Changes in depression trends during and after the COVID-19 pandemic among older adults in Korea.

This study aimed to complement the previous studies conducted within a short period of time by examining the long-term trends in depression levels of older adults through a longitudinal study that includes the period following the onset of COVID-19. For analysis, this study used the data from the 12th (2017) through 16th (2021) Korea Welfare Panel Study, and 2,716 data of older adults 65 years and older were included. Variables included gender, age, equalized annual income (USD $), education background, residential area, living alone and disability status. As a result, two types of changes in depression were identified: the 'rapidly rising' type and the 'steadily increasing'. We found that the lower the equalized annual income, women, the lower the education, living in urban and living alone showed a higher likelihood of belonging to the 'rapidly rising' type. The result suggests that those at risk of depression are at much higher risk during and after the COVID-19 pandemic. It is also necessary to provide timely and effective guidelines to prevent depression in older adults when implementing policies in response to an outbreak of infectious diseases, such as COVID-19.

A study on longitudinal relationship between ultrafine dust and the prevalence of depression.

BACKGROUND: Recently, the fine dust problem caused by rapid industrialization and science and technological development has emerged as a severe social issue worldwide. This also increases the interest in its effect on human life. In particular, there is a growing concern about the harm of fine dust in Korea. METHODS: This study is based on the PM 2.5 data from 2017 to 2021 provided by Air Korea to estimate changes in ultrafine dust. In addition, the data from the Community Health Survey provided by the Korea Centers for Disease Control and Prevention (KCDC) from 2017 to 2021 were used to examine the effect between the change in ultra-fine dust and the prevalence of depression. A total of 229 local governments were included in the analysis. The Latent Growth Modeling was carried out to estimate the change in ultra-fine dust and the prevalence of depressions and verify the relationship between ultra-fine dust and the prevalence of depression. RESULTS: The analysis result revealed that the ultra-fine dust concentration continued to decrease from 2017 to 2021. However, the depression prevalence increased from an average of 2.60% in 2017 to an average of 3.12% in 2021, suggesting the need for adequate and sufficient welfare policies for depression treatment. As a result of estimating the initial value and change rate of ultra-fine dust and depression prevalence, the higher the initial value of ultra-fine dust, the greater the decrease in ultra-fine dust. In terms of depression, the lower the initial value of the prevalence of depression, the larger the increase in depression prevalence. CONCLUSIONS: This study is significant in that it revealed the strong association of the longitudinal relationship between ultra-fine dust and depression, one of the biggest issues in Korea, by utilizing large-scale longitudinal data.

A Study on the Longitudinal Relationship between Changes in Depression and Cognitive Function among Older Adults Living Alone.

BACKGROUND: As South Korea faces unprecedented population aging, this longitudinal study examined the relationship between depression and cognitive function changes in older individuals living alone. METHODS: The study used data from the Korean Longitudinal Study of Aging (KLoSA). A total of 1354 participants with data available over a period of at least three years, from 2016 (wave 1) to 2020 (wave 8), were included, and latent growth modeling (LGM) was used for analysis. RESULTS: Depression levels increased gradually among older individuals living alone and cognitive function declined over time among older adults living alone. Moreover, higher initial depression levels were associated with lower initial cognitive function levels and a more rapid cognitive decline over time. Therefore, it is imperative that depression be addressed as a potential cause of cognitive impairment and dementia. Furthermore, rapid increases in depression corresponded to rapid declines in cognitive function, indicating the need for continuous monitoring and intervention in cases of escalating depression, as it may negatively affect cognitive abilities. CONCLUSIONS: These findings highlight the complex interplay between depression and cognitive function among older individuals living alone. Policy support to encourage participation in these programs is crucial to enhance the well-being of this vulnerable population.

Predictors of Variation in the Cognitive Function Trajectories among Older Adults Living Alone: A Growth Mixture Modeling Approach.

BACKGROUND: Considering the global aging population, this study investigates changes in cognitive function and predictive factors among older adults living alone. METHODS: Using data collected from the Korean Longitudinal Study of Aging (KLoSA), the study examines 1217 participants to identify distinct cognitive change patterns and the variables affecting them. RESULTS: Two primary cognitive function change types emerged: "High-Level Declining Type" and "Low-Level Stable Type." Although the former initially displayed normal cognitive function, it gradually declined over a period of 14 years until it reached mild cognitive impairment (MCI) levels by the year 2020. While the latter group had lower cognitive function from the beginning and remained stable throughout the study. Older age, female gender, rural residence, lower education, lower income, unemployment, and higher levels of depression were linked to a higher likelihood of belonging to the "Low-Level Stable Type". CONCLUSIONS: The findings of these studies emphasize the need for proactive interventions and regular cognitive assessments for older individuals living alone, as cognitive impairment can develop even in individuals whose cognitive abilities are initially good. Also, tailored interventions should target specific demographic and socioeconomic groups to mitigate cognitive decline effectively.

Cross-Lagged Panel Analysis between Physical Frailty, Cognitive Function, and Falls by Sex.

OBJECTIVES: This study investigated the reciprocal longitudinal relationships between physical frailty (PF), cognitive function (CF), and falls among community-dwelling older adults, according to sex. The study proposed hypotheses that present PF and CF will affect the occurrence of falls 2 years later. DESIGN: Secondary data analysis using the first (T1, 2016-2017) and second (T2, 2018-2019) waves of the Korean Frailty and Aging Cohort Study (KFACS). SETTING AND PARTICIPANTS: A total of 2318 community-dwelling older adults aged 70-84 years in South Korea; mean (SD) age: 75.72 (3.83) years; 47.7% men. METHODS: PF and CF were measured with the modified version of the Fried Frailty Phenotype and the Korean version of the Mini-Mental State Examination, respectively. The number of falls were assessed. Multigroup cross-lagged panel analysis was used. RESULTS: The results showed that relationships between PF, CF, and falls were maintained over time through an autoregressive effect. PF at T1 had a statistically significant longitudinal relationship with fall experience at T2 [standardized regression coefficient (ß) = 0.087, 95% CI 0.045-0.129; P < .001], and fall experience at T1 had a significant longitudinal relationship with PF at T2 (ß = 0.041, 95% CI 0.006-0.076; P = .020). There was no statistically significant relationship between CF and fall experience. PF and CF had statistically significant reciprocal longitudinal relationships (all P < .001). Based on sex, there was a statistically significant longitudinal relationship between fall experience at T1 and PF at T2 for men only (ß = 0.063, 95% CI 0.012-0.114; P = .015). CONCLUSIONS AND IMPLICATIONS: Findings highlight that health care providers should plan fall prevention programs through early intervention for PF improvement along with improvement and maintenance of CF. Specifically, even if older men are currently healthy and have a low risk of falls, it is important to prevent future fatal PF through prior interventions, such as risk activities attention and concerns about falls.

Healthcare Utilization and Costs According to Frailty Transitions After Two Years: A Korean Frailty and Aging Cohort Study.

BACKGROUND: Korea's aging population has raised several challenges, especially concerning healthcare costs. Consequently, this study evaluated the association of frailty transitions with healthcare utilization and costs for older adults aged 70 to 84. METHODS: This study linked the frailty status data of the Korean Frailty and Aging Cohort Study to the National Health Insurance Database. We included 2,291 participants who had frailty measured by Fried Frailty phenotype at baseline in 2016-2017 and follow-up in 2018-2019. We conducted a multivariate regression analysis to determine the association between their healthcare utilization and costs by frailty transition groups. RESULTS: After 2 years, changes from "pre-frail" to "frail" (Group 6) and "frail" to "pre-frail" (Group 8) were significantly associated with increased inpatient days (P < 0.001), inpatient frequency (P < 0.001), inpatient cost (P < 0.001 and P < 0.01, respectively), and total healthcare cost (P < 0.001) than "robust" to "robust" (Group 1) older adults. A transition to frailty from "pre-frail" to "frail" (Group 6) resulted in a $2,339 total healthcare cost increase, and from "frail" to "pre-frail" (Group 8), a $1,605, compared to "robust" to "robust" older adults. CONCLUSION: Frailty among community-dwelling older adults is economically relevant. Therefore, it is crucial to study the burden of medical expenses and countermeasures for older adults to not only provide appropriate medical services but also to prevent the decline in their living standards due to medical expenses.

Association between depressive symptoms and the risk of all-cause and cardiovascular mortality among US adults.

Depression is a preventable and treatable mental health condition. Therefore, there are important clinical implications for identifying people with the highest mortality risk in a nationally representative sample. This study included 26,207 participants aged ≥18 years from the 2005-2014 National Health and Nutrition Examination Survey in USA. We investigated the association between depressive symptoms (defined as Patient Health Questionnaire 9 scores ≥10) and all-cause and cardiovascular disease (CVD) mortalities, adjusted for multiple factors (sociodemographic in Model 1, behavioral added in Model 2, and metabolic syndrome added in Model 3) and stratified by age and sex. During an average follow-up of 69.15 months (standard deviation [SD] 34.45), 1872 (7.3%) participants had died (person-years in the non-depressive and depressive groups, 12.12/1000 and 16.43/1000, respectively). Depressive symptoms increased all-cause (crude hazard ratio [HR] 1.37, 95% confidence interval [CI], 1.33-1.58) and CVD mortalities (crude HR 1.64, 95% CI, 1.20-2.24). Although the significance of all-cause mortality and CVD mortality was maintained in Models 1 (HR 1.58 and 2.08) and 2 (HR 1.48 and 1.79), it was not maintained in Model 3. Current smoking and lower physical activity were associated with reduced strength of the association between depression and all-cause mortality risk. The effect of depression on mortality risk was particularly pronounced in middle-aged men and older women. Our findings suggest that depressive symptoms increase mortality risk, even after adjusting for behavioral factors. Depression-induced mortality risk is particularly high among middle-aged men and older women.

A Longitudinal Relationship Between Mother's Smartphone Addiction to Child's Smartphone Addiction.

Children are more likely to become addicted as they become accustomed to using smartphones, and as they observe and imitate their parents using smartphones. This study aims to confirm longitudinally the effect of mother's smartphone addiction on children's smartphone addiction. Latent growth modeling was used to analyze longitudinal relationships between 3615 pairs of children and their mothers from the Korean Children and Youth Panel Survey (KCYPS) (2018-2020). As a result, both the mothers and children's smartphone addiction significantly increased over time. The initial value of the mother's smartphone addiction was found to have a significant effect on the child's initial value and the change rate. Moreover, children's smartphone addiction change rate was significantly affected by the change rate of the mother's smartphone addiction. To intervene in children's smartphone addiction, a family-level approach, as well as parental addiction, must also be addressed, and a preventive approach should focus on those with a low risk of addiction.

Patterns and predictors of fall injury transitions among Korean older adult fallers: a 2-year longitudinal study.

This study was conducted to identify fall injury patterns, the transition from the baseline to follow-up, and the factors associated with the identified fall injury patterns using data obtained from the Korean Frailty and Aging Cohort Study. The participants were 566 community-dwelling older adults with fall experience. Three fall injury patterns were identified as the baseline and follow-up periods. The probability that the participant in the "fracture injury" pattern at Time 1 transitioned to the "fracture injury" pattern at Time 2 was 0.098. The factors associated with the "bruising and/or sprain injury" pattern were education level (relative risk ratio [RRR] = 0.55, p = 0.012), alcohol consumption (RRR = 0.50, p = 0.034), and balancing in tandem position (RRR = 2.77, p < 0.001). In the "fracture injury" pattern, male (RRR = 0.22, p = 0.038), frailty score (RRR = 0.58, p = 0.042), "bruising injury" (RRR = 0.23, p = 0.007), and "sprain injury" (RRR = 0.20, p = 0.007) at the baseline were significant factors. The findings indicate that previous fall experiences, higher alcohol consumption, lower frailty scores, and poor balance levels are associated with fall injury patterns. These patterns should be considered when developing prevention interventions.

A Study on Types of Medication Adherence in Hypertension among Older Patients and Influencing Factors.

BACKGROUND: Hypertension has the characteristic that the risk of complications can be reduced through appropriate medication in daily life. Hence, it is important to consider practical measures to increase medication adherence, particularly among older patients. METHODS: This study used the Korea Health Panel 2020 data (Version 2.0.1), jointly conducted by Korea Institute for Health and Social Affairs and National Health Insurance. A total of 2300 patients with high blood pressure over 65 years of age were selected. In order to identify types of medication adherence in older hypertensive patients, and examine factors that influence the types, the Latent Profile Analysis (LPA) and logistic regression were performed. RESULTS: The types of adherence groups were classified into two groups: an 'adherence group' (87.1%) and a 'non-adherence group' (12.9%). Furthermore, age, living alone, and depressive symptoms were identified as determinants of medication adherence type among older hypertensive patients. CONCLUSION: The significant impact of sociodemographic status (age, living alone, and depressive symptoms) on medication adherence among older hypertensive patients indicates the need to establish more specific empirical interventions based on each type's characteristics. It is expected that this study will provide an in-depth understanding of factors associated with medication adherence among older patients with hypertension, which can support interventions tailored to the specific needs of those who are non-adherent.

Changes in the Suicide Rate of Older Adults According to Gender, Age, and Region in South Korea from 2010 to 2017.

BACKGROUND: South Korea's suicide rates are the highest among Organization for Economic Co-operation and Development (OECD) countries, making it one of the most important societal issues in South Korea. METHODS: the statistics on causes of death and resident registration central population (RRCP) provided by the National Statistical Office were used to calculate the suicide rate among older adults in Korea. We examined gender (male, female), age (young-old, old-old), and region (urban, rural) by conducting latent growth modeling to estimate changes in the overall older adult suicide rate and verify its relationship. RESULTS: over a period of 8 years, the older adult suicide rate was 104.232 on average in 2010 and it decreased by approximately 10.317 every year, and the rate of decrease gradually slowed down. The initial value of the older adult suicide rate was found to be higher among males, the old-old group, and those living in rural regions. In the quadratic function change rate, only males and the old-old group were statistically significant. CONCLUSION: in this study, the direction of and the rate of change in the older adult suicide rates and the relationship between gender, age, and region were examined. It is expected that this study will provide basic data to assist in establishing older adult suicide prevention policies, considering the gender, age, and region of the aging population.

A Study on the Relationship between Depression Change Types and Suicide Ideation before and after COVID-19.

BACKGROUND: The purpose of this study is to explore and categorize changes in depression, and investigate the relationship between suicidal ideations before and after the COVID-19 pandemic. METHODS: In this study, data from the Korea Welfare Panel Study (KoWePS) was used and included 8692 adults, 19 years of age or older, who could estimate the change in depression from 2017 (12th) to 2021 (16th) for final analysis. Depression change was classified into two types, 'low-level ascending' type (n = 7809, 80.9%), and 'increasing after reduction' type (n = 883, 10.2%). The Firth Method was used to examine the relationship between depression change types and suicidal ideation. RESULTS: The lower the equivalized annual income and the lower the educational level, and the likelihood of belonging to the 'increasing after reduction' type, compared to the 'low-level ascending' type, the greater the probability of having suicidal ideation. CONCLUSION: The significant impact of socioeconomic status (income and educational background) on suicidal ideation indicates the need to consider how epidemics affect inequality in society. This study is expected to provide a deeper understanding of depression, as well as to establish a foundation for long-term prevention of the rapid increase in suicide rates after COVID-19.

The effect of sex and physical frailty on incident disability after 2 years among community-dwelling older adults: KFACS study.

BACKGROUND: This study investigated the impact of physical frailty on the development of disabilities in mobility, activities of daily living (ADL), and instrumental activities of daily living (IADL) according to sex among community-dwelling Korean older adults. METHODS: We used data of 2,905 older adults aged 70-84 years from the Korean Frailty and Aging Cohort Study (KFACS) at baseline (2016-2017) and Wave 2 (2018-2019). Fried's physical frailty phenotype was used to identify frailty. RESULTS: After adjustment, frailty showed a higher impact for women than men on developing mobility disability (odds ratio [OR]=14.00, 95% confidence interval [CI]=4.8-40.78 vs. OR=9.89, 95% CI=4.28-22.86) and IADL disability after two years (OR=7.22, 95% CI=2.67-19.56 vs. OR=3.19, 95% CI=1.17-8.70). Pre-frailty led to mobility disability for women and men (OR=2.77, 95% CI=1.93-3.98 vs. OR=2.49, 95% CI=1.66-3.72, respectively), and IADL disability only for women (OR=3.01, 95% CI=1.28-7.09). Among the IADL components, both men and women who were prefrail or frail showed increased disability in 'using transportation'. Among men, pre-frailty was significantly associated with disability in "going out" and "shopping". In women, frailty was significantly associated with disability in "doing laundry," "performing household chores," "shopping," and "managing money". CONCLUSIONS: Physical frailty increased disability over 2 years for women more than men. Physical frailty increased disability in outdoor activity-related IADL components in men and household work-related IADL components in women. This study highlights the need for gender-specific policies and preventative programs for frailty, particularly restorative interventions that focus on women who are physically frail.

The role of microRNA-33 as a key regulator in hepatic lipogenesis signaling and a potential serological biomarker for NAFLD with excessive dietary fructose consumption in C57BL/6N mice.

Limited studies reported mechanisms by which microRNAs (miRNA) are interlinked in the etiology of fructose-induced non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the significance of miRNAs in fructose-induced NAFLD pathogenesis through unbiased approaches. In experiment I, C57BL/6N mice were fed either water or 34% fructose for six weeks ad libitum. In experiment II, time course effects of fructose intervention were monitored using the same conditions; mice were killed at the baseline, fourth, and sixth weeks. Bioinformatic analyses for hepatic proteomics revealed that SREBP1 is the most significant upstream regulator influenced by fructose; miR-33-5p (miR-33) was identified as the key miRNA responsible for SREBP1 regulation upon fructose intake, which was validated by in vitro transfection assay. In experiment II, we confirmed that the longer mice consumed fructose, the more severe liver injury markers (e.g., serum AST) appeared. Moreover, hepatic Srebp1 mRNA expression was increased depending upon the duration of fructose consumption. Hepatic miR-33 was time-dependently decreased by fructose while serum miR-33 expression was increased; these observations indicated that miR-33 from the liver might be released upon cell damage. Finally we observed that fructose-induced ferroptosis might be a cause of liver toxicity, resulting from oxidative damage. Collectively, our findings suggest that fructose-induced oxidative damage induces ferroptosis, and miR-33 could be used as a serological biomarker of fructose-induced NAFLD.

Development of Korean Frailty Index for Primary Care (KFI-PC) and Its Criterion Validity.

BACKGROUND: The objective of this study was to develop and validate the Korean Frailty Index for Primary Care (KFI-PC) based on a comprehensive geriatric assessment. METHODS: We developed a 54-item KFI-PC comprising 10 standard domains: cognitive status including delirium or dementia; mood; communication including vision, hearing, and speech; mobility; balance; bowel function; bladder function; ability to carry out activities of daily living; nutrition; and social resources. To test its validity, we applied KFI-PC to participants of the Korean Frailty Aging and Cohort Study (KFACS). We analyzed 1,242 participants (mean age, 77.9±3.9 years; 47.2% men) from the KFACS who visited 10 study centers in 2018, after excluding 32 participants with missing data required to assess Fried's physical frailty phenotype. RESULTS: The mean KFI-PC score was 0.17±0.08, ranging from 0.02 to 0.52. The median KFI-PC score was higher in women than in men, and there was a trend toward higher values in older age groups. The prevalence of frailty when applying a generally used frailty index cutoff point of >0.25 was 17.5% in the whole study sample. As a construct validation of KFI-PC, the area under the receiver operating characteristic curve for Fried's physical frailty was 0.921, and the optimal cutoff value to predict frailty phenotype was 0.23. The KFI-PC score also correlated well with physical, cognitive, and psychological functions; nutritional status; disability in activities of daily living; and instrumental activities of daily living. The Cronbach's alpha coefficient of the 54 total items was 0.737. CONCLUSION: We developed KFI-PC with 53 deficits, including comprehensive geriatric assessment components, and demonstrated the acceptable construct validity and internal consistency of KFI-PC.

Korean frailty and aging cohort study (KFACS): cohort profile.

PURPOSE: The purpose of the Korean Frailty and Aging Cohort Study (KFACS) is to initiate a nationwide, population-based prospective cohort study of older adults living in the community to assess their frailty status and explore transitions between frailty states over time in Korea. PARTICIPANTS: The KFACS is a multicentre longitudinal study with the baseline survey conducted from May 2016 to November 2017. Each centre recruited participants using quota sampling stratified by age and sex. The number of participants recruited through 2 years of baseline study from 10 centres was 3014, with each site accounting for approximately 300 participants. The inclusion criteria were: having an age of 70-84 years, currently living in the community, having no plans to move out in the next 2 years, having no problems with communication and no prior dementia diagnosis. FINDINGS TO DATE: To define physical frailty, the KFACS used a modified version of the Fried Frailty Phenotype (FFP) consisting of five components of frailty: unintended weight loss, weakness, self-reported exhaustion, slowness and low physical activity. In the baseline study of 2016-2017, 2907 of 3014 individuals fulfilled all five components of FFP. The results indicated that 7.8% of the participants (n=228) were frail, 47.0% (n=1366) were prefrail and 45.2% (n=1313) were robust. The prevalence of frailty increased with age in both sexes; in the group aged 70-74 years, 1.8% of men and 3.7% of women were frail, whereas in the 80-84 years age group, 14.9% of men and 16.7% of women were frail. Women tended to exhibit a higher prevalence of frailty than men in all age groups. FUTURE PLANS: The KFACS plans to identify outcomes and risk factors associated with frailty by conducting a 10-year cohort study, with a follow-up every 2 years, using 3014 baseline participants.

Protective effects of p-coumaric acid against acetaminophen-induced hepatotoxicity in mice.

Acetaminophen (N-acetyl-p-aminophenol, AAP) is an effective analgesic and antipyretic drug with minimal toxicity when used at therapeutic doses. However, AAP overdose is the most common cause of drug-induced acute liver failure and one of the main causes of morbidity and mortality. p-Coumaric acid (PCA) is the most abundant isomer of hydroxycinnamic acid in nature, and it can be widely found in fruits, vegetables, and plants products. PCA has strong antioxidant activity and exhibits protective effects in numerous disease models associated with reactive oxygen species (ROS) generation. In this study, we investigated the protective effects of PCA on AAP-induced hepatotoxicity and the underlying mechanisms using an in vivo model. We found that PCA ameliorates AAP-induced hepatotoxicity as well as the reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Furthermore, we observed that PCA suppressed hepatic apoptosis via ROS-mediated DNA damage responses and inflammation by modulating the mitogen-activated protein kinase (MAPK) signaling axis in an ROS-dependent manner. These findings indicate that the administration of PCA protects against AAP-induced hepatotoxicity, suggesting it could be a novel therapeutic strategy for AAP-induced liver injury.

Idh2 deficiency accelerates renal dysfunction in aged mice.

The free radical or oxidative stress theory of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species (ROS) that are produced as by-products of normal metabolic processes in mitochondria. The oxidative stress may arise as a result of either increased ROS production or decreased ability to detoxify ROS. The availability of the mitochondrial NADPH pool is critical for the maintenance of the mitochondrial antioxidant system. The major enzyme responsible for generating mitochondrial NADPH is mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2). Depletion of IDH2 in mice (idh2-/-) shortens life span and accelerates the degeneration of multiple age-sensitive traits, such as hair grayness, skin pathology, and eye pathology. Among the various internal organs tested in this study, IDH2 depletion-induced acceleration of senescence was uniquely observed in the kidney. Renal function and structure were greatly deteriorated in 24-month-old idh2-/- mice compared with wild-type. In addition, disruption of redox status, which promotes oxidative damage and apoptosis, was more pronounced in idh2-/- mice. These data support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice, and thus support the oxidative stress theory of aging.

Increased susceptibility of IDH2-deficient mice to dextran sodium sulfate-induced colitis.

Inflammatory bowel disease (IBD) is a group of chronic, relapsing, immunological, inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease (CD). It has been reported that UC, which is studied using a dextran sodium sulfate (DSS)-induced colitis model, is associated with the production of reactive oxygen species (ROS) and the apoptosis of intestine epithelial cells (IEC). Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) has been reported as an essential enzyme in the mitochondrial antioxidant system via generation of NADPH. Therefore, we evaluated the role of IDH2 in DSS-induced colitis using IDH2-deficient (IDH2-/-) mice. We observed that DSS-induced colitis in IDH2-/- mice was more severe than that in wild-type IDH2+/+ mice. Our results also suggest that IDH2 deficiency exacerbates PUMA-mediated apoptosis, resulting from NF-κB activation regulated by histone deacetylase (HDAC) activity. In addition, DSS-induced colitis is ameliorated by an antioxidant N-acetylcysteine (NAC) through attenuation of oxidative stress, resulting from deficiency of the IDH2 gene. In conclusion, deficiency of IDH2 leads to increased mitochondrial ROS levels, which inhibits HDAC activity, and the activation of NF-κB via acetylation is enhanced by attenuated HDAC activity, which causes PUMA-mediated apoptosis of IEC in DSS-induced colitis. The present study supported the rationale for targeting IDH2 as an important cancer chemoprevention strategy, particularly in the prevention of colorectal cancer.

Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration.

Clinical and experimental observations indicate a critical role for vascular endothelial growth factor (VEGF), secreted by the retinal pigment epithelium (RPE), in pathological angiogenesis and the development of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). RPE-mediated VEGF expression, leading to angiogenesis, is a major signaling mechanism underlying ocular neovascular disease. Inhibiting this signaling pathway with a therapeutic molecule is a promising anti-angiogenic strategy to treat this disease with potentially fewer side effects. Oxalomalate (OMA) is a competitive inhibitor of NADP+-dependent isocitrate dehydrogenase (IDH), which plays an important role in cellular signaling pathways regulated by reactive oxygen species (ROS). Here, we have investigated the inhibitory effect of OMA on the expression of VEGF, and the associated underlying mechanism of action, using in vitro and in vivo RPE cell models of AMD. We found that OMA reduced the expression and secretion of VEGF in RPE cells, and consequently inhibited CNV formation. This function of OMA was linked to its capacity to activate the pVHL-mediated HIF-1α degradation in these cells, partly via a ROS-dependent ATM signaling axis, through inhibition of IDH enzymes. These findings reveal a novel role for OMA in inhibiting RPE-derived VEGF expression and angiogenesis, and suggest unique therapeutic strategies for treating pathological angiogenesis and AMD development.