Dysregulation of the Wnt pathway causes various diseases including cancer, Parkinson’s disease, Alzheimer’s disease, schizophrenia, osteoporosis, obesity and chronic kidney diseases. The modulation of dysregulated Wnt pathway is absolutely necessary. In the present study, we evaluated the anti-inflammatory effect and the mechanism of action of Wnt-C59, a Wnt signaling inhibitor, in lipopolysaccharide (LPS)-stimulated epithelial cells and macrophage cells. Wnt-C59 showed a dose-dependent anti-inflammatory effect by suppressing the expression of proinflammatory cytokines including IL6, CCL2, IL1A, IL1B, and TNF in LPS-stimulated cells. The dysregulation of the Wnt/β-catenin pathway in LPS stimulated cells was suppressed by WntC59 treatment. The level of β-catenin, the executor protein of Wnt/β-catenin pathway, was elevated by LPS and suppressed by Wnt-C59. Overexpression of β-catenin rescued the suppressive effect of Wnt-C59 on proinflammatory cytokine expression and nuclear factor-kappa B (NF-κB) activity. We found that the interaction between β-catenin and NF-κB, measured by co-immunoprecipitation assay, was elevated by LPS and suppressed by Wnt-C59 treatment. Both NF-κB activity for its target DNA binding and the reporter activity of NF-κB-responsive promoter showed identical patterns with the interaction between β-catenin and NF-κB. Altogether, our findings suggest that the anti-inflammatory effect of Wnt-C59 is mediated by the reduction of the cellular level of β-catenin and the interaction between β-catenin and NF-κB, which results in the suppressions of the NF-κB activity and proinflammatory cytokine expression.

Dysregulation of the Wnt pathway causes various diseases including cancer, Parkinson’s disease, Alzheimer’s disease, schizophrenia, osteoporosis, obesity and chronic kidney diseases. The modulation of dysregulated Wnt pathway is absolutely necessary. In the present study, we evaluated the anti-inflammatory effect and the mechanism of action of Wnt-C59, a Wnt signaling inhibitor, in lipopolysaccharide (LPS)-stimulated epithelial cells and macrophage cells. Wnt-C59 showed a dose-dependent anti-inflammatory effect by suppressing the expression of proinflammatory cytokines including IL6, CCL2, IL1A, IL1B, and TNF in LPS-stimulated cells. The dysregulation of the Wnt/β-catenin pathway in LPS stimulated cells was suppressed by WntC59 treatment. The level of β-catenin, the executor protein of Wnt/β-catenin pathway, was elevated by LPS and suppressed by Wnt-C59. Overexpression of β-catenin rescued the suppressive effect of Wnt-C59 on proinflammatory cytokine expression and nuclear factor-kappa B (NF-κB) activity. We found that the interaction between β-catenin and NF-κB, measured by co-immunoprecipitation assay, was elevated by LPS and suppressed by Wnt-C59 treatment. Both NF-κB activity for its target DNA binding and the reporter activity of NF-κB-responsive promoter showed identical patterns with the interaction between β-catenin and NF-κB. Altogether, our findings suggest that the anti-inflammatory effect of Wnt-C59 is mediated by the reduction of the cellular level of β-catenin and the interaction between β-catenin and NF-κB, which results in the suppressions of the NF-κB activity and proinflammatory cytokine expression.

OBJECTIVES: Dry eye disease (DED) is an increasingly important public health problem in Korea. Previous studies conducted in Korea have reported inconsistent results regarding the protective effects of vitamin D on DED, and these discrepancies may be related to the relatively simple questionnaire that has been used. Thus, we evaluated the association of serum vitamin D levels with DED using the ocular surface disease index (OSDI). METHODS: The present study evaluated data from participants in the Study Group for Environmental Eye Disease (2014-2015). This group included data from 752 participants, and data from 740 participants (253 men and 487 women) were analyzed in the present study. DED severity was evaluated using the OSDI. RESULTS: Higher serum vitamin D levels were associated with a non-significantly reduced risk of DED in the crude analysis (odds ratio [OR], 0.991; 95% confidence interval [CI], 0.971 to 1.011) and in the adjusted analysis (OR, 0.988; 95% CI, 0.966 to 1.010). In the crude analysis of no/mild DED vs. moderate/severe DED, men exhibited a decreased risk with increasing serum vitamin D levels (OR, 0.999; 95% CI, 0.950 to 1.051), while women exhibited an increased risk (OR, 1.003; 95% CI, 0.979 to 1.027). In these analyses, we found no significant associations. CONCLUSIONS: The findings of the present study support previous reports that serum vitamin D levels are not associated with DED.
25-Hydroxyvitamin D 2 ; Dry Eye Syndromes ; Eye Diseases* ; Female ; Humans ; Keratoconjunctivitis Sicca ; Korea ; Male ; Public Health ; Vitamin D* ; Vitamins*

Postconditioning has been shown to protect the mouse brain from ischemic injury. However, the neuroprotective mechanisms of postconditioning remain elusive. We have found that toll-like receptor 5 (TLR5) plays an integral role in postconditioning-induced neuroprotection through Akt/nuclear factor kappa B (NF-κB) activation in cerebral ischemia. Compared to animals that received 30 min of transient middle cerebral artery occlusion (tMCAO) group, animals that also underwent postconditioning showed a significant reduction of up to 60.51% in infarct volume. Postconditioning increased phospho-Akt (p-Akt) levels and NF-κB translocation to the nucleus as early as 1 h after tMCAO and oxygen-glucose deprivation. Furthermore, inhibition of Akt by Akt inhibitor IV decreased NF-κB promoter activity after postconditioning. Immunoprecipitation showed that interactions between TLR5, MyD88, and p-Akt were increased from postconditioning both in vivo and in vitro. Similar to postconditioning, flagellin, an agonist of TLR5, increased NF-κB nuclear translocation and Akt phosphorylation. Our results suggest that postconditioning has neuroprotective effects by activating NF-κB and Akt survival pathways via TLR5 after cerebral ischemia. Additionally, the TLR5 agonist flagellin can simulate the neuroprotective mechanism of postconditioning in cerebral ischemia.
Animals ; Brain ; Brain Ischemia* ; Flagellin ; Immunoprecipitation ; In Vitro Techniques ; Infarction, Middle Cerebral Artery ; Mice* ; Neuroprotection ; Neuroprotective Agents ; NF-kappa B ; Phosphorylation ; Toll-Like Receptor 5

OBJECTIVES: Clinical utility of the Short Form of the Samsung Dementia Questionnaire (S-SDQ) as a screening instrument for Mild Cognitive Impairment (MCI). METHODS: Three groups (n=27, Subjective Memory Impairment (SMI); n=41 MCI; n=79, Early Alzheimer's Disease(AD)) recruited from memory clinic were administered a battery of neuropsychological tests including S-SDQ and Korean version-Mini Mental State Examination (K-MMSE). RESULTS: S-SDQ, unlike the K-MMSE, had no association with the age and education of the subjects. Scores of S-SDQ was found to correlate (r=-.496) with scores of K-MMSE. Result of Receiver Operating Characteristic (ROC) analysis revealed that S-SDQ discriminated between the SMI and the MCI groups. CONCLUSION: S-SDQ may be a solution to the problem of contamination by education and age which affect traditional cognitive screening instruments like K-MMSE, and it may be a useful tool for screening MCI.
Dementia* ; Education ; Mass Screening ; Memory ; Mild Cognitive Impairment* ; Neuropsychological Tests ; Surveys and Questionnaires* ; ROC Curve

Background: There are many models for predicting diabetes mellitus (DM), but their clinical implication remains vague. Therefore, we aimed to create various DM prediction models using easily accessible health screening test parameters. Methods: Two sets of variables were used to develop eight DM prediction models. One set comprised 62 easily accessible examination results of commonly used variables from a tertiary university hospital. The second set comprised 27 of the 62 variables included in the national routine health checkups. Gradient boosting and random forest algorithms were used to develop the models. Internal validation was performed using the stratified 10-fold cross-validation method. Results: The area under the receiver operating characteristic curve (ROC-AUC) for the 62-variable DM model making 12-month predictions for subjects without diabetes was the largest (0.928) among those of the eight DM prediction models. The ROC-AUC dropped by more than 0.04 when training with the simplified 27-variable set but still showed fairly good performance with ROC-AUCs between 0.842 and 0.880. The accuracy was up to 11.5% higher (from 0.807 to 0.714) when fasting glucose was included. Conclusion We created easily applicable diabetes prediction models that deliver good performance using parameters commonly assessed during tertiary university hospital and national routine health checkups. We plan to perform prospective external validation, hoping that the developed DM prediction models will be widely used in clinical practice.

OBJECTIVE: This study examined the efficacy and safety of memantine-an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist-in the treatment of moderate-to-severe dementia. METHODS: Forty-four patients with moderate-to-severe dementia received 20 mg of memantine daily for 24 weeks. The primary efficacy variable was measured by the Korean version of Severe Impairment Battery(K-SIB), and the secondary efficacy variables were measured using the Seoul-Activites of Daily Living(S-ADL) and Neuropsychiatric Inventory-Questionnaire(NPI-Q). Neuropsychological assessments were administrated at baseline, 12 weeks, and 24 weeks. Safety parameters were monitored. RESULTS: Of 44 patients recruited, 30 completed the study and 14 dropped out. Memantine-treated patients showed a therapeutic benefit in all efficacy variables ; the K-SIB, S-ADL, and NPI-Q total scores were not significantly different from baseline either at the endpoint(in the analysis of intention-to-treat, with the last observation carried forward, ITT-LOCF) or at week 24(in the analysis of observed cases, OC). The response rates, when "response" was defined as improved or unchanged in the K-SIB or the S-ADL scores, were 43.3 and 50%, respectively(in the analysis of OC). The responders showed significant improvement in the cognitive subdomain of memory function, praxis, visuospatial ability, and orienting to name. Memantine was shown to be tolerable and safe. CONCLUSIONS: Memantine treatment reduced or delayed clinical deterioration in cognition, function, and behavior in patients with moderate-to-severe dementia.
Cognition ; Dementia* ; Humans ; Memantine* ; Memory ; N-Methylaspartate

Glucagon like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors, which block inactivation of GLP-1, are currently in clinical use for type 2 diabetes mellitus. Recently, GLP-1 has also been reported to have neuroprotective effects in cases of cerebral ischemia. We therefore investigated the neuroprotective effects of GLP-1 receptor (GLP-1R) agonist, exendin-4 (ex-4), after cerebral ischemia-reperfusion injury. Transient middle cerebral artery occlusion (tMCAO) was induced in rats by intracerebroventricular (i.c.v.) administration of ex-4 or ex9-39. Oxygen-glucose deprivation was also induced in primary neurons, bEnd.3 cells, and BV-2. Ischemia-reperfusion injury reduced expression of GLP-1R. Additionally, higher oxidative stress in SOD2 KO mice decreased expression of GLP-1R. Downregulation of GLP-1R by ischemic injury was 70% restored by GLP-1R agonist, ex-4, which resulted in significant reduction of infarct volume. Levels of intracellular cyclic AMP, a second messenger of GLP-1R, were also increased by 2.7-fold as a result of high GLP-1R expression. Moreover, our results showed that ex-4 attenuated pro-inflammatory cyclooxygenase-2 (COX-2) and prostaglandin E₂ after MCAO. C-Jun NH₂ terminal kinase (JNK) signaling, which stimulates activation of COX-2, was 36% inhibited by i.c.v. injection of ex-4 at 24 h. Islet-brain 1 (IB1), a scaffold regulator of JNK, was 1.7-fold increased by ex-4. GLP-1R activation by ex-4 resulted in reduction of COX-2 through increasing IB1 expression, resulting in anti-inflammatory neuroprotection during stroke. Our study suggests that the anti-inflammatory action of GLP-1 could be used as a new strategy for the treatment of neuroinflammation after stroke accompanied by hyperglycemia.
Animals ; Brain Ischemia ; Cyclic AMP ; Cyclooxygenase 2 ; Diabetes Mellitus, Type 2 ; Down-Regulation ; Glucagon* ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; Hyperglycemia ; Infarction, Middle Cerebral Artery ; Insulin ; Mice ; Neurons ; Neuroprotection ; Neuroprotective Agents ; Oxidative Stress ; Phosphotransferases ; Rats ; Reperfusion Injury ; Second Messenger Systems ; Stroke*

OBJECTIVE: To examine the effect of niacin on the progression of carotid intima-media thickness (IMT) in patients with high level of lipoprotein (Lp) (a). METHODS: Patients at low-density lipoprotein-cholesterol goal but with Lp (a) >25 mg/dL and mean carotid IMT >0.75 mm were included. Eligible patients were randomized at a 1:2 ratio into one of two groups for 24 months: control or 1,500 mg extended release niacin. The primary study outcomes were the percentage changes in mean and maximal carotid IMT. The percentage change in lipid profiles including Lp (a) was analyzed as a secondary study outcome. RESULTS: Among 96 randomized patients, 31 completed the study (mean age: 65 years; male: 44%). At follow-up, the percentage change in mean carotid IMT was not significantly different between the two groups (−1.4%±15.5% and −1.1%±7.3% in the control and niacin groups, respectively, p=0.95). The percentage change in maximal carotid IMT was also similar in the two groups (0.7%±16.5% and −4.4%±11.6%, respectively, p=0.35). Elevation of high-density lipoprotein-cholesterol tended to be higher in the niacin group (p=0.07), and there was a significant difference in the percentage change in hemoglobin A1c between the two groups (−1.9%±2.2% and 3.3%±6.7%, respectively, p=0.02). Reduction of Lp (a) was greater in the niacin-treated group compared to placebo, but the difference was not statistically significant. CONCLUSION: Treatment with niacin for two years did not inhibit the progression of carotid intima-media thickening in patients with high Lp (a) level. However, this study may have been underpowered to evaluate the primary study outcome.
Arteries ; Carotid Artery Diseases ; Carotid Intima-Media Thickness ; Drug Therapy ; Follow-Up Studies ; Humans ; Lipoprotein(a) ; Lipoproteins ; Male ; Niacin

Background/Aims: The association between inflammatory bowel disease (IBD) and gallstone and renal stone formation has been established. However, few studies have investigated this association in patients with intestinal Behçet’s disease (BD). We aimed to examine the prevalence of gallstones and renal stones in patients with intestinal BD and identify potential risk factors. Methods: We analyzed gallstone and renal stone occurrences in 553 patients diagnosed with intestinal BD who had undergone cross-sectional imaging examinations between March 2005 and April 2021 at the IBD Center, Severance Hospital, Seoul, South Korea. Logistic regression models were used to identify risk factors for gallstone and renal stone formation. Results: Of 553 patients over a mean 12.1-year duration, 141 (25.4%) patients had gallstones and 35 (6.3%) had renal stones. In multivariate logistic regression analysis, disease duration > 19 years (OR 2.91, 95% CI 1.56–5.44, 0.002). No significant correlation 0.001), prior intestinal BD-related surgery (OR 2.29, 95% CI 1.42–3.68, p < 0.001), and disease activity index for intestinal BD scores ≥ 75 (OR 2.23, 95% CI 1.12–4.45, p = 0.022) were associated with increased gallstone occurrence. A positive correlation was observed between renal stones, disease duration > 19 years (OR 5.61, 95% CI 1.98–15.90, p = 0.001) and frequent hospitalization (> 3 times) (OR 3.29, 95% CI 1.52–7.13, p = 0.002). No significant correlation was observed between gallstone and renal stone occurrence. Conclusions These findings contribute to greater understanding concerning gallstone and renal stone prevalence and associated risk factors in patients with intestinal BD.