Incidence of Tuberculosis Among Immigrants in Korea Who Participated in a Latent Tuberculosis Infection Screening Program.

BACKGROUND: With a rapid decrease in tuberculosis (TB) incidence, the significance of latent tuberculosis infection (LTBI) has been underscored in South Korea. Although South Korea does not have a high proportion of immigrants compared to other countries, there is a growing argument that it should actively embrace immigrants as a solution to address issues of low birth rates and population aging. This study aimed to assess TB incidence among immigrants who participated a pilot LTBI screening program in South Korea. METHODS: Records of immigrants participated in a pilot LTBI screening program in South Korea between 2018 and 2019 were linked with Korean National TB Surveillance System to determine TB development. Participants underwent interferon-gamma release assay (IGRA) and chest X-rays. Standardized incidence ratios (SIRs) stratified by age, country of origin's TB burden was calculated with a reference group of general South Korean population. RESULTS: Of a total of 9,517 participants, 14 TB cases were identified. Participants with positive IGRA results who did not initiate LTBI treatment showed TB incidence of 312.5 per 100,000 person-years, whereas those with negative results showed TB incidence of 34.4 per 100,000 person-years, resulting in an incidence rate ratio of 9.08 (95% confidence interval [CI], 2.50-32.99). SIR of TB among total participants including those with negative IGRA results was 2.60 (95% CI, 1.54-4.38; P < 0.001), whereas SIR among those with positive IGRA results was 5.86 (95% CI, 3.15-10.89; P < 0.001). In the calculation of SIR among participants with positive IGRA results, those aged under 35 from high TB-burden countries or intermediate TB-burden countries showed a high SIR (18.08; 95% CI, 2.55-128.37; P = 0.004), and 11.30 (95% CI, 2.82-45.16; P < 0.001), respectively). Contrary to previous reports that suggest the majority of elderly population with a positive IGRA result were due to remote infection and had a lower TB risk compared to younger ages, SIR among those aged 65 or over from intermediate TB-burden countries was 6.15 (95% CI, 0.87-43.69; P = 0.069), which was comparable to that in younger participants aged between 35 and 49 (SIR, 4.87; 95% CI, 1.22-19.49; P = 0.025) or those aged between 50 and 64 (SIR, 4.62; 95% CI, 1.73-12.31; P = 0.002). CONCLUSION: Young immigrants with positive IGRA results from countries with high or intermediate TB burden showed a relatively high TB risk compared to a general South Korea population. In addition, unexpected high TB risk was observed among elderly immigrants with positive IGRA results. In establishing future policies for LTBI in immigrants in South Korea, screenings should primarily focus on younger age group (who aged under 35). Additionally, further research is needed on the high TB risk observed in elderly immigrants.

The Impact of Infectious Mononucleosis History on the Risk of Developing Lymphoma and Nasopharyngeal Carcinoma: a Retrospective Large-Scale Cohort Study using National Health Insurance Data in South Korea.

Purpose: This study aimed to assess the long-term risks associated with a history of infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV). Specifically analyzing the potential increase in developing nasopharyngeal cancer (NPC) and lymphoma in patients with a history of IM and exploring the prevalence of other EBV-associated conditions. Materials and Methods: The Korean National Health Insurance Service (NHIS) database was utilized for a retrospective analysis, covering data from 2002 to 2021. A total of 25,582 IM patients and controls were included, with 1:1 propensity score matching. The study monitored outcomes, including lymphoma, NPC, gastric cancer, multiple sclerosis, and all-cause mortality. Results: Patients with a history of IM demonstrated a significantly higher incidence of lymphoma (HR=5.32, 95% CI 3.208‒8.82, p<0.001) and NPC (HR=7.116, 95% CI 1.617‒31.314, p=0.009) during the follow-up period compared with the control group. Additionally, the IM group showed an increased rate of all-cause mortality (HR=2.225, 95% CI 1.858‒2.663, p<0.001). Conclusion: This study suggests that individuals with a history of IM have an elevated risk of developing lymphoma and NPC in South Korea, emphasizing the importance of vigilant follow-up and monitoring. The results advocate for heightened awareness and potential national monitoring policies to address the long-term health implications of EBV infection and to implement preventive measures.

The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress.

Mitophagy induction upon mitochondrial stress is critical for maintaining mitochondrial homeostasis and cellular function. Here, we found that Mst1/2 (Stk3/4), key regulators of the Hippo pathway, are required for the induction of mitophagy under various mitochondrial stress conditions. Knockdown of Mst1/2 or pharmacological inhibition by XMU-MP-1 treatment led to impaired mitophagy induction upon CCCP and DFP treatment. Mechanistically, Mst1/2 induces mitophagy independently of the PINK1-Parkin pathway and the canonical Hippo pathway. Moreover, our results suggest the essential involvement of BNIP3 in Mst1/2-mediated mitophagy induction upon mitochondrial stress. Notably, Mst1/2 knockdown diminishes mitophagy induction, exacerbates mitochondrial dysfunction, and reduces cellular survival upon neurotoxic stress in both SH-SY5Y cells and Drosophila models. Conversely, Mst1 and Mst2 expression enhances mitophagy induction and cell survival. In addition, AAV-mediated Mst1 expression reduced the loss of TH-positive neurons, ameliorated behavioral deficits, and improved mitochondrial function in an MPTP-induced Parkinson's disease mouse model. Our findings reveal the Mst1/2-BNIP3 regulatory axis as a novel mediator of mitophagy induction under conditions of mitochondrial stress and suggest that Mst1/2 play a pivotal role in maintaining mitochondrial function and neuronal viability in response to neurotoxic treatment.

TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction.

Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.

Role of autophagy in betaine-promoted hepatoprotection against non-alcoholic fatty liver disease in mice.

Betaine, a compound found in plants and sea foods, is known to be beneficial against non-alcoholic fatty liver disease (NAFLD), but its hepatoprotective and anti-steatogenic mechanisms have been not fully understood. In the present study, we investigated the mechanisms underlying betaine-mediated alleviation of NAFLD induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) in mice, with special focus on the contribution of betaine-stimulated autophagy to NAFLD prevention. Male ICR mice were fed a CDAHFD with or without betaine (0.2-1% in drinking water) for 1 week. Betaine ameliorated the CDAHFD-induced fatty liver by restoring sulfur amino acid (SAA)-related metabolites, such as S-adenosylmethionine and homocysteine, and the phosphorylation of AMPK and ACC. In addition, it reduced the CDAHFD-induced ER stress (BiP, ATF6, and CHOP) and apoptosis (Bax, cleaved caspase-3, and cleaved PARP); however, it induced autophagy (LC3II/I and p62) which was downregulated by CDAHFD. To determine the role of autophagy in the improvement of NAFLD, chloroquine (CQ), an autophagy inhibitor, was injected into the mice fed a CDAHFD and betaine (0.5 % in drinking water). CQ did not affect SAA metabolism but reduced the beneficial effects of betaine as shown by the increases of hepatic lipids, ER stress, and apoptosis. Notably, the betaine-induced improvements in lipid metabolism determined by protein levels of p-AMPK, p-ACC, PPARα, and ACS1, were reversed by CQ. Thus, the results of this study suggest that the activation of autophagy is an important upstream mechanism for the inhibition of steatosis, ER stress, and apoptosis by betaine in NAFLD.

Sudden Sensorineural Hearing Loss and Facial Palsy in Patients with Vestibular Schwannoma Based on the Population Data of Korea.

BACKGROUND: The prevalence of sudden sensorineural hearing loss and facial palsy in patients with vestibular schwannoma and the association of sudden sensorineural hearing loss or facial palsy with vestibular schwannoma were investigated based on the population data of Korea. METHODS: This retrospective study used the Korean National Health Insurance Service data. Patients with vestibular schwannoma and those with a previous history of sudden sensorineural hearing loss or facial palsy were identified based on diagnostic, medication, magnetic resonance imaging, or audiometric codes from 2005 to 2020. The control group was established with propensity score matching. The risk for vestibular schwannoma in patients with a previous history of sudden sensorineural hearing loss or facial palsy was analyzed. RESULTS: There were 5751 patients in the vestibular schwannoma group and 23004 in the control group. The rate of patients with a previous history of sudden sensorineural hearing loss in the vestibular schwannoma group (25.8%) was significantly higher than in the control group (P -lt; .0001), as was the rate of patients with a previous history of facial palsy in the vestibular schwannoma group (4.7%) (P -lt; .0001). Previous history of sudden sensorineural hearing loss was a significant risk factor for vestibular schwannoma (hazard ratio=7.109, 95% confidence interval=6.696-7.547). Previous history of facial palsy was also a significant risk factor for vestibular schwannoma (hazard ratio=3.048, 95% confidence interval=2.695-3.447). CONCLUSION: The prevalence of sudden sensorineural hearing loss or facial palsy was significantly higher in patients with vestibular schwannoma than in those without vestibular schwannoma. Based on the population data of Korea, sudden sensorineural hearing loss and facial palsy were significant risk factors for vestibular schwannoma.

Longitudinal Analyses of Mutational Subclonal Architecture and Tumor Subtypes in Recurrent Bladder Cancer.

Longitudinal tumor sequencing of recurrent bladder cancer (BC) can facilitate the investigation of BC progression-associated genomic and transcriptomic alterations. In this study, we analyzed 18 tumor specimens including distant and locoregional metastases obtained during tumor progression for five BC patients using whole-exome and transcriptome sequencing. Along with the substantial level of intratumoral mutational heterogeneity across the cases, we observed that clonal mutations were enriched with known BC driver genes and apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC)-associated mutation signatures compared with subclonal mutations, suggesting the genetic makeup for BC tumorigenesis associated with APOBEC deaminase activity was accomplished early in the cancer evolution. Mutation-based phylogenetic analyses also revealed temporal dynamics of mutational clonal architectures in which the number of mutational clones varied along the BC progression and notably was often punctuated by clonal sweeps associated with chemotherapy. The bulk-level transcriptome sequencing revealed frequent subtype switching in which transcriptionally defined BC subtypes may vary during tumor progression. Longitudinal whole-exome and transcriptome sequencing of recurrent BC may advance our understanding into the BC heterogeneity in terms of somatic mutations, cell clones and transcriptome-based tumor subtypes during disease progression.

Optimal sequencing of the first- and second-line target therapies in metastatic renal cell carcinoma: based on nationally representative data analysis from the Korean National Health Insurance System.

BACKGROUND: The authors intend to compare the effects of each targeted therapy (TT) in the treatment of patients with metastatic renal cell carcinoma (mRCC) using big data based on the Korean National Health Insurance System (NHIS) and determine the optimal treatment sequence. METHODS: Data on the medical use of patients with kidney cancer were obtained from the NHIS database from January 1, 2002, to December 31, 2020. Patient variables included age, sex, income level, place of residence, prescribing department, and duration from diagnosis to the prescription date. The primary outcome was overall survival (OS) for each drug and sequencing. We performed propensity score matching (PSM) according to age, sex, and Charlson Comorbidity Index based on the primary TTs. RESULTS: After 1:1 PSM, the sunitinib (SUN) (n = 1,214) and pazopanib (PAZ) (n = 1,214) groups showed a well-matched distribution across the entire cohort. In the primary treatment group, PAZ had lower OS than SUN (HR, 1.167; p = 0.0015). In the secondary treatment group, axitinib (AXI) had more favorable OS than cabozantinib (CAB) (HR, 0.735; p = 0.0118), and everolimus had more adverse outcomes than CAB (HR, 1.544; p < 0.0001). In the first to second TT sequencing, SUN-AXI had the highest OS; however, there was no statistically significant difference when compared with PAZ-AXI, which was the second highest (HR, 0.876; p = 0.3312). The 5-year survival rate was calculated in the following order: SUN-AXI (51.44%), PAZ-AXI (47.12%), SUN-CAB (43.59%), and PAZ-CAB (34.28%). When the four sequencing methods were compared, only SUN-AXI versus PAZ-CAB (p = 0.003) and PAZ-AXI versus PAZ-CAB (p = 0.017) were statistically significant. CONCLUSIONS: In a population-based RWD analysis of Korean patients with mRCC, SUN-AXI sequencing was shown to be the most effective among the first to second TT sequencing methods in treatment, with a relative survival advantage over other sequencing combinations. To further support the results of this study, risk-stratified analysis is needed.

Effect of Isoquercitrin on Free Fatty Acid-Induced Lipid Accumulation in HepG2 Cells.

Liver metabolic disorders and oxidative stress are crucial factors in the development of nonalcoholic fatty liver disease (NAFLD); however, treatment strategies to combat NAFLD remain poorly established, presenting an important challenge that needs to be addressed. Herein, we aimed to examine the effect of isoquercitrin on lipid accumulation induced by exogenous free fatty acids (FFA) using HepG2 cells and elucidate the underlying molecular mechanism. The cells were exposed to 0.5 mM FFA to induce intracellular lipid accumulation, followed by co-treatment with isoquercitrin to confirm the potential inhibitory effect on FFA-induced lipid production. HepG2 cells exposed to FFA alone exhibited intracellular lipid accumulation, compromised endoplasmic reticulum (ER) stress, and enhanced expression of proteins and genes involved in lipid synthesis; however, co-treatment with isoquercitrin decreased the expression of these molecules in a dose-dependent manner. Furthermore, isoquercitrin could activate AMP-activated protein kinase (AMPK), a key regulatory protein of hepatic fatty acid oxidation, suppressing new lipid production by phosphorylating acetyl-CoA carboxylase (ACC) and inhibiting sterol regulatory element-binding transcription factor 1 (SREBP-1)/fatty acid synthase (FAS) signals. Overall, these findings suggest that isoquercitrin can be employed as a therapeutic agent to improve NAFLD via the regulation of lipid metabolism by targeting the AMPK/ACC and SREBP1/FAS pathways.

Factors associated with cervical cancer screening behaviors among young married female (aged 20-29) immigrants in South Korea.

OBJECTIVE: To identify factors that affect the participation of female immigrants in their 20s in the national cervical cancer screening programs. METHODS: Data were obtained from the National Health Insurance Services from 2016 to 2017. A total of 17,730 women who agreed to undergo cervical cancer screening during 2016-2017 were included in the study. RESULTS: Of the 17,730 women, 8,149 (46%) participated in cervical cancer screening, whereas, 9,581 (54%) did not. Logistic regression analysis of factors related to cervical cancer screening showed that the odds ratio (OR) of screening was higher in short duration of stay (OR, 1.18; 95% confidence interval [CI], 1.03-1.35), Chinese nationality (OR, 1.43; 95% CI, 1.28-1.59), unemployment (OR, 1; 95% CI, reference), participation in general health screening (OR, 4.16; 95% CI, 3.24-5.33), and comorbidities (OR, 1.16; 95% CI, 1.09-1.24) when compared to the other populations. The highest OR was associated with participation in general health screening. CONCLUSION: Appropriate programs should be developed to increase participation of socially vulnerable groups in cervical cancer screening. Such programs will improve awareness regarding cervical cancer screening and reduce disparities in healthcare.

Green tea extract exhibits antidiabetic effects partly through regulating dipeptidyl peptidase-4 expression in adipose tissue.

The antidiabetic effects of green tea have been demonstrated in clinical trials and epidemiological studies. This study investigated the antidiabetic effects of green tea extract (GTE) and its underlying molecular mechanisms using a leptin receptor-deficient db/db mouse model (Leprdb/db). Treatment with GTE for 2 weeks improved glucose tolerance and insulin sensitivity in Leprdb/db mice. In addition, GTE treatment reduced the body weight and adiposity of Leprdb/db mice. Furthermore, GTE treatment reduced pro-inflammatory gene expression, including nuclear factor kappa B (NF-κB) in white adipose tissue (WAT), and also reduced dipeptidyl peptidase-4 (DPP4) expression levels in WAT as well as in the serum. The promoter region of Dpp4 contains the NF-κB binding site, and DPP4 was found to be a direct target of NF-κB. Consistently, in vitro treatment of cells with GTE or its main constituent epigallocatechin gallate reduced lipopolysaccharide-induced NF-κB/DPP4 expression in 3T3-L1 adipocytes and RAW264.7 cells. Overall, our data demonstrated that GTE exerts an anti-diabetic effect by regulating the expression levels of NF-κB and DPP4 in WAT.

Incidence and Risk Factors of Vestibular Schwannoma in Korea : A Population-Based Study.

OBJECTIVE: This study aims to investigate the incidence of vestibular schwannoma (VS) and demographic characteristics in Korea using population-based National Health Insurance Service data. METHODS: This study analyzed Korean National Health Insurance Service data from 2005 to 2020, based on the International Classification of Diseases, 10th version, Clinical Modification codes D333 and D431. Only those patients who had undergone magnetic resonance imaging and audiologic tests were considered definitive cases. Demographic variables included age, sex, treatment modality, hypertension, diabetics, dyslipidemia, smoking history, alcohol history, and income status. RESULTS: The total number of VS patients was 5751. The average incidence rate was 0.71 per 100000 from 2005 to 2020, and the annual incidence rate increased from 0.33 in 2005 to 1.32 in 2019 but decreased to 0.80 in 2020. Incidence was highest in those aged 60-69 years (1.791) and lowest in those younger than 20 years (0.041). Incidence was higher in females, and the number of patients who received radiosurgery (46.64%) was largest compared to the wait and scan group (37.96%), microsurgery group (12.85%), or the group who received both (2.56%). Diabetes, dyslipidemia, and alcohol consumption increased the risk of VS, while cigarette smoking reduced the risk of VS. CONCLUSION: The incidence of VS exhibited an increasing trend from 2005 to 2019. Radiosurgery (46.64%) was the most common treatment modality. Diabetes, dyslipidemia, and alcohol consumption increased the risk of VS, while cigarette smoking reduced the risk of VS.

Longitudinal Transcription Profiling of Bladder Cancers Dictate the Response to BCG Treatment and Disease Progression.

Although the intravesical instillation of Bacillus Calmette-Guerin (BCG) is widely used as adjuvant treatment for nonmuscle-invasive bladder cancers, the clinical benefit is variable across patients, and the molecular mechanisms underlying the sensitivity to BCG administration and disease progression are poorly understood. To establish the molecular signatures that predict the responsiveness and disease progression of bladder cancers treated with BCG, we performed transcriptome sequencing (RNA-seq) for 13 treatment-naïve and 22 post-treatment specimens obtained from 14 bladder cancer patients. To overcome disease heterogeneity, we used non-negative matrix factorization to identify the latent molecular features associated with drug responsiveness and disease progression. At least 12 molecular features were present, among which the immune-related feature was associated with drug responsiveness, indicating that pre-treatment anti-cancer immunity might dictate BCG responsiveness. We also identified disease progression-associated molecular features indicative of elevated cellular proliferation in post-treatment specimens. The progression-associated molecular features were validated in an extended cohort of BCG-treated bladder cancers. Our study advances understanding of the molecular mechanisms of BCG activity in bladder cancers and provides clinically relevant gene markers for evaluating and monitoring patients.

Identification of Fusobacterium Species Using Matrix-Assisted Laser Desorption/Ionization-Time-of-Flight Mass Spectrometry by Updating ASTA CoreDB.

PURPOSE: Fusobacterium species can cause infections, and associations with cancer are being increasingly reported. As their clinical significance differs, accurate identification of individual species is important. However, matrix-assisted laser desorption/ionization-time of flight mass spectrometry has not been found to be effective in identifying Fusobacterium species in previous studies. In this study, we aimed to improve the accuracy and efficacy of identifying Fusobacterium species in clinical laboratories. MATERIALS AND METHODS: In total, 229 Fusobacterium isolates were included in this study. All isolates were identified at the species level based on nucleotide sequences of the 16S ribosomal RNA gene and/or DNA-dependent RNA polymerase ß-subunit gene (rpoB). Where necessary, isolates were identified based on whole genome sequences. Among them, 47 isolates were used for updating the ASTA database, and 182 isolates were used for the validation of Fusobacterium spp. identification. RESULTS: Fusobacterium isolates used for validation (182/182) were correctly identified at the genus level, and most (180/182) were correctly identified at the species level using the ASTA MicroIDSys system. Most of the F. nucleatum isolates (74/75) were correctly identified at the subspecies level. CONCLUSION: The updated ASTA MicroIDSys system can identify nine species of Fusobacterium and four subspecies of F. nucleatum in good agreement. This tool can be routinely used in clinical microbiology laboratories to identify Fusobacterium species and serve as a springboard for future research.

Fall risk related to subtype-specific alpha-antagonists for benign prostatic hyperplasia: a nationwide Korean population-based cohort study.

BACKGROUND: Subtype-specific alpha-antagonists are medications commonly prescribed for lower urinary-tract symptoms, benign prostatic hyperplasia in older populations. Our study aims to investigate the association between subtype-specific alpha-antagonists and fall risk. METHODS: A total of 4,202,739 men aged 60-75 years eligible for Korean Health Insurance Review and Assessment Service (HIRA) during 2017-2018 were enrolled retrospectively. After propensity score matching, 53,303 people in the exposed and unexposed groups were considered in the final study analysis. RESULTS: The subtype-specific alpha-antagonists significantly increased the risk of fall in the exposed cohort compared to the unexposed cohort (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.62-2.00). Low income increased the fall risk only in the unexposed cohort (OR 1.34; 95% CI 1.04-1.73). A seasonal difference appeared only in the exposed cohort, with a significantly higher risk of fall in summer (OR 1.23; 95% CI 1.03-1.47). A total of 968 events occurred in the exposed group, and 455 of these falls occurred on the first day of medication (47%). CONCLUSIONS: Subtype-specific alpha-antagonists significantly increased the risk of falls, especially on the first day of drug initiation and during the summer season. Education on orthostatic hypotension and fall prevention should be implemented when prescribing subtype-specific alpha-antagonists.

Aurantii Fructus Immaturus enhances natural killer cytolytic activity and anticancer efficacy in vitro and in vivo.

Aurantii Fructus Immaturus (AFI), extensively used in traditional herbal medicine, is known to have diverse physiological effects against various diseases, including obesity, diabetes, and cardiovascular disease. However, the effects of AFI on the immune system, especially natural killer (NK) cells, remain largely unknown. We aimed to investigate the effect of AFI on NK cell activity in vitro and in vivo and to elucidate the underlying mechanisms. Further, we verified the anticancer efficacy of AFI in a mouse lung metastasis model, underscoring the therapeutic potential of AFI in cancer therapy. Our results revealed that AFI significantly enhanced the cytolytic activity of NK cells in a dose-dependent manner, accompanied by an increase in the expression of NK cell-activating receptors, especially NKp30 and NKp46. AFI treatment also increased the expression of cytolytic granules, including granzyme B and perforin. Furthermore, the expression of CD107a, a degranulation marker, was increased upon treatment with AFI. A signaling study using western blot analysis demonstrated that the phosphorylation of extracellular signal-regulated kinase (ERK) was involved in increasing the NK cell activity following AFI treatment. In the in vivo study performed in mice, oral administration of AFI markedly enhanced the cytotoxic activity of spleen mononuclear cells against YAC-1 cells, which was accompanied by NKp46 upregulation. In addition, we confirmed that cancer metastasis was inhibited in a mouse cancer metastasis model, established using the mouse melanoma B16F10 cell line, by the administration of AFI in vivo. Collectively, these results indicate that AFI enhances NK cell-mediated cytotoxicity in vitro and in vivo via activation of the ERK signaling pathway and suggest that AFI could be a potential supplement for cancer immunotherapy.

Anti-obesity effects of the dual-active adenosine A2A/A3 receptor-ligand LJ-4378.

BACKGROUND AND OBJECTIVES: A2A adenosine receptor (A2AAR)-mediated signaling in adipose tissues has been investigated as a potential target for obesity-related metabolic diseases. LJ-4378 has been developed as a dual-acting ligand with A2AAR agonist and A3 adenosine receptor (A3AR) antagonist activity. The current study aimed to investigate the anti-obesity effects of LJ-4378 and its underlying molecular mechanisms. METHODS: Immortalized brown adipocytes were used for in vitro analysis. A high-fat diet (HFD)-induced obesity and cell death-inducing DFFA-like effector A reporter mouse models were used for in vivo experiments. The effects of LJ-4378 on lipolysis and mitochondrial metabolism were evaluated using immunoblotting, mitochondrial staining, and oxygen consumption rate analyses. The in vivo anti-obesity effects of LJ-4378 were evaluated using indirect calorimetry, body composition analyses, glucose tolerance tests, and histochemical analyses. RESULTS: In vitro LJ-4378 treatment increased the levels of brown adipocyte markers and mitochondrial proteins, including uncoupling protein 1. The effects of LJ-4378 on lipolysis of adipocytes were more potent than those of the A2AAR agonist or A3AR antagonist. In vivo, LJ-4378 treatment increased energy expenditure by 17.0% (P value < 0.0001) compared to vehicle controls. LJ-4378 (1 mg/kg, i.p.) treatment for 10 days reduced body weight and fat content by 8.24% (P value < 0.0001) and 24.2% (P value = 0.0044), respectively, and improved glucose tolerance in the HFD-fed mice. LJ-4378 increased the expression levels of brown adipocyte markers and mitochondrial proteins in interscapular brown and inguinal white adipose tissue. CONCLUSION: These findings support the in vivo anti-obesity effects of LJ-4378, and suggest a novel therapeutic approach to combat obesity and related metabolic diseases.

Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism.

Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose tissue lysoplasmalogen levels and increases transmembrane protein 86 A (TMEM86A), a putative lysoplasmalogenase. Untargeted lipidomic analysis demonstrates that adipocyte-specific TMEM86A-knockout (AKO) increases lysoplasmalogen content in adipose tissue, including plasmenyl lysophosphatidylethanolamine 18:0 (LPE P-18:0). Surprisingly, TMEM86A AKO increases protein kinase A signalling pathways owing to inhibition of phosphodiesterase 3B and elevation of cyclic adenosine monophosphate. TMEM86A AKO upregulates mitochondrial oxidative metabolism, elevates energy expenditure, and protects mice from metabolic dysfunction induced by high-fat feeding. Importantly, the effects of TMEM86A AKO are largely reproduced in vitro and in vivo by LPE P-18:0 supplementation. LPE P-18:0 levels are significantly lower in adipose tissue of human patients with obesity, suggesting that TMEM86A inhibition or lysoplasmalogen supplementation might be therapeutic approaches for preventing or treating obesity-related metabolic diseases.

Effects of dietary restriction on hepatic sulfur-containing amino acid metabolism and its significance in acetaminophen-induced liver injury.

Dietary restriction (DR) has been revealed to have health benefits as it induces reduction in oxidative stress. Glutathione (GSH), an important cellular antioxidant, is increased in rodent livers owing to DR; however, the exact mechanism and clinical relevance of DR are yet to be fully understood. In this study, male C57BL/6 mice were administered a 50% restricted diet for 7 d, and the hepatic sulfur-containing amino acid (SAA) metabolism was determined to assess the biosynthesis of GSH. The hepatic methionine level was found to decrease, while the homocysteine, cysteine, and GSH levels were increased owing to decreased betaine-homocysteine methyltransferase (BHMT) and increased CßS, CγL, and glutamate cysteine ligase catalytic subunit (GCLC) proteins in the livers of mice subjected to DR. To determine the effects of DR on drug-induced oxidative liver injury, mice subjected to DR were injected with a toxic dose (300 mg/kg) of acetaminophen (APAP). DR significantly alleviated APAP-induced liver damage and oxidative stress, which might be attributed to the higher levels of GSH and related antioxidant enzyme (GPx, GSTα, and GSTµ) in the livers. The decrease in the levels of hepatic CYP1A, 2E1, and 3A, which imply the inhibition of APAP metabolic activation, could contribute to the lower hepatotoxicity in mice subjected to DR. Overall, our findings revealed that DR stimulated the hepatic transsulfuration pathway and GSH synthesis. The consequent elevation of GSH could thus serve as an important mechanism of DR-mediated liver protection against APAP intoxication.

Relationship between Bone Mineral Density and Dental Caries in Koreans by Sex and Menopausal State.

We aimed to investigate the relationship between bone mineral density and dental caries in adults of over 19 years of age who were categorized according to their sex and menopausal status. The Korea National Health and Nutrition Examination Survey (KNHANES) dataset was used for the study. Bone mineral density (BMD) and oral health examination data were collected between 2008 and 2011. A total of 17,141 adults of ≥19 years old were eligible for inclusion in the present study. Multiple regression analysis was performed after adjustment for age, household income, educational level, smoking status, and alcohol drinking status for men, and pre- and post-menopausal women. In men, the ß-value for the mean decayed, missing, and filled teeth (DMFT) index was 0.98 (95% confidence interval (CI) = 0.71−1.25), and was significantly higher in osteoporotic participants than in participants with normal BMD (p < 0.05). In post-menopausal women, the ß-value for the mean DMFT index was 0.86, and was higher in the osteoporotic participants than in the participants with normal BMD (p < 0.05). Men and post-menopausal women with osteoporosis had higher DMFT indexes than those with normal BMD. In addition, there was a correlation between DMFT index and BMD in men and post-menopausal women. Therefore, the prevention of osteoporosis should be implemented alongside proper oral care.