Mushroom consumption and cardiometabolic health outcomes in the general population: a systematic review.

BACKGROUND/OBJECTIVES: Mushroom consumption, rich in diverse nutrients and bioactive compounds, is suggested as a potential significant contributor to preventing cardiometabolic diseases (CMDs). This systematic review aimed to explore the association between mushrooms and cardiometabolic health outcomes, utilizing data from prospective cohort studies and clinical trials focusing on the general population, with mushrooms themselves as a major exposure. SUBJECTS/METHODS: All original articles, published in English until July 2023, were identified through searches on PubMed, Ovid-Embase, and google scholar. Of 1,328 studies, we finally selected 5 prospective cohort studies and 4 clinical trials. RESULTS: Existing research is limited, typically consisting of 1 to 2 studies for each CMD and cardiometabolic condition. Examination of articles revealed suggestive associations in some cardiometabolic conditions including blood glucose (both fasting and postprandial), high-density lipoprotein cholesterol related indices, high-sensitivity C-reactive protein, and obesity indices (body weight, body mass index, and waist circumference). However, mushroom consumption showed no association with the mortality and morbidity of cardiovascular diseases, stroke, and type 2 diabetes, although there was a potentially beneficial connection with all cause-mortality, hyperuricemia, and metabolic syndrome. CONCLUSION: Due to the scarcity of available studies, drawing definitive conclusions is premature. Further comprehensive investigations are needed to clarify the precise nature and extent of this relationship before making conclusive recommendations for the general population.

Loss of SREBP-1c ameliorates iron-induced liver fibrosis by decreasing lipocalin-2.

Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.

Comparative evaluation of non-invasive tests for risk stratification for cause specific mortality in at-risk population of hepatic fibrosis.

Our study aimed to conduct a comparative evaluation of various noninvasive tests (NITs) for risk stratification in at-risk population for non-alcoholic fatty liver disease (NAFLD), focusing on cardiovascular and liver-related mortality. A total of 21,715 adults aged 40 years and older were enrolled at baseline. The mean follow-up period was 12.39 years. Three types of NITs (fibrosis-4 index [FIB-4], NAFLD fibrosis score [NFS], and steatosis-associated fibrosis estimator [SAFE] score) were used. When using the low cut-off as a 'rule-out' strategy, there were no significant differences in cardiovascular mortality between the 'rule-out' (low-risk) group and the 'rule-in' (intermediate- or high-risk) group based on FIB-4 (aHR = 1.029, P = 0.845) or NFS (aHR = 0.839, P = 0.271) classification. However, the SAFE score exhibited higher sensitivity in predicting cardiovascular mortality compared to FIB-4 or NFS (73.3% in SAFE score vs. 29.6% in FIB-4 or 21.3% in NFS). Only the SAFE score could effectively differentiate the risk between low- and intermediate- or high-risk groups for all types of mortality (all P values for aHR < 0.001). The low cutoff value of the SAFE score discriminated not only liver-related mortality but also identified the cardiovascular high-risk group in the community cohort.

2023 Diabetic Kidney Disease Fact Sheet in Korea.

Background: To investigate the prevalence, incidence, comorbidities, and management status of diabetic kidney disease (DKD) and diabetes-related end-stage kidney disease (ESKD) in South Korea. Methods: We used the Korea National Health and Nutrition Examination Survey data (2019 to 2021, n=2,665) for the evaluation of prevalence, comorbidities, control rate of glycemia and comorbidities in DKD, and the Korean Health Insurance Service-customized database (2008 to 2019, n=3,950,857) for the evaluation of trends in the incidence and prevalence rate of diabetes-related ESKD, renin-angiotensin system (RAS) blockers and sodium glucose cotransporter 2 (SGLT2) inhibitors use for DKD, and the risk of atherosclerotic cardiovascular disease (ASCVD) and mortality according to DKD stages. DKD was defined as albuminuria or low estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in patients with diabetes mellitus. Results: The prevalence of DKD was 25.4% (albuminuria, 22.0%; low eGFR, 6.73%) in patients with diabetes mellitus aged ≥30 years. Patients with DKD had a higher rate of comorbidities, including hypertension, dyslipidemia, and central obesity; however, their control rates were lower than those without DKD. Prescription rate of SGLT2 inhibitors with reduced eGFR increased steadily, reaching 5.94% in 2019. Approximately 70% of DKD patients were treated with RAS blockers. The prevalence rate of diabetesrelated ESKD has been steadily increasing, with a higher rate in older adults. ASCVD and mortality were significantly associated with an in increase in DKD stage. Conclusion: DKD is prevalent among Korean patients with diabetes and is an independent risk factor for cardiovascular morbidity and mortality, which requiring intensive management of diabetes and comorbidities. The prevalence of diabetes-related ESKD has been increasing, especially in the older adults, during past decade.

Tunable Colossal Anomalous Hall Conductivity in Half-Metallic Material Induced by d-Wave-Like Spin-Orbit Gap.

The anomalous Hall conductivity (AHC) in magnetic materials, resulting from inverted band topology, has emerged as a key adjustable function in spin-torque devices and advanced magnetic sensors. Among systems with near-half-metallicity and broken time-reversal symmetry, cobalt disulfide (CoS2) has proven to be a material capable of significantly enhancing its AHC. In this study, the AHC of CoS2 is empirically assessed by manipulating the chemical potential through Fe- (hole) and Ni- (electron) doping. The primary mechanism underlying the colossal AHC is identified through the application of density functional theory and tight-binding analyses. The main source of this substantial AHC is traced to four spin-polarized massive Dirac dispersions in the kz = 0 plane of the Brillouin zone, located slightly below the Fermi level. In Co0.95Fe0.05S2, the AHC, which is directly proportional to the momentum-space integral of the Berry curvature (BC), reached a record-breaking value of 2507 Ω-1cm-1. This is because the BCs of the four Dirac dispersions all exhibit the same sign, a consequence of the d-wave-like spin-orbit coupling among spin-polarized eg orbitals.

A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Associations between breast cancer risk factors and mammographic breast density in a large cross-section of Korean women.

BACKGROUND: We investigated the association between established risk factors for breast cancer and mammographic breast density in Korean women. METHODS: This large cross-sectional study included 8 460 928 women aged >40 years, who were screened for breast cancer between 2009 and 2018. Breast density was assessed using the Breast Imaging Reporting and Data System. This study used multiple logistic regression analyses of age, BMI, age at menarche, menopausal status, menopausal age, parity, breastfeeding status, oral contraceptive use, family history of breast cancer, physical activity, smoking, drinking and hormone replacement therapy use to investigate their associations with mammographic breast density. Analyses were performed using SAS software. RESULTS: Of 8 460 928 women, 4 139 869 (48.9%) had nondense breasts and 4 321 059 (51.1%) had dense breasts. Factors associated with dense breasts were: earlier age at menarche [<15 vs. ≥15; adjusted odds ratio (aOR), 1.18; 95% confidence interval (CI), 1.17-1.18], premenopausal status (aOR, 2.01; 95% CI, 2.00-2.02), later age at menopause (≥52 vs. <52; aOR, 1.23; 95% CI, 1.22-1.23), nulliparity (aOR, 1.64; 95% CI, 1.63-1.65), never breastfed (aOR, 1.23; 95% CI, 1.23-1.24) and use of hormone replacement therapy (aOR, 1.29; 95% CI, 1.28-1.29). Women with a higher BMI and the use of oral contraceptives were more likely to have nondense breasts. CONCLUSION: Lower BMI, reproductive health and behavioral factors were associated with dense breasts in Korean women. Additional research should investigate the relationship between mammographic breast density, breast cancer risk factors and breast cancer risk.

The association of dietary total flavonoids and their subclasses with the risk of type 2 diabetes: a prospective cohort study.

BACKGROUND: Data from mechanistic studies suggest flavonoids may benefit glucose metabolism, but their associations with type 2 diabetes (T2D) remain unclear. This study examined the prospective associations of dietary intake of total, classes, and individual flavonoids, as well as their source foods, with T2D in the CArdioVascular disease Association Study (CAVAS). METHODS: A total of 16,666 Korean men and women were enrolled at baseline, and 953 were newly diagnosed with T2D over a median follow-up of 5.96 years. Intake of flavonoids was cumulatively averaged using all food frequency questionnaires before the censoring events. A Poisson regression model was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). RESULTS: Women with higher total flavonoid, flavonol, isoflavone, and proanthocyanidin intake had a lower risk of T2D (fourth vs. first quartile, IRR 0.62; 95% CI 0.44-0.89; P for linearity and non-linearity < 0.05 for total flavonoids), while in men, flavanones, anthocyanins, and proanthocyanidins, but not total flavonoids, were inversely associated with T2D risk (all P interaction for sex > 0.05). The key source foods contributing to flavonoid intake were also different between men and women, except for apples: tangerines and strawberries in men and green leafy vegetables and soy products in women. CONCLUSIONS: A higher intake of total flavonoids, particularly from vegetables, soybeans, and apples, may be associated with lower risk of T2D in women. However, flavonoids from fruits, rather than total flavonoids, may be inversely associated in men. The association between flavonoid intake and the risk of T2D may be contingent upon the dietary sources of flavonoids consumed.

A prospective association between dietary mushroom intake and the risk of type 2 diabetes: the Korean Genome and Epidemiology Study-Cardiovascular Disease Association Study.

OBJECTIVES: Mushrooms, known for their nutritious and functional components, are considered healthy and medicinal. This study investigated the prospective association between dietary mushroom consumption and the incidence of type 2 diabetes among Korean adults aged ≥40 years. METHODS: In total, 16,666 participants who were not taking anti-diabetic medication or insulin and had normal fasting blood glucose (FBG; <126 mg/dL) were included. We used the cumulative average dietary consumption of mushrooms as an exposure metric, calculated from food frequency questionnaires at every follow-up, along with covariates collected during a baseline survey. To estimate incidence rate ratios (IRRs) for type 2 diabetes, a modified Poisson regression model with a robust error estimator was applied. RESULTS: In multivariable models, dietary mushroom consumption was inversely associated with type 2 diabetes incidence in both genders (men: IRR, 0.65; 95% confidence interval [CI], 0.47 to 0.90; plinearity=0.043 in the highest quartile (Q4) vs. the lowest quartile (Q1); women: IRR, 0.70; 95% CI, 0.54 to 0.93; plinearity=0.114 in Q4 vs. Q1). The inverse association remained after adjustment for dietary factors instead of dietary quality index, the baseline FBG, and the exclusion of incidence within the first year. Additionally, no significant interaction was found regarding the risk of type 2 diabetes between dietary mushroom consumption and participants' gender or other factors. CONCLUSIONS: Dietary mushroom consumption was inversely linked with the risk of type 2 diabetes incidence in both genders, indicating the beneficial role of mushrooms in preventing the disease.

Habitual intake of iron, copper, and zinc and the risk of type 2 diabetes in a prospective cohort: The CAVAS (Cardiovascular Disease Association Study).

BACKGROUND AND AIMS: Unlike iron, evidence of the association between dietary copper and zinc intake and type 2 diabetes (T2D) risk is limited. This study aimed to examine the prospective associations of dietary intake of iron (total, plant-based, and animal-based), copper, and zinc with T2D risk among adults aged ≥40 years. METHODS AND RESULTS: For 16,666 participants, dietary intakes (baseline, cumulative average, and most recent) of iron, copper, and zinc were calculated from repeated food frequency questionnaires; a modified Poisson regression model with a robust error estimator was conducted. In men, positive associations between T2D and baseline dietary intake of Cu and Zn, cumulative average dietary intake of Fe (total and animal-based), Cu and Zn, and most recent dietary intake of Fe (total, plant-based, and animal-based), Cu, and Zn [most recent diet: for total Fe, IRR(95%CI) = 1.93 (1.41-2.64); for plant-based Fe, 1.56 (1.15-2.11); for animal-based Fe, 1.44 (1.09-1.90); for Cu, 3.17 (2.33-4.30); for Zn, 2.18 (1.64-2.89)] were observed, where as in women, there were positive associations of only cumulative average dietary Zn intake and most recent dietary intake of plant-based Fe, Cu, and Zn [most recent diet: for plant-based Fe, 1.30 (1.01-1.68); for Cu, 1.62 (1.27-2.08); for Zn, 2.07 (1.61-2.66)]. CONCLUSION: Dietary intakes of iron (total, plant-based, and animal-based), copper, and zinc may be positively associated with T2D risk. These positive associations are predominantly observed in most recent diet and appear to be stronger compared to baseline and cumulative average diet.

2023 Korean Endocrine Society Consensus Guidelines for the Diagnosis and Management of Primary Aldosteronism.

Primary aldosteronism (PA) is a common, yet underdiagnosed cause of secondary hypertension. It is characterized by an overproduction of aldosterone, leading to hypertension and/or hypokalemia. Despite affecting between 5.9% and 34% of patients with hypertension, PA is frequently missed due to a lack of clinical awareness and systematic screening, which can result in significant cardiovascular complications. To address this, medical societies have developed clinical practice guidelines to improve the management of hypertension and PA. The Korean Endocrine Society, drawing on a wealth of research, has formulated new guidelines for PA. A task force has been established to prepare PA guidelines, which encompass epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and follow-up care. The Korean clinical guidelines for PA aim to deliver an evidence-based protocol for PA diagnosis, treatment, and patient monitoring. These guidelines are anticipated to ease the burden of this potentially curable condition.

Hyperthermic Intraperitoneal Chemotherapy After Interval Cytoreductive Surgery for Patients With Advanced-Stage Ovarian Cancer Who Had Received Neoadjuvant Chemotherapy.

Importance: Hyperthermic intraperitoneal chemotherapy (HIPEC) followed by interval cytoreductive surgery (ICS) has shown survival benefits for patients with advanced-stage ovarian cancer. However, there is still a lack of consensus regarding the integration of HIPEC into clinical practice. Objective: To evaluate the safety and effectiveness of ICS with HIPEC compared with ICS alone in clinical practice for patients with advanced-stage ovarian cancer. Design, Setting, and Participants: This prospective, multicenter, comparative effectiveness cohort study enrolled 205 patients with stage III or IV ovarian cancer who had received at least 3 cycles of neoadjuvant chemotherapy followed by ICS with HIPEC or ICS without HIPEC at 7 Korean Gynecologic Oncology Group institutions between September 1, 2017, and April 22, 2022. Nine patients were excluded because they did not meet the inclusion criteria. Exposures: Neoadjuvant chemotherapy followed by ICS with HIPEC or ICS without HIPEC. Main Outcomes and Measures: The primary end point was progression-free survival (PFS). Overall survival (OS) and the safety profile were the key secondary end points. Results: This study included 196 patients (median age, 58.0 years [range, 38-82 years]), of whom 109 underwent ICS with HIPEC and 87 underwent ICS without HIPEC. The median duration of follow-up was 28.2 months (range, 3.5-58.6 months). Disease recurrence occurred in 128 patients (65.3%), and 30 patients (15.3%) died. Interval cytoreductive surgery with HIPEC was associated with a significant improvement in median PFS compared with ICS without HIPEC (22.9 months [95% CI, 3.5-58.6 months] vs 14.2 months [95% CI, 4.0-56.2 months]; P = .005) and median OS (not reached [95% CI, 3.5 months to not reached] vs 53.0 [95% CI, 4.6-56.2 months]; P = .002). The frequency of grade 3 or 4 postoperative complications was similar in both groups (ICS with HIPEC, 3 of 109 [2.8%] vs ICS without HIPEC, 3 of 87 [3.4%]; P > .99). Among patients with recurrence, the frequency of peritoneal recurrence was lower in the ICS with HIPEC group than in the ICS without HIPEC group (21 of 64 [32.8%] vs 41 of 64 [64.1%]; P = .001). Conclusions and Relevance: This study suggests that ICS in conjunction with HIPEC was associated with longer PFS and OS than ICS without HIPEC for patients with advanced-stage ovarian cancer and was not associated with higher rates of postoperative complications. The lower rate of peritoneal recurrence after HIPEC may be associated with improved OS.

Clinicopathologic significance of mismatch repair protein expression in endometrioid endometrial cancer.

OBJECTIVE: To evaluate the association between mismatch repair (MMR) protein expression and clinico-pathologic outcomes in patients with endometrioid endometrial cancer (EC). MATERIALS AND METHODS: A retrospective review of the clinico-pathologic outcomes was performed on patients who were diagnosed with EC and had results of MMR protein immunohistochemistry. MMR-deficient (MMR-d) was defined as absence of expression in any of the 4 MMR proteins (MLH1, MSH2, MSH6, and PMS2). Demographics, pathologic variables, and survival outcomes were compared according to the MMR status. RESULTS: A total of 193 EC patients with available MMR expression data were included, of whom 163 patients had endometrioid type EC. Overall, 44 patients (27.0%) were classified as MMR-d. Compared with MMR-proficient (MMR-p) group, MMR-d group was associated with more frequent lymphovascular space invasion (LVSI, p = 0.001). MMR-d was also related with higher risk of lymph node (LN) metastasis in endometrioid type EC (p = 0.008), especially para-aortic LN metastasis. During the median follow-up period of 19.1 months (1-44.5), MMR-d group, especially MLH1/PMS2 subgroup, showed a tendency of reduced PFS (p = 0.036 and p = 0.008, respectively). On Cox regression analysis, however, LN metastasis remained as the only independent risk factor for PFS (p = 0.004) in endometrioid EC, and MLH1/PMS2 loss showed a marginally significant association (p = 0.054). CONCLUSION: Our findings of the associations between MMR deficiency and poor prognostic factors, such as LVSI and LN metastasis, may suggest the prognostic value of MMR status in EC and need further prospective validation studies.

Comparison of treatment outcomes and complications of coil embolization in elderly and very elderly patients with cerebral aneurysms: a propensity score matching analysis.

PURPOSE: This single center study aims to compare the treatment outcomes and procedure-related complications of coil embolization in elderly patients (60-79 years) and very elderly patients (aged 80 years or older) with cerebral aneurysms. METHODS: Data was collected from 504 elderly patients aged 60 years or older who underwent coil embolization for intracranial aneurysms from 2018 to 2021. The study evaluated patient-related and anatomical factors and assessed various outcomes, comparing results between groups using statistical analysis and propensity score matching. RESULTS: A total of 503 cerebral aneurysms were analyzed from individuals aged 60-79 years (n = 472) and those aged 80 years or older (n = 31). The majority of the aneurysms were unruptured with an average size of 3.5 mm in height and 3.4 mm in width. The patients were compared using 1:1 propensity score matching, and no significant differences were found in factors other than age and aortic elongation. Logistic analysis revealed that being over 80 years old and having a severe aortic arch elongation were identified as risk factors for procedure-related events in both total and unruptured cases. CONCLUSIONS: The study compared coil embolization treatment for cerebral aneurysms in patients aged 60-79 and over 80, finding no significant difference in treatment outcomes except for procedure-related events. Procedure-related events were associated with severe aortic arch elongation and being over 80 years old. Coil embolization can be considered safe and effective for patients over 80, but further trials are needed for accurate conclusions.

GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling.

BACKGROUND AND PURPOSE: GPR119 activation has been suggested to improve hyperglycemia, dyslipidemia and hepatic steatosis. But its therapeutic potential for metabolic dysfunction-associated steatohepatitis (MASH) are underexplored. Here, we investigated the effects of DA-1241, a novel GPR119 agonist, on MASH and explored its underlying mechanism of anti-inflammatory effects. EXPERIMENTAL APPROACH: The in vivo anti-MASH effect was assessed by examining the preventive effect in MS-MASH and Ob-MASH mice and the therapeutic effect in MASH with severe hyperglycemia and diet-induced obese (DIO)-MASH mice. Histological and biochemical changes in liver tissue were assessed. Both plasma and hepatic biomarkers related to inflammation and fibrosis were comprehensively analyzed. To understand its mode of action, changes in NFκB signaling were determined in HepG2 and THP-1 cells. KEY RESULTS: DA-1241 attenuated MASH progression and alleviated the MASH phenotypes in MASH mouse models with different etiologies, regardless of glucose-lowering activity. In DIO-MASH mice, DA-1241 significantly reduced biochemical parameters related to steatosis, inflammation and fibrosis in the liver with reduced plasma liver enzymes. When used in combination with a dipeptidyl peptidase 4 (DPP4) inhibitor, DA-1241 further improved the MASH phenotype by increasing endogenous glucagon-like peptide-1 effect. Notably, DA-1241 alone and in combination reduced liver inflammation and restored inflammation-related hepatic gene expression, leading to remission of systemic inflammation as assessed by plasma inflammatory cytokines and chemokines. We demonstrated that DA-1241 reduces macrophage differentiation through downregulation of NFκB signaling by activating GPR119. CONCLUSION: Our data suggest the therapeutic potential of DA-1241, alone and in combination with a DPP4 inhibitor, for MASH.

Lobeglitazone inhibits LPS-induced NLRP3 inflammasome activation and inflammation in the liver.

Liver inflammation is a common feature of chronic liver disease and is often associated with increased exposure of the liver to lipopolysaccharide (LPS). Kupffer cells (KCs) are macrophages in the liver and produce various cytokines. Activation of KCs through the NLRP3 inflammasome pathway leads to release of proinflammatory cytokines and induces hepatocyte injury and hepatic stellate cell (HSC) activation. Lobeglitazone is a peroxisome proliferator-activated receptor gamma ligand and a type of thiazolidinedione that elicits anti-inflammatory effects. However, there is no clear evidence that it has direct anti-inflammatory effects in the liver. This study showed that lobeglitazone reduces LPS-induced NLPR3 inflammasome activation and production of proinflammatory cytokines in primary KCs and hepatocytes. Cytokines secreted by activated KCs increased hepatocyte inflammation and HSC activation, and lobeglitazone inhibited these responses. In addition, lobeglitazone suppressed liver fibrosis by inhibiting LPS-induced transforming growth factor (TGF)-ß secretion and TGF-ß-induced CTGF expression. The inhibitory effect of lobeglitazone on inflammasome activation was associated with suppression of liver fibrosis. These results suggest that lobeglitazone may be a treatment option for inflammation and fibrosis in the liver.

Associations of cumulative average dietary total antioxidant capacity and intake of antioxidants with metabolic syndrome risk in Korean adults aged 40 years and older: a prospective cohort study (KoGES_CAVAS).

OBJECTIVES: Limited and inconsistent prospective evidence exists regarding the relationship of dietary total antioxidant capacity (dTAC) and antioxidant intake with metabolic syndrome (MetS) risk. We evaluated the associations of the cumulative averages of dTAC and antioxidant intake (in 5 classes: retinol, vitamin C, vitamin E, carotenoids, and flavonoids, as well as 7 flavonoid subclasses) with the risk of MetS. METHODS: This study included 11,379 participants without MetS, drawn from the Korean Genome and Epidemiology Study_CArdioVascular disease Association Study (KoGES_CAVAS). The cumulative average consumption was calculated using repeated food frequency questionnaires. Incidence rate ratios were estimated using a modified Poisson regression model with a robust error estimator. RESULTS: The median follow-up period was 5.16 years, and 2,416 cases of MetS were recorded over 58,750 person-years. In men, significant inverse associations were observed in all 5 antioxidant classes, except for the highest quartile of dTAC. In women, dTAC and total flavonoids were not significantly associated with MetS; however, significant L-shaped associations were found for the remaining 4 antioxidant classes. Of the 7 flavonoid subclasses, only flavones in the highest quartile for men and flavan-3-ols in women lacked significant associations with MetS. The inverse associations were not sex-specific, but they were particularly pronounced among participants with a body mass index (BMI) of 23 kg/m2 or higher. CONCLUSIONS: The findings suggest that most antioxidant classes and flavonoid subclasses, unlike dTAC, exhibit a clear beneficial association with MetS in an L-shaped pattern in both men and women, particularly those with a high BMI.

Serum 25-Hydroxyvitamin D Levels and Risk of Colorectal Cancer: An Age-Stratified Analysis.

BACKGROUND & AIMS: The role of circulating 25-hydroxyvitamin D (25(OH)D) in the prevention of early-onset colorectal cancer (CRC) in young adults aged <50 years is uncertain. We evaluated the age-stratified associations (<50 vs ≥50 years) between circulating 25(OH)D levels and the risk of CRC in a large sample of Korean adults. METHODS: Our cohort study included 236,382 participants (mean age, 38.0 [standard deviation, 9.0] years) who underwent a comprehensive health examination, including measurement of serum 25(OH)D levels. Serum 25(OH)D levels were categorized as <10, 10 to 20, and ≥20 ng/mL. CRC, along with the histologic subtype, site, and invasiveness, was ascertained through linkage with the national cancer registry. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CRC according to the serum 25(OH)D status, with adjustment for potential confounders. RESULTS: During the 1,393,741 person-years of follow-up (median, 6.5 years; interquartile range, 4.5-7.5 years), 341 participants developed CRC (incidence rate, 19.2 per 105 person-years). Among young individuals aged <50 years, serum 25(OH)D levels were inversely associated with the risk of incident CRC with HRs (95% CIs) of 0.61 (0.43-0.86) and 0.41 (0.27-0.63) for 25(OH)D 10 to 19 ng/mL and ≥20 ng/mL, respectively, with respect to the reference (<10 ng/mL) (P for trend <.001, time-dependent model). Significant associations were evident for adenocarcinoma, colon cancer, and invasive cancers. For those aged ≥50 years, associations were similar, although slightly attenuated compared with younger individuals. CONCLUSIONS: Serum 25(OH)D levels may have beneficial associations with the risk of developing CRC for both early-onset and late-onset disease.

Co-transient expression of PSA-Fc and PAP-Fc fusion protein in plant as prostate cancer vaccine candidates and immune responses in mice.

KEY MESSAGE: PAP-FcK and PSA-FcK prostate cancer antigenic proteins transiently co-expressed in plant induce their specific humoral immune responses in mice. Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) have been considered as immunotherapeutic antigens for prostate cancer. The use of a single antigenic agent is unlikely to be effective in eliciting immunotherapeutic responses due to the heterogeneous and multifocal nature of prostate cancer. Thus, multiple antigens have been combined to enhance their anti-cancer effects. In the current study, PSA and PAP were fused to the crystallizable region (Fc region) of immunoglobulin G1 and tagged with KDEL, the endoplasmic reticulum (ER) retention signal motif, to generate PSA-FcK and PAP-FcK, respectively, and were transiently co-expressed in Nicotiana benthamiana. Western blot analysis confirmed the co-expression of PSA-FcK and PAP-FcK (PSA-FcK + PAP-FcK) with a 1:3 ratios in the co-infiltrated plants. PSA-FcK, PAP-FcK, and PSA-FcK + PAP-FcK proteins were successfully purified from N. benthamiana by protein A affinity chromatography. ELISA showed that anti-PAP and anti-PSA antibodies successfully detected PAP-FcK and PSA-FcK, respectively, and both detected PSA-FcK + PAP-FcK. Surface plasmon resonance (SPR) analysis confirmed the binding affinity of the plant-derived Fc fusion proteins to FcγRI/CD64. Furthermore, we also confirmed that mice injected with PSA-FcK + PAP-FcK produced both PSA- and PAP-specific IgGs, demonstrating their immunogenicity. This study suggested that the transient plant expression system can be applied to produce the dual-antigen Fc fusion protein (PSA-FcK + PAP-FcK) for prostate cancer immunotherapy.

Daily SARS-CoV-2 Nasal Antigen Tests Miss Infected and Presumably Infectious People Due to Viral Load Differences among Specimen Types.

In a recent household transmission study of SARS-CoV-2, we found extreme differences in SARS-CoV-2 viral loads among paired saliva, anterior nares swab (ANS), and oropharyngeal swab specimens collected from the same time point. We hypothesized these differences may hinder low-analytical-sensitivity assays (including antigen rapid diagnostic tests [Ag-RDTs]) by using a single specimen type (e.g., ANS) from reliably detecting infected and infectious individuals. We evaluated daily at-home ANS Ag-RDTs (Quidel QuickVue) in a cross-sectional analysis of 228 individuals and a longitudinal analysis (throughout infection) of 17 individuals enrolled early in the course of infection. Ag-RDT results were compared to reverse transcription-quantitative PCR (RT-qPCR) results and high, presumably infectious viral loads (in each, or any, specimen type). The ANS Ag-RDT correctly detected only 44% of time points from infected individuals on cross-sectional analysis, and this population had an inferred limit of detection of 7.6 × 106 copies/mL. From the longitudinal cohort, daily Ag-RDT clinical sensitivity was very low (<3%) during the early, preinfectious period of the infection. Further, the Ag-RDT detected ≤63% of presumably infectious time points. The poor observed clinical sensitivity of the Ag-RDT was similar to what was predicted based on quantitative ANS viral loads and the inferred limit of detection of the ANS Ag-RDT being evaluated, indicating high-quality self-sampling. Nasal Ag-RDTs, even when used daily, can miss individuals infected with the Omicron variant and even those presumably infectious. Evaluations of Ag-RDTs for detection of infected or infectious individuals should be compared with a composite (multispecimen) infection status to correctly assess performance. IMPORTANCE We reveal three findings from a longitudinal study of daily nasal antigen rapid diagnostic test (Ag-RDT) evaluated against SARS-CoV-2 viral load quantification in three specimen types (saliva, nasal swab, and throat swab) in participants enrolled at the incidence of infection. First, the evaluated Ag-RDT showed low (44%) clinical sensitivity for detecting infected persons at all infection stages. Second, the Ag-RDT poorly detected (≤63%) time points that participants had high and presumably infectious viral loads in at least one specimen type. This poor clinical sensitivity to detect infectious individuals is inconsistent with the commonly held view that daily Ag-RDTs have near-perfect detection of infectious individuals. Third, use of a combination nasal-throat specimen type was inferred by viral loads to significantly improve Ag-RDT performance to detect infectious individuals.