Socioeconomic disparities in alcohol-related depression: a national cohort study of low-income medical aid beneficiaries and national health insurance beneficiaries in Korea.

OBJECTIVE: To examine the association between patterns of alcohol consumption in the past and the risk of depression among medical aid beneficiaries and National Health Insurance beneficiaries in Korea. METHODS: We used data from the National Health Information Database (NHID) of 1,292,618 participants who underwent health checkups in 2015-16 and 2017-18. We categorized alcohol consumption into four groups: continuous high, increased, decreased, and non-consumers. We followed the participants from 2019 to 2021 and identified new episodes of depression. We calculated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for depression by alcohol consumption groups and socioeconomic status. RESULTS: Medical aid beneficiaries had higher risks of depression than National Health Insurance beneficiaries across all alcohol consumption groups. The highest risk was observed among continuous high consumers (aOR, 2.31; 95% CI, 1.36-3.93), followed by increased (aOR, 1.51; 95% CI, 1.17-1.94), decreased (aOR, 1.48; 95% CI, 1.18-1.84), and non-consumers (aOR, 1.37; 95% CI, 1.22-1.54). CONCLUSIONS: Socioeconomic status and patterns of alcohol consumption in the past are associated with the risk of depression. Public health interventions should consider both factors to reduce alcohol-related depression and health inequalities.

Antibody-Conjugated Nanogel with Two Immune Checkpoint Inhibitors for Enhanced Cancer Immunotherapy.

Cancer immunotherapy by immune checkpoint inhibitors (ICIs) acts on antitumor responses by stimulating the immune system to attack cancer cells. However, this powerful therapy is hampered by its high treatment cost and limited efficacy. Here, it is shown that the development of an antibody-conjugated nanogel (ANGel), consisting of N-isopropylacrylamide-co-acrylic acid and antibody-binding protein (protein A), potentiates the efficacy of two ICI monoclonal antibodies (mAbs) (cytotoxic-T-lymphocyte-associated antigen 4 and programmed death ligand-1 mAbs). Compared with mAb treatment alone, treatment with a bispecific ANGel surface-conjugated with the mAbs significantly decreases both the survival of Michigan Cancer Foundation-7 (MCF-7) and M D Anderson-Metastatic Breast-231 (MDA-MB-231) breast cancer cells in vitro and the burden of 4T1-luciferase-2-derived orthotopic syngeneic tumors in vivo. The bispecific ANGel is also more potent than the conventional treatment at prolonging survival in animals with triple-negative breast cancer. The advantage of the bispecific ANGel over other engineered bispecific antibodies arises not only from the adaptability to link multiple antibodies quickly and easily, but also from the capability to maintain the anticancer effect steadily at subcutaneously delivered tumor site. This finding has an important implication for cancer immunotherapy, opening a new paradigm to treat solid tumors.

Rice pollen-specific OsRALF17 and OsRALF19 are essential for pollen tube growth.

Pollen tube growth is essential for successful double fertilization, which is critical for grain yield in crop plants. Rapid alkalinization factors (RALFs) function as ligands for signal transduction during fertilization. However, functional studies on RALF in monocot plants are lacking. Herein, we functionally characterized two pollen-specific RALFs in rice (Oryza sativa) using multiple clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9-induced loss-of-function mutants, peptide treatment, expression analyses, and tag reporter lines. Among the 41 RALF members in rice, OsRALF17 was specifically expressed at the highest level in pollen and pollen tubes. Exogenously applied OsRALF17 or OsRALF19 peptide inhibited pollen tube germination and elongation at high concentrations but enhanced tube elongation at low concentrations, indicating growth regulation. Double mutants of OsRALF17 and OsRALF19 (ralf17/19) exhibited almost full male sterility with defects in pollen hydration, germination, and tube elongation, which was partially recovered by exogenous treatment with OsRALF17 peptide. This study revealed that two partially functionally redundant OsRALF17 and OsRALF19 bind to Oryza sativa male-gene transfer defective 2 (OsMTD2) and transmit reactive oxygen species signals for pollen tube germination and integrity maintenance in rice. Transcriptomic analysis confirmed their common downstream genes, in osmtd2 and ralf17/19. This study provides new insights into the role of RALF, expanding our knowledge of the biological role of RALF in regulating rice fertilization.

OsSNDP3 Functions for the Polar Tip Growth in Rice Pollen Together with OsSNDP2, a Paralog of OsSNDP3.

Understanding pollen tube growth is critical for crop yield maintenance. The pollen tube provides a path for sperm cells for fertilization with egg cells. Cells must be subdivided into functionally and structurally distinct compartments for polar tip growth, and phosphoinositides are thought to be one of the facilitators for polarization during pollen tube growth. OsSNDP3 encodes Sec14-nodulin domain-containing protein and localizes in the nucleus and the microdomains of the plasma membrane in tobacco leaf epidermis cells. OsSNDP3 is thought to bind with phosphatidylinositol 4,5-bisphosphate based on the data including the information of basic amino acids in the C-terminal and colocalization with 2X Pleckstrin homology domain of Phospholipase C delta-1. OsSNDP3 interacts with a protein that contains a class I nodulin domain. We discovered that OsSNDP3 plays a significant role in pollen tube germination using CRISPR/Cas9 systems, whereas another pollen-preferential Sec14-nodulin domain-containing protein, OsSNDP2, additively functions with OsSNDP3 during pollen tube germination. Gene Ontology analysis using downregulated genes in ossndp3 indicated that the expression of genes involved in the phosphatidylinositol metabolic process and tip growth was significantly altered in ossndp3. OsSNDP3 aids pollen polar tip growth by binding with phosphatidylinositol 4,5-bisphosphate. We can better understand the roles of phosphoinositides during pollen tube growth by studying the functions of OsSNDP3 and OsSNDP2. And downregulated genes in ossndp3 might be useful targets for future research on polar tip growth.

Cytokine Response to Diet and Exercise Affects Atheromatous Matrix Metalloproteinase-2/9 Activity in Mice.

BACKGROUND: The aim of this study is to identify the principal circulating factors that modulate atheromatous matrix metalloproteinase (MMP) activity in response to diet and exercise.Methods and Results:Apolipoprotein-E knock-out (ApoE-/-) mice (n=56) with pre-existing plaque, fed either a Western diet (WD) or normal diet (ND), underwent either 10 weeks of treadmill exercise or had no treatment. Atheromatous MMP activity was visualized using molecular imaging with a MMP-2/9 activatable near-infrared fluorescent (NIRF) probe. Exercise did not significantly reduce body weight, visceral fat, and plaque size in either WD-fed animals or ND-fed animals. However, atheromatous MMP-activity was different; ND animals that did or did not exercise had similarly low MMP activities, WD animals that did not exercise had high MMP activity, and WD animals that did exercise had reduced levels of MMP activity, close to the levels of ND animals. Factor analysis and path analysis showed that soluble vascular cell adhesion molecule (sVCAM)-1 was directly positively correlated to atheromatous MMP activity. Adiponectin was indirectly negatively related to atheromatous MMP activity by way of sVCAM-1. Resistin was indirectly positively related to atheromatous MMP activity by way of sVCAM-1. Visceral fat amount was indirectly positively associated with atheromatous MMP activity, by way of adiponectin reduction and resistin elevation. MMP-2/9 imaging of additional mice (n=18) supported the diet/exercise-related anti-atherosclerotic roles for sVCAM-1. CONCLUSIONS: Diet and exercise affect atheromatous MMP activity by modulating the systemic inflammatory milieu, with sVCAM-1, resistin, and adiponectin closely interacting with each other and with visceral fat.

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.

Requirement of AMPK activation for neuronal metabolic-enhancing effects of antidepressant paroxetine.

Reduced glucose metabolism has been implicated as a pathophysiology of depressive disorder. Normalization of such impaired neurometabolism has been related to the therapeutic actions of antidepressant medication. However, the molecular mechanism underlying the neurometabolic actions of antidepressants has not been fully understood. Given that AMP-activated protein kinase (AMPK) is a master switch for energy homeostasis, we aimed to determine whether selective serotonin reuptake inhibitor paroxetine enhances energy metabolism by activating AMPK in neuroblastoma cells. We found that paroxetine dose dependently increased mitochondrial biogenesis, which involves the AMPK-peroxisome proliferator-activated receptor-γ coactivator-1α pathway. In addition, paroxetine-induced AMPK activation increases glucose uptake and ATP production. These neurometabolic effects of paroxetine were suppressed by cotreatment with compound C (CC), an AMPK inhibitor. These findings suggest a possibility that modulation of the AMPK pathway might be a previously unrecognized mechanism underlying the neurometabolic action of antidepressants. Further study is warranted to examine the region-specific and time-specific effects of AMPK modulation by antidepressants on mood-related behaviors.

Metabolomic signatures in peripheral blood associated with Alzheimer's disease amyloid-ß-induced neuroinflammation.

Discovery of biomarkers in peripheral blood is a crucial step toward the early diagnosis and repetitive monitoring of treatment response for Alzheimer's disease (AD). Metabolomics is a promising technology that can identify unbiased biomarkers. To explore potential blood biomarkers for AD via metabolic profiling with high-resolution magic angle spinning nuclear magnetic resonance techniques, we identified changes in peripheral blood metabolomic profiles in response to amyloid-ß (Aß)-induced neuroinflammation and co-treatment with gallate, a phytochemical known to have anti-neuroinflammatory properties. Alzheimer's-like (AL) model mice were produced by intracerebroventricular infusion of Aß and compared with normal control mice with infusion of vehicle. AL mice were treated with either gallate (treated AL mice) or vehicle (untreated AL mice). Metabolomic analyses of both whole blood and plasma showed a clear separation between untreated AL mice and the other two groups, with levels of several metabolites involved in energy metabolism, including pyruvate and creatine, being significantly reduced in untreated AL mice compared with control and treated AL mice. Gallate treatment suppressed Aß-induced overproduction of the inflammatory cytokine tumor necrosis factor-α in the hippocampus and normalized plasma levels of the affected metabolites. These results suggest that plasma levels of several metabolites could be indicative of both brain pathology and therapeutic responses, supporting the possibility of a close relationship between central neuroinflammation and systemic metabolic disturbance. These findings also suggest the potential of NMR-based metabolomics as a method to identify novel plasma biomarkers for AD, which could be confirmed by future translational research with human patients.

An Analysis of the Thickness of Abdominal Muscles during Forceful Expiration and Pulmonary Function in Teenage Smokers and Nonsmokers.

[Purpose] The purpose of this study was to examine the effects of smoking on teenagers' internal oblique (IO) and transverses abdominis (TrA) expiratory muscles and their pulmonary function. [Subjects] A total of 30 healthy teenagers (15 smokers; 15 nonsmokers) voluntarily participated in the study. [Methods] The subjects were instructed to maintain an upright standing posture with their scapulars against the wall. Measurements were then taken to determine the thickness of their right IO and their right TrA while they were at rest and in a state of forced expiration using a 7.5 MHz linear probe of an ultrasonic imaging system. The measured thickness was converted into the percentage of change in muscle thickness (PCMT) and the relative contribution ratio (RCR) using a calculation formula, and then the data were analyzed. [Results] No significant differences were found between the two groups in the thickness, PCMT, and RCR of both the IO and TrA muscles, while there were significant differences in the forced expiratory volume at one second (FEV1) and the peak expiratory flow (PEF). [Conclusion] This study examined teenage smokers whose duration of smoking was relatively short. The two groups did not show significant differences in the thickness of both the IO and TrA muscles. However, based on the forced expiratory volume at one second (FEV1) and PEF measurements, the smokers showed greater decreases in pulmonary function than the nonsmokers.

Persistent human papillomavirus DNA is associated with local recurrence after radiotherapy of uterine cervical cancer.

Human papillomavirus (HPV) DNA is considered as a hallmark of cervical cancer. We investigated whether persistent HPV DNA at the cervix is associated with local recurrence after radiotherapy in patients with locally advanced cervical cancer. A total of 156 patients with HPV-positive cervical cancer (International Federation of Gynecology and Obstetrics stage IB-IVB) treated with radiotherapy between July 2003 and December 2006 were analyzed. HPV DNA was measured prior to radiotherapy and after completion of radiotherapy. The results of HPV DNA test at postradiotherapy 1, 3, 6 and 12 months were analyzed individually for association with local recurrence-free survival (LRFS). In addition, the result of any last follow-up HPV test within 24 months postradiotherapy was defined as the overall status of HPV at 24 months and was also analyzed for association with LRFS. HPV DNA was cleared in 127 patients (81.4%) and persistent in 29 patients (18.6%) by 24 months. In 18 patients with local recurrences, 14 patients (78%) showed positive HPV tests at 1-3 months. Among the various time points analyzed, a positive HPV test at 3 months was the most accurate predictor of local recurrence. Multivariate analysis indicated that overall status of HPV at 24 months, low HPV viral load and histologic grade as being significantly related to poor LRFS. In HPV-positive cervical carcinoma treated primarily with radiotherapy, persistent HPV DNA within 24 months after treatment indicates a high risk of local recurrence. Diagnostic accuracy of HPV test was highest at 3 months.

Carbonic anhydrase XII expression is associated with histologic grade of cervical cancer and superior radiotherapy outcome.

BACKGROUND: To investigate whether expression of carbonic anhydrase XII (CA12) is associated with histologic grade of the tumors and radiotherapy outcomes of the patients with invasive cervical cancer. METHODS: CA12 expression was examined by immunohistochemical stains in cervical cancer tissues from 183 radiotherapy patients. Histological grading was classified as well (WD), moderately (MD) or poorly differentiated (PD). Oligonucleotide microarray experiment was performed using seven cervical cancer samples to examine differentially expressed genes between WD and PD cervical cancers. The association between CA12 and histological grade was analyzed by chi-square test. CA12 and histological grades were analyzed individually and as combined CA12 and histologic grade categories for effects on survival outcome. RESULTS: Immunohistochemical expression of CA12 was highly associated with the histologic grade of cervical cancer. Lack of CA12 expression was associated with PD histology, with an odds ratio of 3.9 (P = 0.01). Microarray analysis showed a fourfold reduction in CA12 gene expression in PD tumors. CA12 expression was marginally associated with superior disease-free survival. Application of the new combined categories resulted in further discrimination of the prognosis of patients with moderate and poorly differentiated tumor grade. CONCLUSIONS: Our study indicates that CA12 may be used as a novel prognostic marker in combination with histologic grade of the tumors.

Low initial human papilloma viral load implicates worse prognosis in patients with uterine cervical cancer treated with radiotherapy.

PURPOSE: To evaluate whether human papillomavirus (HPV) viral load measured in cervical smear and HPV type 18 are associated with radiotherapy outcomes in uterine cervical cancer. PATIENTS AND METHODS HPV DNA: was semiquantitatively measured in the cervical smears of 169 radiotherapy patients. HPV viral load was classified as low or high according to median HPV DNA titer and examined for its prognostic value. The multivariable Cox proportional hazards model was used to adjust for covariates. A relapse-predicting model was constructed to classify three risk groups for disease-free survival (DFS), which were used for internal validation. RESULTS: Patients with lower HPV viral load showed worse DFS in univariate analysis. HPV type 18, younger patient age, stage group, nodal status, histologic grade, and histologic type were other prognostic factors for poor DFS. Among these factors, all except stage group were associated with HPV viral load. Multivariate analysis showed the strong influence of HPV viral load for poor DFS. The prognostic model developed using our outcome data performed well in predicting the risk of relapse. CONCLUSION: Our data suggest that HPV viral load is a strong independent prognostic factor for DFS. HPV type 18 showed a significant relationship with poor radiotherapy outcome in univariate analysis, but not in multivariate analysis.