Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44.

B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.

Dietary cholesterol intake is not associated with the development of chronic kidney disease: Results from two Korean cohort studies.

BACKGROUND AND AIMS: Although dyslipidemia is a major risk factor for chronic kidney disease (CKD), the relationship between dietary cholesterol and CKD remains unknown. We investigated the association between cholesterol intake and CKD risk. METHODS AND RESULTS: The Korea National Health and Nutrition Examination Survey (KNHANES) 2019-2021 (n = 13,769) and the Korean Genome and Epidemiology Study (KoGES) (n = 9225) data were used for this study. Cholesterol intake was assessed using a 24-h recall food frequency questionnaire, and participants were categorized into three groups (T1, T2, and T3) based on cholesterol intake. Primary outcomes were prevalence and incidence of CKD. Higher cholesterol intake was modestly associated with increased serum levels of total, low-density lipoprotein, and high-density lipoprotein cholesterol in the KNHANES. However, we found no significant association between cholesterol intake and CKD prevalence in the KNHANES, regardless of a history of hypercholesterolemia. In the KoGES, during a median follow-up of 11.4 years, cholesterol intake was not associated with incident CKD in participants without hypercholesterolemia (hazard ratio [HR] per 10 mg increase, 1.00; 95 % confidence interval [CI], 0.99-1.01) and in those with hypercholesterolemia (HR, 1.01; 95 % CI, 0.98-1.04). Egg consumption also showed no significant association with the risk of incident CKD. Additionally, cholesterol intake had no significant interaction on the relationships between serum cholesterol levels and incident CKD. CONCLUSION: Although cholesterol intake was associated with increased serum cholesterol levels, it was not associated with CKD prevalence and incidence. Our findings suggest that reducing cholesterol intake alone may not be sufficient to prevent CKD.

Euglycemic diabetic ketoacidosis following traumatic brain injury.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels by reducing glucose reabsorption in the kidneys, which can lead to ketogenesis. Euglycemic diabetic ketoacidosis (DKA) is a rare but potentially life-threatening complication of SGLT2 inhibitors that can be triggered by trauma. However, the absence of significant hyperglycemia can delay its diagnosis and treatment, which may lead to detrimental consequences. Herein, we report a case of euglycemic DKA following traumatic brain injury in a patient with type 2 diabetes who was taking an SGLT2 inhibitor. Delayed recognition of euglycemic DKA in this case led to progressive metabolic deterioration. This report emphasizes the importance of promptly suspecting, diagnosing, and treating euglycemic DKA in patients with traumatic injuries who exhibit high anion-gap metabolic acidosis, ketonuria, and glucosuria-even if they do not have significant hyperglycemia.

Relationship between high-density lipoprotein cholesterol and mortality in elderly hemodialysis patients: Data from the Korean Society of Geriatric Nephrology Retrospective Cohort.

BACKGROUND: The association between high-density lipoprotein (HDL) cholesterol levels and mortality in elderly patients undergoing hemodialysis is not well established. Thus, this study investigated HDL levels and mortality in elderly Korean patients undergoing hemodialysis. METHODS: We recruited 1860 incident hemodialysis patients aged > 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology. The primary outcome measure was the all-cause mortality. RESULTS: The mean age of the cohort was 77.8 years and 1049 (56.4%) were men. When we grouped the patients into HDL cholesterol tertiles, the T1 group (HDL level <30 mg/dL in men and <33 mg/dL in women) had a higher proportion of patients with end-stage kidney disease due to diabetic nephropathy. During the median follow-up period of 3.1 years, 1109 (59.7%) deaths occurred. In a multivariable Cox regression model, the T1 group had significantly higher risk of mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.10-1.50; p=0.002) compared to the T3 group. A nonlinear analysis using a restrictive spline curve showed that low HDL cholesterol levels were associated with increased HR when HDL cholesterol levels were < 40 mg/dL; however, there was no association between HDL cholesterol and mortality when HDL cholesterol levels were > 40 mg/dL. Triglyceride/HDL ratio was not significantly associated with risk of mortality (HR per 1 log increase, 1.08; 95% CI, 0.99-1.18; p=0.069). CONCLUSIONS: Low HDL cholesterol levels are associated with an increased risk of mortality in elderly patients undergoing hemodialysis. However, there was no significant relationship between HDL cholesterol levels and mortality when levels were below 40 mg/dL. Therefore, low HDL cholesterol levels may be a useful risk factor for predicting mortality in elderly patients undergoing hemodialysis.

Changes in abdominal fat depots after bariatric surgery are associated with improved metabolic profile.

BACKGROUND AND AIMS: Obesity associated with a change in the quantity and quality of fat depots. Using computed tomography (CT), we analyzed abdominal fat depots in patients with obesity after bariatric surgery according to their metabolic health status. METHODS AND RESULTS: We recruited 79 individuals with metabolically unhealthy obesity before bariatric surgery and compared them with age-sex matched healthy controls. The volume and fat attenuation index (FAI) of fat depots were measured using CT scans that were conducted prior to and a year after bariatric surgery. 'Metabolically healthy' was defined as having no hypertension, normal fasting glucose and a waist-to-hip ratio of <1.05 for men and <0.95 for women. Individuals who achieved a metabolic health status conversion (MHC) (n = 29, 37%)-from unhealthy to healthy-were younger (p < 0.001) as compared to individuals without MHC. Pre-surgery BMI and reduction of BMI did not differ between the two groups (p = 0.099, p = 0.5730). Bariatric surgery reduced the volume and increased the FAI of fat depots. Baseline lower abdominal periaortic adipose tissue (AT) volume (p = 0.014) and great percent reduction in renal sinus AT volume after surgery (p = 0.019) were associated with MHC after surgery. Increased intraperitoneal AT FAI (p = 0.031) was also associated with MHC. CONCLUSION: MHC was not associated with improvement in general obesity, based on indicators such as reduction of BMI after surgery. Weight reduction induced specific abdominal fat depot changes measured by CT are positively associated with MHC.

Circulating miRNAs in extracellular vesicles related to treatment response in patients with idiopathic membranous nephropathy.

BACKGROUND: Extracellular vesicle (EV)-microRNAs (miRNAs) are potential biomarkers for various renal diseases. This study attempted to identify the circulating EV-miRNA signature not only for discriminating idiopathic membranous nephropathy (IMN) from idiopathic nephrotic syndrome (INS), but also to predict the treatment response of patients with IMN. METHODS: We prospectively enrolled 60 participants, including those with IMN (n = 19) and INS (n = 21) and healthy volunteers (HVs; n = 20) in this study. Using RNA sequencing, we assessed the serum EV-miRNA profiles of all participants. To identify the EV-miRNAs predictive of treatment response in IMN, we also analyzed EV-miRNAs among patients with IMN with and without clinical remission. RESULTS: The expression levels of 3 miRNAs differed between IMN patients, INS patients and HVs. In addition, compared to HVs, RNA sequencing revealed differential expression of 77 and 44 EV-miRNAs in patients with IMN without and with remission, respectively. We also identified statistically significant (|fold change ≥ 2, p < 0.05) differences in the expression levels of 23 miRNAs in IMN without remission. Biological pathway analysis of miRNAs in IMN without remission indicated that they are likely involved in various pathways, including renal fibrosis. CONCLUSION: Our study identified EV-miRNAs associated with IMN as well as those associations with therapeutic response. Therefore, these circulating EV-miRNAs may be used as potential markers for the diagnosis and prediction of treatment response in patients with IMN.

Reversible pH Responsive Aggregation Behavior of Size-Controlled Calcium Carbonate Composite Nanoparticles by Phytic Acid in Aqueous Solution.

Composite colloidal nanoparticles were prepared by a carbonate controlled-addition method in the presence of phytic acid, in which an aqueous ammonium carbonate solution was added into an aqueous solution of phytic acid and CaCl2. The number-average particle size of the colloidal particles was 76 ± 18 nm formed by using the molar ratio [phytic acid]/[Ca2+] = 0.5 from the complexation time of 1 h. The composite nanoparticles were stable for more than 5 days in the suspension under the quiescent condition. After isolation of the nanoparticles by ultrafiltration, the dried samples could be redispersed in water. Effects of the complexation times of the aqueous solution of phytic acid and CaCl2 and the molar ratio ([phytic acid]/[Ca2+]) were studied. Increasing the concentration of the calcium reagents as well as increasing the complexation times increased the particle sizes. The minimum and maximum average particle sizes of 29 and 142 nm were obtained. The plot of the transmittance at 350 nm of the aqueous solution of the dispersion against pH values after addition of 0.05 M HCl for 6 h showed that, by gradually increasing turbidity with decreasing pH from 9.6 to 7.3, precipitates were recognized at below pH 7.5, and turbidity decreased with further decreasing pH beyond 7.2. Dynamic light scattering analysis showed that the particle diameters increased from 90 to 200 nm with decreasing pH from 9.6 to 7.2. When increasing the pH from 6.2, the precipitate was redispersed and the turbidity increased to a pH of 7.4. No precipitates were observed above a pH of 7.4. These results suggest that the present phytic acid stabilized nanoparticles exhibit pH-dependent reversible precipitation and redispersion without degradation under slightly acidic conditions.

Eculizumab therapy on a patient with co-existent lupus nephritis and C3 mutation-related atypical haemolytic uremic syndrome: a case report.

BACKGROUND: Thrombotic microangiopathy (TMA), a rare but serious complication of systemic lupus erythematosus (SLE), is associated with poor outcomes to conventional immunosuppressive therapy. Recently, eculizumab, a humanised monoclonal antibody that blocks the complement factor 5, has been known to effectively treat atypical haemolytic uremic syndrome (aHUS). Here, we report a case of aHUS co-existing with lupus nephritis that was successfully treated with eculizumab. CASE PRESENTATION: A 23-year-old man presented with abdominal pain and diarrhoea. Initial laboratory tests have shown thrombocytopaenia, microangiopathic haemolytic anaemia, and acute kidney injury. Immunologic tests were consistent with SLE. Kidney biopsy have revealed lupus nephritis class IV-G with TMA. Genetic analysis have shown complement C3 gene mutations, which hints the co-existence of lupus nephritis with aHUS, a form of complement-mediated TMA. Although initial treatment with haemodialysis, plasma exchange, and conventional immunosuppressive therapy (steroid and cyclophosphamide) did not appreciably improve kidney function and thrombocytopaenia, the patient was able to respond to eculizumab therapy. CONCLUSIONS: Due to the similar features of TMA and SLE, clinical suspicion of aHUS in patients with lupus nephritis is important for early diagnosis and prompt management. Timely administration of eculizumab should be considered as a treatment option for aHUS in lupus nephritis patients to yield optimal therapeutic outcomes.

ID1-Mediated BMP Signaling Pathway Potentiates Glucagon-Like Peptide-1 Secretion in Response to Nutrient Replenishment.

Glucagon-like peptide-1 (GLP-1) is a well-known incretin hormone secreted from enteroendocrinal L cells in response to nutrients, such as glucose and dietary fat, and controls glycemic homeostasis. However, the detailed intracellular mechanisms of how L cells control GLP-1 secretion in response to nutrients still remain unclear. Here, we report that bone morphogenetic protein (BMP) signaling pathway plays a pivotal role to control GLP-1 secretion in response to nutrient replenishment in well-established mouse enteroendocrinal L cells (GLUTag cells). Nutrient starvation dramatically reduced cellular respiration and GLP-1 secretion in GLUTag cells. Transcriptome analysis revealed that nutrient starvation remarkably reduced gene expressions involved in BMP signaling pathway, whereas nutrient replenishment rescued BMP signaling to potentiate GLP-1 secretion. Transient knockdown of inhibitor of DNA binding (ID)1, a well-known target gene of BMP signaling, remarkably reduced GLP-1 secretion. Consistently, LDN193189, an inhibitor of BMP signaling, markedly reduced GLP-1 secretion in L cells. In contrast, BMP4 treatment activated BMP signaling pathway and potentiated GLP-1 secretion in response to nutrient replenishment. Altogether, we demonstrated that BMP signaling pathway is a novel molecular mechanism to control GLP-1 secretion in response to cellular nutrient status. Selective activation of BMP signaling would be a potent therapeutic strategy to stimulate GLP-1 secretion in order to restore glycemic homeostasis.

Performance of the Dimension TAC assay and comparison of multiple platforms for the measurement of tacrolimus.

BACKGROUND: Therapeutic monitoring of tacrolimus is essential for reducing organ rejection and adverse effects. The measurement of tacrolimus in whole blood is taken by many automated platforms. We evaluated the analytical performance of the Dimension TAC assay, which is an upgraded reagent from the previous Dimension TACR assay. METHODS: The evaluations involved determination of precision, linearity, detection capability, and reagent lot-to-lot variability between three lot numbers. Correlation studies were conducted using the Dimension TACR assay, Architect, Elecsys assay, and MassTrak LC-MS/MS. RESULTS: The total coefficient of variation was below 10%. Acceptable linearity was observed in their respective reportable ranges. The limit of blank, limit of detection, and limit of quantification were 0.29, 0.47, and 0.81 ng/mL, respectively. Correlation analysis indicated that the Dimension TAC assay results were comparable to that of the Dimension TACR assay, Architect, and Elecsys results in liver and heart transplant patients. In kidney transplant patients, the Dimension TAC assay showed the poor correlation with Architect and Elecsys. The results from these assays were slightly higher than that of MassTrak. We found little lot-to-lot reagent variation among the reagents evaluated. CONCLUSION: The overall analytical performance of the Dimension TAC assay is acceptable for therapeutic monitoring in clinical practice. Our study that compared different platforms may provide some useful information regarding which test method to use.

Chronic Hepatitis C Virus Infection and the Proinflammatory Effects of Injection Drug Use.

BACKGROUND: Chronic inflammation, as defined by persistent immune activation, is associated with adverse clinical outcomes. People who inject drugs (PWID) have evidence of persistent immune activation. Here, in a cohort of PWID with or without hepatitis C virus (HCV) infection, we sought to dissect out the contribution of chronic HCV infection (common in PWID) from the effects of injection drug use itself. METHODS: Four groups of study volunteers were recruited: group 1 comprised active PWID; group 2, individuals who ceased injecting drugs 1-2 months before recruitment; group 3, individuals who ceased injecting drugs 3-4 months before recruitment; and group 4, healthy volunteers. Soluble and cell-associated markers of immune activation were quantified. RESULTS: HCV-viremic PWID have elevated levels of immune activation when compared to healthy volunteers. Cessation of injection drug use results in a decline in immune activation in the absence of HCV viremia, while HCV-viremic individuals who previously were PWID continue to harbor elevated levels of immune activation, as defined by increased levels of soluble CD14 and tumor necrosis factor α and by the presence of CD38+HLA-DR+ CD4+ and CD8+ T cells. CONCLUSIONS: Immune activation, a well-defined surrogate of poor clinical outcome that is elevated in PWID, can regress to normal levels in former injection drug users who are HCV aviremic. Therefore, enhanced harm-reduction efforts should incorporate aggressive treatment of HCV infection. CLINICAL TRIALS REGISTRATION: NCT01831284.

Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury.

Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2-deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed lectin pathway-dependent C4-bypass. Lectin pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti-MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders.

MicroRNA-5010-5p ameliorates high-glucose induced inflammation in renal tubular epithelial cells by modulating the expression of PPP2R2D.

INTRODUCTION: We previously reported the significant upregulation of eight circulating exosomal microRNAs (miRNAs) in patients with diabetic kidney disease (DKD). However, their specific roles and molecular mechanisms in the kidney remain unknown. Among the eight miRNAs, we evaluated the effects of miR-5010-5p on renal tubular epithelial cells under diabetic conditions in this study. RESEARCH DESIGN AND METHODS: We transfected the renal tubular epithelial cell line, HK-2, with an miR-5010-5p mimic using recombinant plasmids. The target gene of hsa-miR-5010-5p was identified using a dual-luciferase assay. Cell viability was assessed via the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Moreover, mRNA and protein expression levels were determined via real-time PCR and western blotting, respectively. RESULTS: High glucose levels did not significantly affect the intracellular expression of miR-5010-5p in HK-2 cells. Transfection of the miR-5010-5p mimic caused no change in cell viability. However, miR-5010-5p-transfected HK-2 cells exhibited significantly decreased expression levels of inflammatory cytokines, such as the monocyte chemoattractant protein-1, interleukin-1ß, and tumor necrosis factor-ɑ, under high-glucose conditions. These changes were accompanied by the restored expression of phosphorylated AMP-activated protein kinase (AMPK) and decreased phosphorylation of nuclear factor-kappa B. Dual-luciferase assay revealed that miR-5010-5p targeted the gene, protein phosphatase 2 regulatory subunit B delta (PPP2R2D), a subunit of protein phosphatase 2A, which modulates AMPK phosphorylation. CONCLUSIONS: Our findings suggest that increased miR-5010-5p expression reduces high glucose-induced inflammatory responses in renal tubular epithelial cells via the regulation of the target gene, PPP2R2D, which modulates AMPK phosphorylation. Therefore, miR-5010-5p may be a promising therapeutic target for DKD.

Dapagliflozin Reduces Urinary Kidney Injury Biomarkers in Chronic Kidney Disease Irrespective of Albuminuria Level.

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD) with low albuminuria levels have not been established. This study aimed to compare the effects of dapagliflozin on kidney injury biomarkers in patients with CKD stratified by albuminuria level. We prospectively enrolled healthy volunteers (HVs; n = 20) and patients with CKD (n = 54) with and without diabetes mellitus. Patients with CKD were divided into two age-matched and sex-matched subgroups according to urinary albumin-creatinine ratio (uACR) levels (<300 mg/g and ≥300 mg/g). The CKD group received dapagliflozin (10 mg/day). Urine samples were collected before treatment and after 3 and 6 months of dapagliflozin. Urinary kidney injury molecule-1 (KIM-1), interleukin-1ß (IL-1ß), and mitochondrial DNA nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND1) copy number were measured. The estimated glomerular filtration rate (eGFR) of patients with CKD was lower than that of HVs (P < 0.001). During the study period, eGFR decreased and uACR did not change in the CKD group. Kidney injury markers were significantly elevated in patients with CKD compared with those in HVs. Dapagliflozin reduced urinary KIM-1, IL-1ß, and mtDNA copy number in patients with CKD after 6 months of treatment. In further, the levels of urinary KIM-1 and IL-1ß, patients with CKD decreased after 6 months of dapagliflozin treatment regardless of albuminuria level. Dapagliflozin reduced urinary kidney injury biomarkers in patients with CKD, regardless of albuminuria level. These findings suggest that SGLT2 inhibitors may also attenuate the progression of low albuminuric CKD.

The clinical relevance of a polygenic risk score for type 2 diabetes mellitus in the Korean population.

The clinical utility of a type 2 diabetes mellitus (T2DM) polygenic risk score (PRS) in the East Asian population remains underexplored. We aimed to examine the potential prognostic value of a T2DM PRS and assess its viability as a clinical instrument. We first established a T2DM PRS for 5490 Korean individuals using East Asian Biobank data (269,487 samples). Subsequently, we assessed the predictive capability of this T2DM PRS in a prospective longitudinal study with baseline data and data from seven additional follow-ups. Our analysis showed that the T2DM PRS could predict the transition of glucose tolerance stages from normal glucose tolerance to prediabetes and from prediabetes to T2DM. Moreover, T2DM patients in the top-decile PRS group were more likely to be treated with insulin (hazard ratio = 1.69, p value = 2.31E-02) than were those in the remaining PRS groups. T2DM PRS values were significantly high in the severe diabetes subgroup, characterized by insulin resistance and ß -cell dysfunction (p value = 0.0012). The prediction models with the T2DM PRS had significantly greater Harrel's C-indices than did corresponding models without it. By utilizing prospective longitudinal study data and extensive clinical risk factor information, our analysis provides valuable insights into the multifaceted clinical utility of the T2DM PRS.

Evaluation of ITX 5061, a scavenger receptor B1 antagonist: resistance selection and activity in combination with other hepatitis C virus antivirals.

ITX 5061 is a scavenger receptor B1 antagonist that has entered phase 1 clinical trials in hepatitis C virus (HCV)-infected humans. We evaluated ITX 5061 in combination with interferon-α, ribavirin, and HCV protease and polymerase inhibitors in a genotype 2a infectious virus system. ITX 5061 is a potent inhibitor of HCV replication and is additive to synergistic with interferon-α, ribavirin, BILN2061, VX950, VX1, and 2'-C-methyladenosine. Resistance selection experiments were performed using a Jc1-FEO virus co-culture system and intermittent ITX 5061 exposure under neomycin selection. We identified a mutant virus with a substitution of aspartic acid for asparagine at the highly conserved position 415 in E2 (N415D). Introduction of this mutation into wild-type virus conferred high-level resistance to ITX 5061. There was no cross-resistance between ITX 5061 and HCV protease inhibitors or interferon-α. These results suggest that ITX 5061 is a promising compound for study in combination with other HCV inhibitors.

The role of complement C3 in the outcome of regional myocardial infarction.

Coronary heart disease leading to myocardial ischemia is a major cause of heart failure. A hallmark of heart failure is myocardial fibrosis. Using a murine model of myocardial ischemia/reperfusion injury (IRI), we showed that, following IRI, in mice genetically deficient in the central factor of complement system, C3, myocardial necrosis was reduced compared with WT mice. Four weeks after the ischemic period, the C3-/- mice had significantly less cardiac fibrosis and better cardiac function than the WT controls. Overall, our results suggest that innate immune response through complement C3 plays an important role in necrotic cell death, which contributes to the cardiac fibrosis that underlies post-infarction heart failure.

Association between abdominal perivascular adipose tissue quantity and quality assessed by CT and cardiometabolic risk.

BACKGROUND & AIMS: Changes in the perivascular adipose tissue (PVAT) are associated with the risk of metabolic syndrome (MetS). We hypothesized that the quantity and quality of PVAT measured by computed tomography (CT) are associated with cardiometabolic risk. METHODS: This study analyzed the data of 505 participants (men, 72.7%) who underwent general health checkups, including abdominal and pelvic CT. We measured the volume and fat attenuation index (FAI) of the abdominal periaortic (APA) and renal sinus (RS) adipose tissues. Participants were categorized into three groups according to the number of MetS components they had based on the modified ATP III criteria (0, 1-2, and ≥3). RESULTS: Moving stepwise from the no MetS component group to the 1-2 components group to the ≥3 components group, all PVAT volumes increased and all PVAT FAIs decreased consistently. Greater PVAT volume was independently associated with greater prevalence of MetS components in the ≥3 components group (P = 0.002 for right RS, P = 0.027 for left RS, and P = 0.001 for APA), whereas lower FAI in all PVATs was associated with greater prevalence of MetS components in the 1-2 components group after adjusting for the corresponding adipose tissue volumes (P = 0.007 for right RS, P = 0.002 for left RS, and P = 0.001 for APA). CONCLUSION: Higher abdominal PVAT volume was independently associated with prevalent MetS. Moreover, lower abdominal PVAT FAI was associated with mild metabolic derangement. Image-based assessment of abdominal PVAT may be a potential biomarker for cardiometabolic risk.

Association of glomerular hyperfiltration with carotid artery plaque in the general population.

BACKGROUND AND AIMS: Glomerular hyperfiltration (GHF) is a hemodynamic change of the kidney as an adaptive response to nephron loss. Although GHF is associated with metabolic risk factors and cardiovascular disease (CVD), the mechanisms that explain these relationships remain largely unknown. This is partially caused by a non-unified definition of GHF based on pathophysiologic vascular changes. Thus, the objective of this study was to evaluate the association between various definitions of GHF and carotid plaque in a health checkup cohort. METHODS: A total of 4493 individuals without history of CVD who had carotid ultrasonography (USG) results available between January 2016 and June 2018 were enrolled. GHF was defined as >90th percentile of eGFR residuals after adjusting for confounding factors. Carotid plaque score was calculated based on carotid USG results. RESULTS: Of 4493 individuals (mean age, 52.3 ± 10.1 years; 3224 [71.8%] males), 449 subjects were included in the GHF group (mean eGFR, 107.0 ± 7.1 ml/min/1.73 m2) and 4044 subjects were included in the non-GHF group (mean eGFR, 92.5 ± 12.3 ml/min/1.73 m2). When the GHF group was compared to the non-GHF group, GHF was associated with the presence of significant carotid plaque (carotid plaque score ≥2) (adjusted OR: 1.46; 95% CI: 1.16 to 1.83; p = 0.001). GHF defined in this study showed higher sensitivity to the presence of carotid plaque than other definitions of GHF. CONCLUSIONS: GHF status was associated with risk of carotid plaque in individuals without history of CVD. Presence of subclinical carotid plaque was associated with risk of future CVD. Therefore, GHF based on creatinine could be a useful surrogate marker for surveillance of CVD in asymptomatic individuals.

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors with an extremely poor prognosis. Based on the several biological features related to glutamine metabolism in ATC, we hypothesized glutaminolysis inhibition induces cell death in ATC cells. However, glutamine metabolism inhibition triggered cell growth arrest independent of cell death in ATC, suggesting that other signaling pathways avoid glutamine metabolism inhibition-induced stress exist. To investigate the functional mechanism against glutamine metabolism inhibition, we conducted mRNA and ATAC-Sequencing data analysis and found that glutamine deprivation increased ATF4-mediated one-carbon metabolism. When we inhibited PHGDH, the first rate-limiting enzyme for one-carbon metabolism, cell growth arrest was promoted upon glutamine metabolism inhibition by accumulating intracellular ROS. We next observed that the co-inhibition of glutamine and one-carbon metabolism could augment the anticancer effects of drugs used in patients with ATC. Finally, single-cell RNA sequencing analysis revealed that one-carbon metabolism was strengthened through the evolutionary process from PTC to ATC. Collectively, our data demonstrate that one-carbon metabolism has a potential role of modulation of cell fate in metabolic stress and can be a therapeutic target for enhancing antitumor effects in ATC.