The Relationship Between Perceived Stress and Smartphone Addiction: The Mediating Effect of Rumination and The Mediated Moderating Effect of Mindfulness.

OBJECTIVE: This study was to examine the mediated moderation effect of mindfulness through rumination on the relationship between perceived stress and smartphone addiction. In particular, this study examined the moderating effect of mindfulness in detail by dividing it into five sub-factors. METHODS: An online self-report questionnaires were conducted on 697 participants aged 20 to 59. Finally, 681 participants (male=356, female=325) were included final analysis. Moderating effect, mediated moderating effect were verified using PROCESS macro for SPSS v3.5. RESULTS: First, perceived stress was positively related to smartphone addiction. Second, rumination mediated the relationship between perceived stress and smartphone addiction. Third, acting with awareness and nonjudging of experience, which are a sub-factor of mindfulness, moderated the relationship between perceived stress and smartphone addiction. Fourth, mindfulness facets (acting with awareness and nonjudging of experience) moderated the relationship between rumination and smartphone addiction. Finally, there was a mediated moderating effect of mindfulness facets (acting with awareness and nonjudging of experience) on the relationship between perceived stress and smartphone addiction through rumination. CONCLUSION: This research suggests the useful and specific therapeutic interventions that help lower the level of the adults' addiction on smartphones.

Association between hemoglobin trajectories and the incidence of dementia in a cohort of females aged 55-79 years.

PURPOSE: To assess the association between pattern changes in hemoglobin levels over time and the incidence of dementia using trajectories in females aged 55-79 years. MATERIALS AND METHODS: We conducted a retrospective cohort study using females of aged 55-79 years from the National Health Insurance Service National Health Screening Cohort in Korea. To identify hemoglobin trajectories over eight years (2002-2009), we performed a three-step approach comprising measures of change, factor analysis, and cluster analysis. Univariate and multivariate Cox proportional hazard models were used to assess the associations between hemoglobin trajectories and the incidence of dementia. RESULTS: We included 20,195 of 235,742 female participants. New dementia (N = 2664) was developed during follow-up period (2010-2015). Five hemoglobin trajectories were identified: high, mid, low, increasing, and decreasing. With high as a reference, the hazard ratios (HRs) for low and decreasing trajectories were significant, 1.28 (95% confidence interval [CI], 1.13-1.45) and 1.21 (95% CI, 1.10-1.34) in univariate models, respectively. However, only the HR for the decreasing trajectory was significant, 1.12 (95% CI, 1.01-1.24) after adjustment for confounders. CONCLUSION: The decreasing trajectory of hemoglobin levels within the normal range was associated with dementia. Even females aged 55-79 years without anemia might be vulnerable to dementia development risk.

Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer's model mice.

Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer's disease (AD), also known as "type 3 diabetes". Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, ß-amyloid oligomers, plaques, phosphorylated tau, and GSK3ß expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.

Association between Antacid Exposure and Risk of Interstitial Lung Diseases.

BACKGROUND: The mechanisms leading to lung fibrosis are still under investigation. This study aimed to demonstrate whether antacids could prevent the development of interstitial lung disease (ILD). METHODS: This population-based longitudinal cohort study was conducted between January 2006 and December 2010 in South Korea. Eligible subjects were ≥40 years of age, exposed to proton pump inhibitors (PPI)±histamine-2 receptor antagonists (H-2 blockers) or H-2 blockers only, and had no history of ILD between 2004 and 2005. Exposure to antacids was defined as the administration of either PPI or H-2 receptor antagonists for >14 days, whereas underexposure was defined as antacid treatment administered for less than 14 days. Newly developed ILDs, including idiopathic pulmonary fibrosis (IPF), were counted during the 5-year observation period. The association between antacid exposure and ILD development was evaluated using adjusted Cox regression models with variables, such as age, sex, smoking history, and comorbidities. RESULTS: The incidence rates of ILD with/without antacid use were 43.2 and 33.8/100,000 person-years, respectively and those of IPF were 14.9 and 22.9/100,000 person-years, respectively. In multivariable analysis, exposure to antacid before the diagnosis of ILD was independently associated with a reduced development of ILD (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.45 to 0.71; p<0.001), while antacid exposure was not associated with development of IPF (HR, 0.88; 95% CI, 0.72 to 1.09; p=0.06). CONCLUSION: Antacid exposure may be independently associated with a decreased risk of ILD development.

Constant Association between Low High-Density Lipoprotein Cholesterol and Gastric Cancer Regardless of Site.

Background: Some epidemiologic factors and body mass index (BMI) have site-specific effects on gastric cancer. The site-specific effect of high-density lipoprotein cholesterol (HDL-C) and hyperglycemia on gastric cancer has not been reported. Methods: This study included adults who underwent national gastric cancer screening in 2011 (n=5.49 million). The validation set included gastric cancer patients (n=3,262) and gastric cancer-free persons who underwent health screening (n=14,121) in a single hospital. The site-specific effects of metabolic components and epidemiologic factors on gastric cancer were investigated. Results: Among 5.49 million individuals, 10,417 gastric cancer cases (6,764 non-cardiac gastric cancer [NCGC] and 152 cardiac gastric cancer [CGC]) were detected. BMI was inversely associated with NCGC (P for trend <0.001) but not with CGC. Low HDL-C was associated with both CGC (adjusted odds ratio [aOR], 1.90; 95% confidence interval [CI], 1.34 to 2.71) and NCGC (aOR, 1.41; 95% CI, 1.34 to 1.49). Fasting glucose ≥110 mg/dL was associated with NCGC (aOR, 1.19) and CGC (aOR, 1.50). Men predominance was larger in CGC (aOR, 3.28) than in NCGC (aOR, 1.98). Smoking, alcohol drinking, and family history were associated with NCGC but not with CGC. In the validation set, low HDL-C was associated with CGC (aOR, 2.80) and NCGC (aOR, 2.32). BMI was inversely associated with NCGC (P for trend <0.001), and hyperglycemia was positively associated with both NCGC and CGC. Conclusion: Many epidemiologic factors had site-specific effects on gastric cancer, whereas low HDL-C and hyperglycemia were constantly associated with gastric cancer regardless of the site in two independent sets.

Association between the use of statins and risk of interstitial lung disease/idiopathic pulmonary fibrosis: time-dependent analysis of population-based nationwide data.

BACKGROUND: We aimed to study whether statin use is associated with lowering the development of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). METHODS: The study population was the Korean National Health Insurance Service-Health Screening Cohort. ILD and IPF cases were identified using diagnosis codes (J84.1 for ILD and J84.1A as a special code for IPF) based on the International Classification of Diseases, 10th Revision. The study participants were followed up from 1 January 2004 to 31 December 2015. Statin use was defined by the cumulative defined daily dose (cDDD) per 2-year interval and participants were categorised into never-users, <182.5, 182.5-365.0, 365.0-547.5 and ≥547.5 by cDDD. A Cox regression was used to fit models with time-dependent variables of statin use. RESULTS: Incidence rates for ILD with and without statin use were 20.0 and 44.8 per 100 000 person-years, respectively, and those for IPF were 15.6 and 19.3 per 100 000 person-years, respectively. The use of statins was independently associated with a lower incidence of ILD and IPF in a dose-response manner (p-values for trend <0.001). ILD showed respective adjusted hazard ratios (aHRs) of 1.02 (95% CI 0.87-1.20), 0.60 (95% CI 0.47-0.77), 0.27 (95% CI 0.16-0.45) and 0.24 (95% CI 0.13-0.42) according to the increasing category of statin use compared with never-users. IPF showed respective aHRs of 1.29 (95% CI 1.07-1.57), 0.74 (95% CI 0.57-0.96), 0.40 (95% CI 0.25-0.64) and 0.21 (95% CI 0.11-0.41). CONCLUSION: A population-based cohort analysis found that statin use is independently associated with a decreased risk of ILD and IPF in a dose-response manner.

The Relationship Between Types of Smartphone Use, Digital Literacy, and Smartphone Addiction in the Elderly.

OBJECTIVE: There is limited understanding of which specific factors relate to smartphone addiction in the elderly. The aim of this study was to examine the relationship between types of smartphone use, digital literacy, and smartphone addiction in the elderly. METHODS: It used data from a survey on smartphone overdependence by the South Korea National Information Society Agency in 2019. Participants were 3,121 older people (1,627 males, 1,494 females; mean age=63.83 [standard deviation=2.88 years]). We conducted hierarchical multiple regression analysis. RESULTS: The results of a hierarchical multiple regression analysis indicated that smartphone usage time was positively related to smartphone addiction. Entertainment-seeking and life service types of smartphone use, and digital literacy were positively associated with smartphone addiction. Conversely, smartphone use for information-seeking and communication-seeking was negatively related to smartphone addiction. CONCLUSION: This study suggests that it is necessary to understand different types of smartphone uses in the elderly and to educate the elderly on digital literacy to prevent smartphone addiction. In future studies, it will be necessary to re-confirm the relationship between smartphone usage type, digital literacy, and smartphone addiction in the elderly (including participants in their 70s or older).

Association between use of antacid medications (proton pump inhibitors and histamine-2 receptor antagonists) and the incidence of lung cancer: A population-based cohort analysis.

This study investigated the association between antacid administration and lung cancer incidence in a real-world setting. This was a nationwide, retrospective cohort study. The cohort comprised random samples (n = 1,031,392) from the entire South Korean population in 2002. The duration of antacid administration between January 2006 and December 2010 was recorded for each participant. Newly developed lung cancers were counted during the 5-year observation period (January 1, 2006 to December 31, 2010). A total of 437,370 participants aged ≥ 40 years were included, of whom 301,201 (68.9%) had antacid exposure before the diagnosis of lung cancer. A total of 1230 (0.28%) antacid-exposed patients developed lung cancer. Among patients with no antacid exposure or underexposure (n = 136,171), 597 (0.44%) developed lung cancer. In the multivariable analysis, antacid exposure before the diagnosis of lung cancer was independently associated with a reduced incidence of lung cancer (hazard ratio: 0.64; 95% confidence interval: 0.55-0.74; P < .001). Antacid use might be independently associated with a decreased risk of lung cancer development in this cohort study.

Prognostic outcome of treatment modalities for epidermal growth factor receptor-mutated advanced lung cancer.

BACKGROUND/AIMS: The treatment of epidermal growth factor receptor (EGFR)-mutated lung cancer cases has shown remarkable development in the past two decades. However, there have been limited studies comparing the prognostic effects of EGFR-tyrosine kinase inhibitor (TKI) and other treatment modalities. Therefore, we compared the survival outcomes of patients treated with EGFR-TKIs versus those treated with other treatment modalities. METHODS: Patient data were collected from the Korean National Health Insurance Database, National Health Insurance Service- National Sample Cohort 2002 to 2015, which was released by the Korean National Health Insurance Service in 2015. The lung cancer group included patients (n = 2,003) initially diagnosed with lung cancer between January 2010 and December 2013. The main outcome was all-cause mortality. A Cox proportional hazard regression analysis was used to calculate the relative risk of mortality. RESULTS: Among the newly diagnosed lung cancer cases, 1,004 (50.1%) were included in the analysis. A 15.1-month median survival benefit was observed in the EGFR-TKI group than that of the multimodality therapy group. The risk of mortality was as follows: EGFR-TKI treatment group (n = 142; hazard ratio [HR], 5.29; 95% confidence interval [CI], 3.57 to 7.86) and multimodality therapy group (n = 326; HR, 7.42; 95% CI, 5.19 to 10.63) compared to surgery only (n = 275). CONCLUSION: Patients with advanced lung cancer harbouring EGFR mutations treated with EGFR-TKIs showed better median survival and lower risk of mortality than those in the multimodality therapy group. In the case of EGFR-mutated advanced lung cancer, there is room for downstaging in the TNM classification.

Sex-specific effect of body mass index and fasting glucose on gastric cancer risk and all causes mortality; a cohort study of 5.17 million.

BACKGROUND: Simultaneous evaluation of sex-specific effect of body mass index (BMI) and hyperglycemia on the risk of gastric cancer has been rarely reported. Here, we investigated the sex-specific effect of BMI and hyperglycemia on gastric cancer. METHODS: Persons who underwent National gastric cancer screening from 2006 to 2007 and had no gastric cancer at baseline, were enrolled and followed up to 2015. The risk of gastric cancer by BMI and glucose was measured using risk ratios (RRs) and 95% confidence intervals (CI). Adjusted Cox analysis was performed to evaluate the risk of death. RESULTS: Gastric cancers developed in 29,775 of 5.17 million. In the adjusted analysis, low BMI (<18.5 kg/m2; RR, 1.44; 95% CI, 1.36-1.53) and high fasting glucose (≥126 mg/dL; RR, 1.09; 95% CI, 1.05-1.13) increased the risk of gastric cancer. In sex-specific analysis, its risk by BMI was modified L-shape with cut-off value of 23 kg/m2 in men and 18.5 kg/m2 in women. Low BMI increased gastric cancer risk in men (RR, 1.39; 95% CI, 1.30-1.50) and women (RR, 1.48; 95% CI, 1.33-1.64). High fasting glucose increased the risk of gastric cancer in women (RR, 1.19; 95% CI, 1.11-1.28), but not in men. Low BMI increased all-cause mortality with cut-off value of 23 kg/m2 in men and 18.5 kg/m2 in women. CONCLUSIONS: Gastric cancer risk and all-cause mortality by BMI was L-shape with sex-specific cut-off value. The effect of fasting glucose on gastric cancer risk was different by sex.

Protein Kinase CK2 Is Upregulated by Calorie Restriction and Induces Autophagy.

Calorie restriction (CR) and the activation of autophagy extend healthspan by delaying the onset of age-associated diseases in most living organisms. Because protein kinase CK2 (CK2) downregulation induces cellular senescence and nematode aging, we investigated CK2's role in CR and autophagy. This study indicated that CR upregulated CK2's expression, thereby causing SIRT1 and AMP-activated protein kinase (AMPK) activation. CK2α overexpression, including antisense inhibitors of miR-186, miR-216b, miR-337-3p, and miR-760, stimulated autophagy initiation and nucleation markers (increase in ATG5, ATG7, LC3BII, beclin-1, and Ulk1, and decrease in SQSTM1/p62). The SIRT1 deacetylase, AKT, mammalian target of rapamycin (mTOR), AMPK, and forkhead homeobox type O (FoxO) 3a were involved in CK2-mediated autophagy. The treatment with the AKT inhibitor triciribine, the AMPK activator AICAR, or the SIRT1 activator resveratrol rescued a reduction in the expression of lgg-1 (the Caenorhabditis elegans ortholog of LC3B), bec-1 (the C. elegans ortholog of beclin-1), and unc-51 (the C. elegans ortholog of Ulk1), mediated by kin-10 (the C. elegans ortholog of CK2ß) knockdown in nematodes. Thus, this study indicated that CK2 acted as a positive regulator in CR and autophagy, thereby suggesting that these four miRs' antisense inhibitors can be used as CR mimetics or autophagy inducers.

4-Phenylbutyric acid, a potent endoplasmic reticulum stress inhibitor, attenuates the severity of collagen-induced arthritis in mice via inhibition of proliferation and inflammatory responses of synovial fibroblasts.

4-Phenylbutyric acid (4-PBA) exerts potent pharmacological effects, including anti-inflammatory properties, via inhibition of endoplasmic reticulum (ER) stress. However, it is not known whether 4-PBA attenuates the severity of rheumatoid arthritis. The present study aimed to determine whether the inhibition of ER stress by 4-PBA ameliorated experimentally induced arthritis. The proliferation of synovial fibroblasts (SFs) and expression of matrix metalloproteinases (MMPs) were evaluated in the presence of interleukin (IL)-1ß with or without 4-PBA. The effect of 4-PBA on the phosphorylation of Mitogen-activated protein kinase (MAPK) and the activation of Nuclear factor-κB (NF-κB) in IL-1ß-stimulated SFs was assessed. In an in vivo study, the effects of 4-PBA were investigated using DBA/1 mice with collagen-induced arthritis (CIA). Clinical, histological, and serological assessments of CIA treated with 4-PBA were performed to determine the therapeutic effect of 4-PBA. In vitro, 4-PBA inhibited the proliferation and expression of IL-1ß-stimulated SFs and MMP-1 and MMP-3 through the suppression of both the phosphorylation of MAPKs and NF-κB in IL-1ß-stimulated SFs. The 4-PBA treatment markedly attenuated the severity of arthritis in CIA mice. The 4-PBA treatment ameliorated joint swelling and the degree of bone erosion and destruction and decreased the level of inflammatory cytokines and MMP-3 and Cox-2. Furthermore, remarkable improvements in histopathological findings occurred in 4-PBA-treated mice. These findings suggested that 4-PBA could attenuate the severity of arthritis in CIA mice by partially blocking the phosphorylation of MAPKs and the activation of NF-κB in SFs. Thus, through the inhibition of ER stress, 4-PBA may be a potent agent for the treatment of RA.

Identification and characterization of GAL4 drivers that mark distinct cell types and regions in the Drosophila adult gut.

The gastrointestinal tract in the adult Drosophila serves as a model system for exploring the mechanisms underlying digestion, absorption and excretion, stem cell plasticity, and inter-organ communication, particularly through the gut-brain axis. It is also useful for studying the cellular and adaptive responses to dietary changes, alterations in microbiota and immunity, and systematic and endocrine signals. Despite the various cell types and distinct regions in the gastrointestinal tract, few tools are available to target and manipulate the activity of each cell type and region, and their gene expression. Here, we report 353 GAL4 lines and several split-GAL4 lines that are expressed in enteric neurons (ENs), progenitors (ISCs and EBs), enterocytes (ECs), enteroendocrine cells (EEs), or/and other cell types that are yet to be identified in distinct regions of the gut. We had initially collected approximately 600 GAL4 lines that may be expressed in the gut based on RNA sequencing data, and then crossed them to UAS-GFP to perform immunohistochemistry to identify those that are expressed selectively in the gut. The cell types and regional expression patterns that are associated with the entire set of GAL4 drivers and split-GAL4 combinations are annotated online at http://kdrc.kr/index.php (K-Gut Project). This GAL4 resource can be used to target specific populations of distinct cell types in the fly gut, and therefore, should permit a more precise investigation of gut cells that regulate important biological processes.

Cesarean delivery may be protective against neoplasms of the uterine cervix in women of childbearing age.

Parity has been reported as a risk factor for cervical cancer. However, no study has investigated the risk of neoplasms of the uterine cervix according to the delivery type. We carried out a retrospective cohort study using nationwide data from the Korean Health Insurance Review and Assessment Database to investigate whether cesarean delivery might be associated with less development of neoplasms of the uterine cervix than a vaginal delivery in women of childbearing age. Women aged 20-44 years, who had undergone vaginal or cesarean deliveries in 2009 were included as subjects. Two individual datasets for carcinoma in situ (CIS) and cancer of the cervix were followed for 8 years until either disease outcomes or 31 December 2016. In total, 260 438 and 132 232 women had undergone vaginal only and cesarean only deliveries, respectively. There were 1505 and 423 new cases of CIS and cervical cancer, respectively, with median follow-up durations of 89.9 and 90.0 months for vaginal delivery and cesarean delivery, respectively. The unadjusted CIS risk ratio for cesarean delivery compared with vaginal delivery was 0.90 [95% confidence interval, (CI), 0.80-1.00]. After adjusting for categorical age, residential area, facility types, and number of visits to obstetrics and gynecology clinics, it was 0.83 (95% CI, 0.75-0.93). The unadjusted and adjusted risk ratios for cervical cancer for cesarean delivery were 0.98 (95% CI, 0.80-1.20) and 0.87 (95% CI, 0.71-1.08), respectively. Cesarean delivery may be more protective against CIS than vaginal delivery in women of childbearing age.

Association between EGFR mutation and ageing, history of pneumonia and gastroesophageal reflux disease among patients with advanced lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation is the most frequently encountered oncogenic driver in lung cancer. Risk factors for EGFR mutation may help prevention, surveillance and diagnosis strategies of EGFR-mutated lung cancer. PATIENTS AND METHODS: A nationwide, retrospective, longitudinal, cohort study was performed between January 2002 and December 2015. Patient data were collected from the Korean National Health Insurance Database. The lung cancer group included EGFR tyrosine kinase inhibitor (TKI)-treated patients. Controls were randomly selected from people without a history of lung cancer and determined to be four times the number of patients with EGFR-mutated advanced lung cancer. The risk model of developing EGFR-mutated lung cancer was constructed by multiple logistic regression analysis. RESULTS: Among the 2010 new cases of lung cancer treated in 2010-2015, 214 cases were classified as EGFR-mutated advanced lung cancer. The risk of developing EGFR-mutated advanced lung cancer was higher in patients in their 50s (odds ratio [OR]: 3.42; 95% confidence interval [CI]: 1.68-6.93), 60s (OR: 7.04; 95% CI: 3.35-14.77) and 70s (OR: 10.27; 95% CI: 4.73-22.30) and in those aged >80 years (OR: 5.98; 95% CI: 2.25-15.92) than those in their 40s. The risk of developing EGFR-mutated lung cancer was also higher in hospitalised patients with a history of pneumonia (OR: 5.22; 95% CI: 1.88-14.46) and those with gastroesophageal reflux disease (OR: 2.02; 95% CI: 1.32-3.07). CONCLUSIONS: Patients with EGFR-mutated advanced lung cancer were associated with ageing, history of being hospitalised for pneumonia and gastroesophageal reflux disease.

Higher Age Puts Lung Cancer Patients at Risk for Not Receiving Anti-cancer Treatment.

PURPOSE: We aimed to determine the demographic and epidemiologic variables that are associated with no treatment in lung cancer patients. MATERIALS AND METHODS: Patient data were collected from the Korean National Health Insurance Database. The lung cancer group included patients with an initial diagnosis of lung cancer between January 2009 and December 2014. Treated cases were defined as those that underwent surgery, radiation, or chemotherapy until death, after the diagnosis of lung cancer. Risk of no treatment was calculated by multiple logistic regression analysis. RESULTS: Among the 2148 new cases of lung cancer from 2009 to 2104, 612 (28.4%) were not treated. Risk of no treatment was higher in the following patients: patients in their 60s (odds ratio [OR], 1.18; 95% confidence interval [CI], 0.75 to 1.84), 70s (OR, 3.64; 95% CI, 2.41 to 5.50), and >80 years old (OR, 16.55; 95% CI, 10.53 to 25.03) than those in their 50s; patients with previous myocardial infarction (OR, 2.07; 95% CI, 1.01 to 4.25) or chronic kidney disease (OR, 2.88; 95% CI, 1.57 to 5.30); and patients diagnosed at a non-referral hospital (OR, 1.40; 95% CI, 1.01 to 1.92) or primary care provider (OR, 1.81; 95% CI, 1.43 to 2.29) compared with referral hospital. Low-income patients receiving Medicaid were 1.75 times (95% CI, 1.14 to 2.68) more likely to forgo treatment than high-income patients (upper 20%). Risk was not associated with sex or the year in which the lung cancer was diagnosed. CONCLUSION: Age predominantly determines whether patients with lung cancer undergo anti-cancer treatment.

Tacrolimus regulates endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation: In vitro and collagen-induced arthritis mouse model.

Tacrolimus is an immunosuppressive drug that inhibits the release of inflammatory cytokines involved in rheumatoid arthritis development by blocking T cell activation. "Endoplasmic reticulum stress," an imbalance between protein folding load and capacity leading to the accumulation of unfolded proteins in the endoplasmic reticulum lumen, has been implicated in rheumatoid arthritis and other inflammatory and metabolic diseases. We aimed to investigate the effect of tacrolimus on endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation and elucidate the underlying mechanisms. In vitro studies were performed using mouse bone marrow cells that were cultured with or without interleukin-1ß, thapsigargin, or tacrolimus to induce osteoclast differentiation. A mouse model of arthritis was established by immunizing mice with bovine type II collagen. Tacrolimus was orally administered to mice from day 20 to 45 following the initial immunization, and histopathological changes and expression of specific biomarkers of endoplasmic reticulum stress-mediated inflammatory signaling pathways were examined. In vitro, tacrolimus inhibited receptor activator of nuclear factor-κB ligand-mediated osteoclast formation augmented by interleukin-1ß, thapsigargin, or both. Furthermore, tacrolimus inhibited glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 (IRE 1), and activating transcription factor 6 (ATF6) augmented by interleukin-1ß, thapsigargin, or both. Tacrolimus significantly ameliorated osteolysis and endoplasmic reticulum stress intensity in mice. Simultaneously, it reduced inflammatory cell infiltration, osteoclastogenesis, and inflammatory responses by inhibiting GRP78, IRE 1, and ATF6. These findings suggest that tacrolimus exhibits an anti-inflammation effect in rheumatoid arthritis and might inhibit joint damage progression by inhibiting endoplasmic reticulum stress.

Suppression of AIMP1 protects cognition in Alzheimer's disease model mice 3xTg-AD.

Neuroinflammation has been raised as a candidate of unifying pathogenesis and a target of a disease-modifying strategy for Alzheimer's disease (AD). Aminoacyl-tRNA synthetase complex (ARS)-interacting multifunctional protein 1 (AIMP1) is a cytokine that is known to amplify the actions of tumor necrosis factor-α and to be involved in microglial activation and neuronal death. In this respect, AIMP1 could be a plausible target for the treatment of AD. Therefore, we aimed to examine whether anti-AIMP1 antibody could exert therapeutic effects against cognitive impairment using 3xTg-AD mice. Through the passive avoidance test, we found that an intraperitoneal injection of anti-AIMP1 antibody over 4 weeks was effective in protecting memory function in 3xTg-AD mice (16 weeks old). In addition, to address the translational implications of AIMP1, we measured blood AIMP1 levels in patients with AD (n=22), mild cognitive impairment (n=25), and normal cognition (n=23). Blood AIMP1 levels were associated negatively with global cognitive function and were significantly higher in individuals with a higher degree of medial temporal lobe atrophy, which is one of the representative clinical markers of AD. Our results suggested a possible association of AIMP1 with AD pathogenesis, as well as the potential of the anti-AIMP1 antibody as a novel therapeutic option for AD.

Blunted response of hippocampal AMPK associated with reduced neurogenesis in older versus younger mice.

The rate of hippocampal neurogenesis declines with aging. This is partly explained by decreased neural responsiveness to various cues stimulating metabolism. AMP-activated protein kinase (AMPK), a pivotal enzyme regulating energy homeostasis in response to metabolic demands, showed the diminished sensitivity in peripheral tissues during aging. AMPK is also known to be involved in neurogenesis. We aimed to see whether AMPK reactivity is also blunted in the aged hippocampus, and thus is associated with aging-related change in neurogenesis. Following subchronic (7days) intraperitoneal and acute intracerebroventricular (i.c.v.) administration of either 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR; AMPK activator) or saline (sham) to young (16-week-old) and old (72-week-old) mice, we measured changes in AMPK activity, brain-derived neurotrophic factor (BDNF) expression or neurogenesis in the hippocampus. AICAR-induced changes in AMPK activity were observed in the hippocampus of young mice after acute i.c.v. injection. However, neither subchronic nor acute treatment induced significant changes in AMPK activity in old mice. Intriguingly, directions of AICAR-induced changes in AMPK activity were opposite between the hippocampus (decrease) and skeletal muscle (increase). ATP levels were inversely correlated with hippocampal AMPK activity, suggesting that the higher energy levels achieved by AICAR treatment might deactivate neuronal AMPK in young mice. The blunted response of AMPK to AICAR in old age was also indicated by the observations that the levels of neurogenesis and BDNF expression were significantly changed only in young mice upon AICAR treatment. Our findings suggest that the blunted response of neuronal AMPK in old age might be responsible for aging-associated decline in neurogenesis. Therefore, in addition to activation of AMPK, recovering its sensitivity may be necessary to enhance hippocampal neurogenesis in old age.

Cholinesterase Inhibitor Donepezil Increases Mitochondrial Biogenesis through AMP-Activated Protein Kinase in the Hippocampus.

OBJECTIVE: Donepezil, a widely prescribed drug for Alzheimer's disease (AD), is now considered to have multimodal actions beyond cholinesterase inhibition. We aimed to see whether donepezil enhances mitochondrial biogenesis and relevant signaling pathways since mitochondrial dysfunction is a key feature of the hypometabolic AD brain. METHODS: As a metabolic gauge, AMP-activated protein kinase (AMPK) was investigated as a tentative mediator of neurometabolic action of donepezil. Changes in phospho-AMPK levels, mitochondrial biogenesis, and ATP levels were measured upon donepezil treatment using neuroblastoma cells, primary cultured neurons and ex vivo hippocampal tissue of adult mice. RESULTS: Donepezil dose-dependently increased mitochondrial biogenesis and ATP levels as well as expression of PGC-1α and NRF-1 in neuroblastoma cells. Donepezil dose-dependently activated AMPK; however, inhibition of AMPK abolished the observed effects of donepezil, indicating that AMPK is a key mediator of donepezil's action. Notably, mitochondrial biogenesis upon donepezil treatment was mainly observed within dendritic regions of primary cultured hippocampal neurons. Levels of synaptic markers were also increased by donepezil. Finally, AMPK- dependent mitochondrial biogenesis by donepezil was confirmed in organotypic hippocampal tissue. CONCLUSIONS: Our findings indicate that AMPK/PGC-1α signaling is involved in beneficial actions of donepezil on neurometabolism. Pharmacological activation of AMPK might be a promising approach to counteract AD pathogenesis associated with brain hypometabolism.