OCD and 201 controls aged between 18 and 40 years were recruited. Demographic and clinical assessment, FKBP5 rs1360780 genotyping, and pyrosequencing of FKBP5 intron 7 were conducted. DNA was extracted from peripheral blood leucocytes. First, multivariate analysis of covariance for differential DNA methylation levels between OCD patients and controls was conducted with adjustment for FKBP5 rs1360780 genotype, early-life trauma, depressive symptoms, and age as covariates in each sex. Next, path analysis was conducted to determine the mediation effects of DNA methylation levels of FKBP5 between early-life trauma and OCD status. In addition, sensitivity analyses for medication and lifetime major depression were also performed. RESULTS: DNA methylation at the FKBP5 intron 7 CpG site was significantly lower in men with OCD, compared to controls (mean difference -1.33%, 95% CI -2.11 to -0.55, p < 0.001). The results remained significant for drug naïve or free subjects (mean difference -1.27%, 95% CI -2.18 to -0.37, p = 0.006, in men) and for subjects without lifetime major depressive disorder (mean difference -1.60%, 95% CI -2.54 to -0.66, p < 0.001, in men). The mediation effect of DNA methylation levels was not significant between early-life trauma and OCD status. CONCLUSION: These findings suggest that epigenetic factors of HPA axis-related gene FKBP5 may play a role in the pathogenesis of OCD. Further studies are needed to determine how altered DNA methylation of FKBP5 intron 7 and HPA axis function are involved in OCD.

Psychological factors associated with COVID-19 related anxiety and depression in young adults during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and the corresponding lockdown have drastically changed our lives and led to high psychological distress and mental health problems. This study examined whether psychological factors such as loneliness, perfectionism, and health anxiety are associated with COVID-19 related anxiety and depression during the pandemic in young Korean adults, after controlling for various socio-demographic factors and early life stress. METHODS: A total of 189 participants (58.2% women) completed a cross-sectional online survey including the Fear of COVID-19 Scale, Center for Epidemiologic Studies Depression Scale, 3-item Revised UCLA Loneliness Scale, Frost Multidimensional Perfectionism Scale, and Whiteley Index-6. Hierarchical linear regression analyses with three blocks were employed to identify the factors that contributed to COVID-19 related anxiety and depressive symptoms. RESULTS: Hierarchical regression analyses showed that higher health anxiety was significantly associated with more severe COVID-19 related anxiety (standardized regression coefficient, ß = 0.599, p < 0.001). Additionally, higher levels of loneliness (ß = 0.482, p < 0.001), perfectionism (ß = 0.124, p = 0.035), and health anxiety (ß = 0.228, p < 0.001) were significantly associated with higher depression scores. The three psychological factors explained 32.8% of the total variance in depressive symptom scores, after taking all covariates into account. CONCLUSION: The results showed that health anxiety was a risk factor for both COVID-19 related anxiety and depression in young adults. Loneliness was the strongest predictor of depressive symptoms during the COVID-19 pandemic. These findings highlight the importance of identifying vulnerable individuals and encouraging psychological counselling and social connections to reduce the burden of psychiatric disorders during the pandemic.

Dysfunctional Metacognitive Beliefs in Patients With Obsessive-Compulsive Disorder and Pattern of Their Changes Following a 3-Month Treatment.

Introduction: Metacognitions are considered to be crucial factors for the development and maintenance of pathologic anxiety. The present case-control study aimed to examine how metacognitive beliefs are associated with the diagnostic status and subtypes of obsessive-compulsive disorder (OCD). In addition, we examined the pattern of changes in metacognitive beliefs after a 3-month pharmacological treatment in patients with OCD. Methods: A total of 562 cases with OCD and 236 healthy controls were assessed with the Metacognitions Questionnaire (MCQ) and various measures of OC symptom severity. Multivariate analyses of variance (MANOVAs) with covariates were conducted to explore the relationship between subdimensions of metacognitive beliefs and OCD disease status. In addition, for the OCD patients, Pearson's correlation was performed between baseline MCQ subdimensions and Obsessive-Compulsive Inventory-Revised-Korean subscales (OCI-R-K). Finally, in a subset of drug-free OCD patients (n = 144), the MCQ was reassessed after 3 months of treatment and patterns of changes in subdimensions of the MCQ were examined. Results: Patients with OCD scored significantly higher on the four dimensions of the MCQ. There were significant associations between all MCQ subdimensions and OCI-R-K subscales. In the repeated-measure MANOVA, a significant group (non-responders vs. responders)-by-time interaction effect was found only for the negative beliefs about the uncontrollability and danger of worry (NB) subdimension (F = 10.75; η2 = 0.072; p = 0.001). Conclusion: The presence of dysfunctional metacognitive beliefs in OCD subjects and their association with OCD characteristics suggest that dysfunctional metacognitions may play a crucial role in the pathophysiology of OCD. Improvement of metacognitive beliefs in the NB dimension may be a clinically meaningful correlate of good treatment response in the pharmacological treatment of OCD.

Smad7 and Smad6 bind to discrete regions of Pellino-1 via their MH2 domains to mediate TGF-beta1-induced negative regulation of IL-1R/TLR signaling.

Transforming growth factor-beta1 (TGF-beta1) performs diverse cellular functions, including anti-inflammatory activity. The inhibitory Smad (I-Smad) Smad6 was previously shown to play an important role in TGF-beta1-induced negative regulation of Interleukin-1/Toll-like receptor (IL-1R/TLR) signaling through binding to Pellino-1, an adaptor protein of interleukin-1 receptor associated kinase 1(IRAK1). However, it is unknown whether Smad7, the other inhibitory Smad, also has a role in regulating IL-1R/TLR signaling. Here, we demonstrate that endogeneous Smad7 and Smad6 simultaneously bind to discrete regions of Pellino-1 upon TGF-beta1 treatment, via distinct regions of the Smad MH2 domains. In addition, the Smad7-Pellino-1 interaction abrogated NF-kappaB activity by blocking formation of the IRAK1-mediated IL-1R/TLR signaling complex, subsequently causing reduced expression of pro-inflammatory genes. Double knock-down of endogenous Smad6 and Smad7 genes by RNA interference further reduced the anti-inflammatory activity of TGF-beta1 than when compared with single knock-down of Smad7. These results provide evidence that the I-Smads, Smad6 and Smad7, act as critical mediators for effective TGF-beta1-mediated suppression of IL-1R/TLR signaling, by simultaneous binding to discrete regions of Pellino-1.

Geldanamycin inhibits TGF-beta signaling through induction of Hsp70.

Dysregulation of transforming growth factor-beta (TGF-beta) signaling has been implicated in the pathogenesis of a variety of diseases including cancer; therefore, pharmacological inhibitors that target the TGF-beta signaling pathway might be promising drugs for disease therapy. In this study, we investigated the mechanism of inhibition of TGF-beta signaling by the Hsp90 inhibitor geldanamycin (GA). Treatment with GA suppressed TGF-beta signaling, as evidenced by inhibition of TGF-beta-induced phosphorylation and transcriptional activity of Smad3 and decreased induction of target genes. Western blot analysis revealed that GA induced degradation of TGF-beta type I and type II receptors through a proteasome-dependent pathway. Notably, induction of Hsp70 by GA correlated with inhibition of TGF-beta signaling. Suppression of Hsp70 expression by Hsp70 siRNA or KNK437, an inhibitor of Hsp70 synthesis, blocked the inhibition of TGF-beta signaling by GA. Furthermore, Hsp70 interacted directly with TGF-beta receptors following GA treatment. Our results suggest that GA-mediated induction of Hsp70 and its subsequent interaction with TGF-beta receptors plays a crucial role in inhibition of TGF-beta signaling.

Multidimensional impulsivity as a mediator of early life stress and alcohol dependence.

Early life stress (ELS) leads to increased susceptibility to serious psychiatric problems such as alcohol dependence, but the mechanisms through which ELS affects alcohol dependence are unclear. We investigated the mediating role of multi-dimensional impulsivity in the associations between ELS and alcohol dependence. 330 male patients with alcohol dependence (mean age = 48.39) completed self-rating scales of ELS and several self-report measures of impulsivity as well as balloon analogue risk task (BART). After classifying different dimensions of impulsivity using factor analysis, structural equation modeling was conducted to test the mediation effects of impulsivity between ELS and alcohol dependence severity and social onset of hazardous drinking. Among the participants, 64.8%, 42.1% and 47.9% reported at least one episode of childhood maltreatment, sexual abuse and parental conflict, respectively. Response impulsivity-sensation seeking, reflection impulsivity and aggression partially mediated the association between ELS and severity of alcohol dependence (CFI = 0.902 and RMSEA = 0.079). Reflection impulsivity dimension partially mediated the association between ELS and social onset of hazardous drinking (CFI = 0.939, RMSEA = 0.091). These finding imply that stabilizing vulnerabilities such as reflection impulsivity via intervention programs that target young individuals with ELS may be helpful in delaying the onset of hazardous drinking and prevent alcohol dependence.

Age- and sex-dependent susceptibility to phenobarbital-resistant neonatal seizures: role of chloride co-transporters.

Ischemia in the immature brain is an important cause of neonatal seizures. Temporal evolution of acquired neonatal seizures and their response to anticonvulsants are of great interest, given the unreliability of the clinical correlates and poor efficacy of first-line anti-seizure drugs. The expression and function of the electroneutral chloride co-transporters KCC2 and NKCC1 influence the anti-seizure efficacy of GABAA-agonists. To investigate ischemia-induced seizure susceptibility and efficacy of the GABAA-agonist phenobarbital (PB), with NKCC1 antagonist bumetanide (BTN) as an adjunct treatment, we utilized permanent unilateral carotid-ligation to produce acute ischemic-seizures in post-natal day 7, 10, and 12 CD1 mice. Immediate post-ligation video-electroencephalograms (EEGs) quantitatively evaluated baseline and post-treatment seizure burdens. Brains were examined for stroke-injury and western blot analyses to evaluate the expression of KCC2 and NKCC1. Severity of acute ischemic seizures post-ligation was highest at P7. PB was an efficacious anti-seizure agent at P10 and P12, but not at P7. BTN failed as an adjunct, at all ages tested and significantly blunted PB-efficacy at P10. Significant acute post-ischemic downregulation of KCC2 was detected at all ages. At P7, males displayed higher age-dependent seizure susceptibility, associated with a significant developmental lag in their KCC2 expression. This study established a novel neonatal mouse model of PB-resistant seizures that demonstrates age/sex-dependent susceptibility. The age-dependent profile of KCC2 expression and its post-insult downregulation may underlie the PB-resistance reported in this model. Blocking NKCC1 with low-dose BTN following PB treatment failed to improve PB-efficacy.

KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78.

Recent advances in genome and transcriptome analysis have contributed to the identification of many potential cancer-related genes. Furthermore, biological and clinical investigations of the candidate genes provide us with a better understanding of carcinogenesis and development of cancer treatment. Here, we report a novel role of KIAA1324 as a tumor suppressor in gastric cancer. We observed that KIAA1324 was downregulated in most gastric cancers from transcriptome sequencing data and found that histone deacetylase was involved in the suppression of KIAA1324. Low KIAA1324 levels were associated with poor prognosis in gastric cancer patients. In the xenograft model, KIAA1324 significantly reduced tumor formation of gastric cancer cells and decreased development of preformed tumors. KIAA1324 also suppressed proliferation, invasion, and drug resistance and induced apoptosis in gastric cancer cells. Through protein interaction analysis, we identified GRP78 (glucose-regulated protein 78 kDa) as a KIAA1324-binding partner. KIAA1324 blocked oncogenic activities of GRP78 by inhibiting GRP78-caspase-7 interaction and suppressing GRP78-mediated AKT activation, thereby inducing apoptosis. In conclusion, our study reveals a tumor suppressive role of KIAA1324 via inhibition of GRP78 oncoprotein activities and provides new insight into the diagnosis and treatment of gastric cancer.

Temporal- and Location-Specific Alterations of the GABA Recycling System in Mecp2 KO Mouse Brains.

Rett syndrome (RTT), associated with mutations in methyl-CpG-binding protein 2 (Mecp2), is linked to diverse neurological symptoms such as seizures, motor disabilities, and cognitive impairments. An altered GABAergic system has been proposed as one of many underlying pathologies of progressive neurodegeneration in several RTT studies. This study for the first time investigated the temporal- and location-specific alterations in the expression of γ-amino butyric acid (GABA) transporter 1 (GAT-1), vesicular GABA transporter (vGAT), and glutamic acid decarboxylase 67kD (GAD67) in wild type (WT) and knockout (KO) mice in the Mecp2(tm1.1Bird/y) mouse model of RTT. Immunohistochemistry (IHC) co-labeling of GAT-1 with vGAT identified GABAergic synapses that were quantitated for mid-sagittal sections in the frontal cortex (FC), hippocampal dentate gyrus (DG), and striatum (Str). An age-dependent increase in the expression of synaptic GABA transporters, GAT-1, and vGAT, was observed in the FC and DG in WT brains. Mecp2 KO mice showed a significant alteration in this temporal profile that was location-specific, only in the FC. GAD67-positive cell densities also showed an age-dependent increase in the FC, but a decrease in the DG in WT mice. However, these densities were not significantly altered in the KO mice in the regions examined in this study. Therefore, the significant location-specific downregulation of synaptic GABA transporters in Mecp2 KO brains with unaltered densities of GAD67-positive interneurons may highlight the location-specific synaptic pathophysiology in this model of RTT.

Suppressed Gastric Mucosal TGF-beta1 Increases Susceptibility to H. pylori-Induced Gastric Inflammation and Ulceration: A Stupid Host Defense Response.

BACKGROUND/AIMS: Loss of transforming growth factor beta1 (TGF-beta1) exhibits a similar pathology to that seen in a subset of individuals infected with Helicobacter pylori, including propagated gastric inflammation, oxidative stress, and autoimmune features. We thus hypothesized that gastric mucosal TGF-beta1 levels could be used to determine the outcome after H. pylori infection. METHODS: Northern blot for the TGF-beta1 transcript, staining of TGF-beta1 expression, luciferase reporter assay, and enzyme-linked immunosorbent assay for TGF-beta1 levels were performed at different times after H. pylori infection. RESULTS: The TGF-beta1 level was markedly lower in patients with H. pylori-induced gastritis than in patients with a similar degree of gastritis induced by nonsteroidal anti-inflammatory drugs. There was a significant negative correlation between the severity of inflammation and gastric mucosal TGF-beta1 levels. SNU-16 cells showing intact TGF-beta signaling exhibited a marked decrease in TGF-beta1 expression, whereas SNU-638 cells defective in TGF-beta signaling exhibited no such decrease after H. pylori infection. The decreased expressions of TGF-beta1 in SNU-16 cells recovered to normal after 24 hr of H. pylori infection, but lasted very spatial times, suggesting that attenuated expression of TGF-beta1 is a host defense mechanism to avoid attachment of H. pylori. CONCLUSIONS: H. pylori infection was associated with depressed gastric mucosal TGF-beta1 for up to 24 hr, but this apparent strategy for rescuing cells from H. pylori attachment exacerbated the gastric inflammation.

14-3-3 sigma and 14-3-3 zeta plays an opposite role in cell growth inhibition mediated by transforming growth factor-beta 1.

The expression of 14-3-3 proteins is dysregulated in various types of cancer. This study was undertaken to investigate the effects of 14-3-3 zeta and 14-3-3 sigma on cell growth inhibition mediated by transforming growth factor-beta 1 (TGF-beta1). Mouse mammary epithelial cells (Eph4) that are transformed with oncogenic c-H-Ras (EpRas) and no longer sensitive to TGF-beta1-mediated growth inhibition displayed increased expression of 14-3-3 zeta and decreased expression of 14-3-3 sigma compared with parental Eph4 cells. Using small interfering RNA-mediated knockdown and overexpression of 14-3-3 sigma or 14-3-3 zeta, we showed that 14-3-3 sigma is required for TGF-beta1-mediated growth inhibition whereas 14-3-3 zeta negatively modulates this growth inhibitory response. Notably, overexpression of 14-3-3 zeta increased the level of Smad3 protein that is phosphorylated at linker regions and cannot mediate the TGF-beta1 growth inhibitory response. Consistent with this finding, mutation of the 14-3-3 zeta phosphorylation sites in Smad3 markedly reduced the 14-3-3 zeta-mediated inhibition of TGF-beta1-induced p15 promoter-reporter activity and cell cycle arrest, suggesting that these residues are critical targets of 14-3-3 zeta in the suppression of TGF-beta1-mediated growth. Taken together, our findings indicate that dysregulation of 14-3-3 sigma or 14-3-3 zeta contributes to TGF-beta1 resistance in cancer cells.