The Role of PNPLA3_rs738409 Gene Variant, Lifestyle Factors, and Bioactive Compounds in Nonalcoholic Fatty Liver Disease: A Population-Based and Molecular Approach towards Healthy Nutrition.

This study aimed to investigate the impact of a common non-synonymous gene variant (C>G, rs738409) in patatin-like phospholipase domain-containing 3 (PNPLA3), leading to the substitution of isoleucine with methionine at position 148 (PNPLA3-I148M), on susceptibility to nonalcoholic fatty liver disease (NAFLD) and explore potential therapeutic nutritional strategies targeting PNPLA3. It contributed to understanding sustainable dietary practices for managing NAFLD, recently referred to as metabolic-dysfunction-associated fatty liver. NAFLD had been diagnosed by ultrasound in a metropolitan hospital-based cohort comprising 58,701 middle-aged and older Korean individuals, identifying 2089 NAFLD patients. The interaction between PNPLA3 and lifestyle factors was investigated. In silico analyses, including virtual screening, molecular docking, and molecular dynamics simulations, were conducted to identify bioactive compounds from foods targeting PNPLA3(I148M). Subsequent cellular experiments involved treating oleic acid (OA)-exposed HepG2 cells with selected bioactive compounds, both in the absence and presence of compound C (AMPK inhibitor), targeting PNPLA3 expression. Carriers of the risk allele PNPLA3_rs738409G showed an increased association with NAFLD risk, particularly with adherence to a plant-based diet, avoidance of a Western-style diet, and smoking. Delphinidin 3-caffeoyl-glucoside, pyranocyanin A, delta-viniferin, kaempferol-7-glucoside, and petunidin 3-rutinoside emerged as potential binders to the active site residues of PNPLA3, exhibiting a reduction in binding energy. These compounds demonstrated a dose-dependent reduction in intracellular triglyceride and lipid peroxide levels in HepG2 cells, while pretreatment with compound C showed the opposite trend. Kaempferol-7-glucoside and petunidin-3-rutinoside showed potential as inhibitors of PNPLA3 expression by enhancing AMPK activity, ultimately reducing intrahepatic lipogenesis. In conclusion, there is potential for plant-based diets and specific bioactive compounds to promote sustainable dietary practices to mitigate NAFLD risk, especially in individuals with genetic predispositions.

Porcine Brain Enzyme Hydrolysate Enhances Immune Function and Antioxidant Defense via Modulation of Gut Microbiota in a Cyclophosphamide-Induced Immunodeficiency Model.

This study examined how consuming porcine brain enzyme hydrolysate (PBEH) affects the immune function and composition of the gut microbiota in an immunodeficient animal model. Male Wistar rats aged 6 weeks were fed casein (control), 100 mg/kg body weight (BW), red ginseng extract (positive-control), and 6, 13, and 26 mg PBEH per kg BW (PBEH-L, PBEH-M, and PBEH-H, respectively) daily for 4 weeks. At 30 min after consuming assigned compounds, they were orally administered cyclophosphamide (CTX; 5 mg/kg BW), an immunosuppressive agent, to suppress the immune system by inhibiting the proliferation of lymphocytes. The normal-control rats were fed casein and water instead of CTX. Natural killer cell activity and splenocyte proliferation induced by 1 µg/mL lipopolysaccharide were lower in the control group than the normal-control group, and they significantly increased with PBEH consumption, particularly at high doses. The PBEH consumption increased dose-dependently in the Th1/Th2 ratio compared to the control. The lipid peroxide contents were lower in the PBEH group than in the control group. Moreover, PBEH m and PBEH-H consumption mitigated white pulp cell damage, reduced red pulp congestion, and increased spleen mast cells in the histological analysis. Intestinal microbiota composition demonstrated differences between the groups at the genus levels, with Akkermansia being more abundant in the control group than the normal-control group and the PBEH-H group showing a decrease. However, Bifidobacterium decreased in the control group but increased in the PBEH-H group. The ß-diversity revealed distinct microbial communities of PBEH and positive-control groups compared to the control group (p < 0.05). The metagenome predictions revealed that PBEH-H influenced amino acid metabolism, antioxidant defense, insulin sensitivity, and longevity pathways. In conclusion, PBEH-H intake boosted immune responses and reduced lipid peroxides by modulating gut microbiota composition. These findings suggest that PBEH-H has the potential as a dietary supplement for improving immune function and gut health in individuals with immunodeficiency.

Safety and Efficacy of Moderate-Intensity Stereotactic Body Radiation Therapy for Ultra-Central Lung Tumor.

Background and Objectives: Ultra-central (UC) lung tumors are defined as those abutting the proximal bronchial tree. Stereotactic body radiation therapy (SBRT) for UC tumors is difficult because of concerns about severe toxicities. Therefore, we report the safety and efficacy of moderate-intensity SBRT for UC tumors at our institution. Materials and Methods: From January 2017 to May 2021, we treated 20 patients with UC tumors with SBRT at a dose of 45-60 Gy in 10 fractions. The primary endpoints were local control (LC) and overall survival (OS). Results: The median follow-up time was 15.8 months (range: 2.7-53.8 months). Ten of the 20 patients (50.0%) showed a complete response, five (25.0%) had a partial response, two (10.0%) had stable disease, and three (15.0%) showed progressive disease (PD). The response and disease control rates were 75.0% and 85.0%, respectively. Patients with PD showed local progression at median 8.3 months (range: 6.8-19.1 months) after SBRT. One-year and 2-year OS rates were 79.4% and 62.4%, respectively. One-year and 2-year LC rates are 87.1% and 76.2%, respectively. Eight patients died due to a non-radiation therapy related cause. One patient experienced grade 5 massive hemoptysis 6 months after SBRT, resulting in death. One patient experienced grade 2 esophageal pain and two experienced grade 2 radiation pneumonitis. Otherwise, no grade 3 or higher toxicities were reported. Conclusions: Moderate-intensity SBRT offers effective control of UC tumors and is a well-tolerated treatment for such tumors.

Incidence, Prevalence, and Mortality of Eosinophilic Granulomatosis With Polyangiitis in Korea: A Nationwide Population-Based Study.

PURPOSE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of vasculitis with multiorgan involvement. The incidence and prevalence of EGPA vary geographically and ethnically. This study investigated the incidence, prevalence, and mortality of EGPA in a nationwide population-based cohort in Korea. METHODS: This retrospective cohort study used data from the National Health Insurance database that covers almost all Korean residents. EGPA was identified using relevant diagnostic codes from 2007 to 2018. Newly diagnosed EGPA cases since 2007 and patients who visited outpatient clinics for EGPA at least three times were included. Age- and sex-adjusted standardized incidence and prevalence rates were analyzed. RESULTS: A total of 843 patients with EGPA were identified. The mean annual standardized incidence between 2007 and 2018 was 1.2 (per 1,000,000 individuals). The incidence of EGPA has increased from 1.1 (per 1,000,000 individuals) in 2007 to 1.6 (per 1,000,000 individuals) in 2017. The standardized prevalence of EGPA has increased from 1.1(per 1,000,000 individuals) in 2007 to 11.2 (per 1,000,000 individuals) in 2018. The incidence and prevalence of EGPA were higher in women than in men. The standardized mortality rate was 1.61 (95% confidence interval [CI], 1.34-1.93) in total population, 1.59 (95% CI, 1.23-2.02) in males, and 1.63 (95% CI, 1.22-2.13) in females. CONCLUSIONS: The incidence of EGPA has increased over the past decade. Incidence and prevalence rates were higher in females than in males. The overall mortality rate associated with EGPA was higher than that in the general population.

Inhibitory effects of bioactive compounds on UVB-induced photodamage in human keratinocytes: modulation of MMP1 and Wnt signaling pathways.

UVB radiation significantly threatens skin health, contributing to wrinkle formation and an elevated risk of skin cancer. This study aimed to explore bioactive compounds with potential UVB-protective properties. Using in silico analysis, we chose compounds to reduce binding energy with matrix metalloproteinase-1 (MMP1). Piperitoside, procyanidin C1, and mulberrofuran E emerged as promising candidates through this computational screening process. We investigated the UVB-protective efficacy of the selected compounds and underlying mechanisms in human immortalized keratinocytes (HaCaT). We also investigated the molecular pathways implicated in their action, focusing on the transforming growth factor (TGF)-ß and wingless-related integration site (Wnt)/ß-catenin signaling pathways. In UVB-exposed HaCaT cells (100 mJ/cm2 for 30 min), piperitoside, procyanidin C1, and mulberrofuran E significantly reduced reactive oxygen species (ROS) and lipid peroxides, coupled with an augmentation of collagen expression. These compounds suppressed MMP1, tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS) expression, while they concurrently enhanced collagen-1 (COL1A1), ß-catenin (CTNNB1), and superoxide dismutase type-1 (SOD1) expression. Furthermore, Wnt/ß-catenin inhibitors, when administered subsequently, partially counteracted the reduction in MMP1 expression and alleviated inflammatory and oxidative stress markers induced by the bioactive compounds. In conclusion, piperitoside, procyanidin C1, and mulberrofuran E protected against UVB-induced damage in HaCaT cells by inhibiting MMP1 expression and elevating ß-catenin expression. Consequently, these bioactive compounds emerge as promising preventive agents for UVB-induced skin damage, promoting skin health.

Inhaled Corticosteroids May Not Affect the Clinical Outcomes of Pneumonia in Patients with Chronic Obstructive Pulmonary Disease.

Background: Although inhaled corticosteroids (ICS) is reportedly associated with a higher risk of pneumonia in chronic obstructive pulmonary disease (COPD), the clinical implications of ICS have not been sufficiently verified to determine their effect on the prognosis of pneumonia. Methods: The electronic health records of patients hospitalized for pneumonia with underlying COPD were retrospectively reviewed. Pneumonia was confirmed using chest radiography or computed tomography. The clinical outcomes of pneumonia in patients with COPD who received ICS and those who received long-acting bronchodilators other than ICS were compared. Results: Among the 255 hospitalized patients, 89 met the inclusion criteria. The numbers of ICS and non-ICS users were 46 and 43, respectively. The CURB-65 scores at the initial presentation of pneumonia were comparable between the two groups. The proportions of patients with multilobar infiltration, pleural effusion, and complicated pneumonia in the radiological studies did not vary between the two groups. Additionally, the defervescence time, proportion of mechanical ventilation, intensive care unit admission, length of hospital stays, and mortality rate at 30 and 90 days were not significantly different between the two groups. ICS use and blood eosinophils count were not associated with all pneumonia outcomes and mortality in multivariate analyses. Conclusion: The clinical outcomes of pneumonia following ICS use in patients with COPD did not differ from those in patients treated without ICS. Thus, ICS may not contribute to the severity and outcomes of pneumonia in patients with COPD.

Interplay between polygenic variants related immune response and lifestyle factors mitigate the chances of stroke in a genome-wide association study.

We aimed to investigate the intricate interplay between genetic predisposition and lifestyle factors on stroke. We conducted a comprehensive genome-wide association study to identify the genetic variants linked to stroke in the participants who experienced a stroke event (cases; n 672) and those with no stroke history (non-stroke; n 58 029) in a large hospital-based cohort. Using generalised multifactor dimensionality reduction, we identified genetic variants with interactive effects and constructed polygenic risk scores (PRS) by summing up the risk alleles from the genetic variants. Food intake was measured with a validated semi-quantitative FFQ. No significant differences in stroke incidence were seen in demographic variables between the two groups. Among the metabolic indicators, only serum TAG levels were higher in males with stroke than those without stroke. The daily nutrient intake, dietary inflammation index, glycaemic index, dietary patterns, alcohol consumption, exercise and smoking did not display associations with the OR for stroke. The stroke-linked genetic variants were related to the IL-18 pathway. After accounting for covariates, the PRS derived from the 5-, 6- and 7-SNP models were positively associated with stroke chance with 2·5-, 2·9- and 2·8-fold. Furthermore, interactions between genetic predisposition and dietary components, including energy, carbohydrates, n-3 fatty acids and branched-chain amino acids (BCAA), that affected OR for stroke were observed. A high intake of energy, carbohydrates and BCAA and a low intake of n-3 fatty acids were positively associated with the chances of stroke occurrence. In conclusion, understanding the interaction between genetic variants and lifestyle factors can assist in developing stroke prevention and management strategies.

Microbial Dysbiosis Linked to Metabolic Dysfunction-Associated Fatty Liver Disease in Asians: Prevotella copri Promotes Lipopolysaccharide Biosynthesis and Network Instability in the Prevotella Enterotype.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by hepatic fat accumulation by metabolic dysfunction. The rising prevalence of MAFLD, especially among Asians, may be associated with changes in gut microbiota. We investigated gut microbiota characteristics and potential mechanisms leading to MAFLD development according to enterotypes. Case-control studies examining the gut microbiota composition between MAFLD and non-MAFLD participants were searched in public databases until July 2023. Gut microbiota was categorized into two enterotypes by principal component analysis. According to the enterotypes, LEfSe, ALDEx2, XGBoost, and DCiPatho were utilized to identify differential abundances and pathogenic microbes in the gut between the MAFLD and non-MAFLD groups. We analyzed microbial community networks with the SprCC module and predicted microbial functions. In the Prevotella enterotype (ET-P), 98.6% of Asians and 65.1% of Caucasians were associated with MAFLD (p = 0.049). MAFLD incidence was correlated with enterotype, age, obesity, and ethnicity (p < 0.05). Asian MAFLD patients exhibited decreased Firmicutes and Akkermansia muciniphila and increased Bacteroidetes and P. copri. The pathogenicity scores were 0.006 for A. muciniphila and 0.868 for P. copri. The Asian MAFLD group showed decreased stability and complexity in the gut microbiota network. Metagenome function analysis revealed higher fructose metabolism and lipopolysaccharide (LPS) biosynthesis and lower animal proteins and α-linolenic acid metabolism in Asians with MAFLD compared with the non-MAFLD group. LPS biosynthesis was positively correlated with P. copri (p < 0.05). In conclusion, P. copri emerged as a potential microbial biomarker for MAFLD. These findings enhance our understanding of the pathological mechanisms of MAFLD mediated through the gut microbiota, providing insights for future interventions.

Association of a High Healthy Eating Index Diet with Long-Term Visceral Fat Loss in a Large Longitudinal Study.

We aimed to investigate the association of a sustainable diet with a long-term reduction in waist circumference (WC) while identifying novel biomarkers for WC reduction (WCR). The participants were recruited initially during 2004-2013 in a large hospital-based cohort, and the follow-up measurements were conducted during 2012-2016. The 65,611 adults aged 45-75 were categorized into WC-loss (n = 22,290) and WC-gain (n = 43,321). Each study investigated demographic, anthropometric, biochemical, genetic, and dietary factors. The modified Healthy Eating Index (MHEI), dietary patterns, and glycemic index were calculated from a validated semi-quantitative food frequency questionnaire. Novel biomarkers influencing WC reduction were identified using machine learning approaches. A WCR was inversely associated with metabolic syndrome (MetS) risk and its components. Daily energy intake did not differ between those with and without WCR. However, MHEI, which represents diet quality, demonstrated a positive association with WCR. Among various dietary patterns, the Asian-style balanced diet (ABD), including more fermented soybeans and less restricted salt than the Diet Approach to Stop Hypertension, was positively associated with WCR. However, an inverse association was observed between the diet that was high in noodle and processed meat consumption and that which was high in rice consumption. However, the PRS for abdominal obesity did not significantly interrupt WCR. The receiver operating characteristic curve in the prediction model for WCR was about 0.86. The biomarkers in the models included MetS components, inflammation index, diet components, alcohol consumption, and smoking status, but not genetic factors. In conclusion, adopting a high-quality diet with a high MHEI like ABD leads to WCR, irrespective of genetic influences. These results could be applied to develop effective strategies for preventing and managing abdominal obesity.

A Potential Radiomics-Clinical Model for Predicting Failure of Lymph Node Control after Definite Radiotherapy in Locally Advanced Head and Neck Cancer.

Background and Objectives: To optimally predict lymph node (LN) failure after definite radiotherapy (RT) in head and neck cancer (HNC) with LN metastases, this study examined radiomics models extracted from CT images of different periods during RT. Materials and Methods: This study retrospectively collected radiologic and clinical information from patients undergoing definite RT over 60 Gy for HNC with LN metastases from January 2010 to August 2021. The same largest LNs in each patient from the initial simulation CT (CTpre) and the following simulation CT (CTmid) at approximately 40 Gy were indicated as regions of interest. LN failure was defined as residual or recurrent LN within 3 years after the end of RT. After the radiomics features were extracted, the radiomics alone model and the radiomics plus clinical parameters model from the set of CTpre and CTmid were compared. The LASSO method was applied to select features associated with LN failure. Results: Among 66 patients, 17 LN failures were observed. In the radiomics alone model, CTpre and CTmid had similar mean accuracies (0.681 and 0.697, respectively) and mean areas under the curve (AUC) (0.521 and 0.568, respectively). Radiomics features of spherical disproportion, size zone variance, and log minimum 2 were selected for CTpre plus clinical parameters. Volume, energy, homogeneity, and log minimum 1 were selected for CTmid plus clinical parameters. Clinical parameters including smoking, T-stage, ECE, and regression rate of LN were important for both CTpre and CTmid. In the radiomics plus clinical parameters models, the mean accuracy and mean AUC of CTmid (0.790 and 0.662, respectively) were more improved than those of CTpre (0.731 and 0.582, respectively). Conclusions: Both models using CTpre and CTmid were improved by adding clinical parameters. The radiomics model using CTmid plus clinical parameters was the best in predicting LN failure in our preliminary analyses.

Benefit of perioperative radiotherapy for hepatocellular carcinoma: a quality-based systematic review and meta-analysis.

INTRODUCTION: Although surgery is the standard curative modality for hepatocellular carcinoma, more than two-thirds experience intrahepatic recurrence. Since no standard perioperative treatment has been established, the authors performed a meta-analysis to evaluate the benefits of perioperative radiotherapy (RT). METHODS: The PubMed, MEDLINE, EMBASE, and Cochrane Library were searched until May 2023. Randomized or propensity-matched studies evaluating at least five major clinical factors investigating benefit of perioperative RT, were included. The main effect measure were the pooled odds ratios (OR) regarding the benefit of perioperative RT using 2-year overall survival (OS) and 1-year disease-free survival (DFS) data. RESULTS: Seven studies (five randomized and two propensity-matched studies) involving 815 patients were included. The pooled ORs for 1-year DFS and 2-year OS were 0.359 (95% CI: 0.246-0.523) and 0.371 (95% CI: 0.293-0.576), respectively, favoring perioperative RT, with very low heterogeneity. In the subgroup analyses, the benefits of OS and DFS were consistent between the two subgroups [portal vein thrombosis (PVT) and narrow resection margin (RM) groups]. In the PVT subgroup, the pooled OS rates at both 1-year and 2-year (75.6 vs. 36.9%, P <0.001; 25.6 vs. 9.9%, P =0.004) and DFS rates at both 1-year and 2-year (25.2 vs. 10.3%, P =0.194; 11.9 vs. 3.0%, P =0.022) were higher in the perioperative RT group. In the narrow RM subgroup, the surgery and RT groups showed higher pooled OS rates for both 1-year and 2-year (97.3 vs. 91.9%, P =0.042; 90.4 vs. 78.7%, P =0.051) and DFS (88.1 vs. 72.6%, P <0.001; 70.1 vs. 51.7%, P <0.001). Grade 5 toxicity was not reported, and three studies reported grade ≥3 or higher liver function test abnormalities, ranging from 4.8-19.2%. CONCLUSION: The present study supports the oncological benefits of perioperative RT, for cases with high-risk of recurrence. Oncologic outcomes between subgroups differed according to clinical indications.

The impact of gut microbiome enterotypes on ulcerative colitis: identifying key bacterial species and revealing species co-occurrence networks using machine learning.

Ulcerative colitis (UC) is a chronic inflammatory intestinal disease affecting the colon and rectum, with its pathogenesis attributed to genetic background, environmental factors, and gut microbes. This study aimed to investigate the role of enterotypes in UC by conducting a hierarchical analysis, determining differential bacteria using machine learning, and performing Species Co-occurrence Network (SCN) analysis. Fecal bacterial data were collected from UC patients, and a 16S rRNA metagenomic analysis was performed using the QIIME2 bioinformatics pipeline. Enterotype clustering was conducted at the family level, and deep neural network (DNN) classification models were trained for UC and healthy controls (HC) in each enterotype. Results from eleven 16S rRNA gut microbiome datasets revealed three enterotypes: Bacteroidaceae (ET-B), Lachnospiraceae (ET-L), and Clostridiaceae (ET-C). Ruminococcus (R. gnavus) abundance was significantly higher in UC subjects with ET-B and ET-C than in those with ET-L. R. gnavus also showed a positive correlation with Clostridia in UC SCN for ET-B and ET-C subjects, with a higher correlation in ET-C subjects. Conversely, Odoribacter (O.) splanchnicus and Bacteroides (B.) uniformis exhibited a positive correlation with tryptophan metabolism and AMP-activated protein kinase (AMPK) signaling pathways, while R. gnavus showed a negative correlation. In vitro co-culture experiments with Clostridium (C.) difficile demonstrated that fecal microbiota from ET-B subjects had a higher abundance of C. difficile than ET-L subjects. In conclusion, the ET-B enterotype predisposes individuals to UC, with R. gnavus as a potential risk factor and O. splanchnicus and B. uniformis as protective bacteria, and those with UC may have ultimately become ET-C.

Genetic and Lifestyle-Related Factors Influencing Serum Hyper-Propionylcarnitine Concentrations and Their Association with Metabolic Syndrome and Cardiovascular Disease Risk.

The genetic and environmental determinants of serum propionylcarnitine concentrations (PC) remain largely unexplored. This study investigated the impact of genetic and environmental factors on serum propionylcarnitine levels in middle-aged and elderly participants from the Ansan/Ansung cohort of the Korean Genome and Epidemiology Study. Our goal was to understand the role of PC on the risk of metabolic syndrome (MetS) leading to cardiovascular disease, particularly concerning branched-chain amino acid (BCAA) metabolism. We analyzed participants' demographic, lifestyle, and biochemical data with and without MetS. Serum metabolite concentrations, including carnitine, acylcarnitine, and amino acid concentrations, were measured, and the components of MetS were evaluated. Genetic variants associated with low and high PC were selected using genome-wide association studies after adjusting for MetS-related parameters. Further, genetic variants and lifestyle factors that interacted with the polygenic risk score (PRS) were analyzed. Participants with MetS were older and less educated, and their alcohol intake was higher than non-MetS participants. PC was significantly associated with the MetS risk and increased the serum levels of BCAAs and other amino acids. Higher PC positively correlated with MetS components, insulin resistance, and cardiovascular risk factors. Intake of calcium, sodium, and vitamin D were inversely associated with PC, but coffee consumption was positively linked to PC. Multiple C2 And Transmembrane Domain Containing-1 (MCTP1)_rs4290997, Kinesin Family Member-7 (KIF7)_rs2350480, Coagulation Factor-II (F2)_rs2070850, Peroxisomal Biogenesis Factor-3 (PEX3)_rs223231, TBC1 Domain Family Member-22A (TBC1D22A)_rs910543, and Phospholipase A2 Group-IV-C (PLA2G4C)_rs7252136 interact with each other to have a threefold influence on PC. The PRS for the six-genetic variant model also interacted with age; the diet rich in beans, potato, and kimchi; and smoking status, influencing PC. In conclusion, elevated PC was associated with MetS and cardiovascular disease risk, suggesting their potential as disease biomarkers.

Interaction of energy and sulfur microbial diet and smoking status with polygenic variants associated with lipoprotein metabolism.

Introduction: Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants associated with hypo-HDL-C interact with lifestyle factors was examined in 58,701 middle-aged Korean adults who participated in the Korean Genome and Epidemiology Study (KoGES). Methods: Participants were categorized into the Low-HDL (case; n = 16,980) and Normal-HDL (n = 41,721) groups. The participants in the Low-HDL group were selected using the guideline-based cutoffs for hypo-HDL-C (<40 mg/dL for men and < 50 mg/dL for women) and included those taking medication for dyslipidemia. The genes associated with hypo-HDL-C were determined through a genome-wide association study (GWAS) in a city hospital-based cohort, and the results were validated in the Ansan/Anung study. The genetic variants for the single nucleotide polymorphism (SNP)-SNP interaction were selected using a generalized multifactor dimensionality reduction analysis, and the polygenic risk score (PRS) generated was evaluated for interaction with lifestyle parameters. Results: The participants with hypo-HDL-C showed a 1.45 and 1.36-fold higher association with myocardial infarction and stroke, respectively. The High-PRS with four SNPs, namely ZPR1_rs3741297, CETP_rs708272, BUD13_rs180327, and ALDH1A2_rs588136, and that with the 11q23.3 haplotype were positively associated with hypo-HDL-C by about 3 times, which was a 2.4-fold higher association than the PRS of 24 SNP with p < 5×10-8. The risk alleles of CETP_rs708272 and ALDH1A2_rs588136 were linked to increased expression in the heart and decreased in the brain, respectively. The selected SNPs were linked to the reverse cholesterol transport pathway, triglyceride-rich lipoprotein particle remodeling pathway, cholesterol storage, and macrophage-derived foam cell differentiation regulation. The PRS of the 4-SNP model interacted with energy intake and smoking status, while that of the haplotype interacted with a glycemic index of the diet, sulfur microbial diet, and smoking status. Discussion: Adults with a genetic risk for hypo-HDL-C need to modulate their diet and smoking status to reduce their risk.

Gut Microbiota Alterations and Their Functional Differences in Depression According to Enterotypes in Asian Individuals.

This study aimed to investigate alterations in the gut microbiota of patients with depression compared to those in the gut microbiota of healthy individuals based on enterotypes as a classification framework. Fecal bacteria FASTA/Q samples from 333 Chinese participants, including 107 healthy individuals (Healthy group) and 226 individuals suffering from depression (DP group), were analyzed. The participants were classified into three enterotypes: Bacteroidaceae (ET-B), Lachnospiraceae (ET-L), and Prevotellaceae (ET-P). An α-diversity analysis revealed no significant differences in microbial diversity between the Healthy and DP groups across all enterotypes. However, there were substantial differences in the gut microbial composition for ß-diversity, particularly within ET-L and ET-B. The DP group within ET-B exhibited a higher abundance of Proteobacteria, while a linear discriminant analysis (LDA) of the DP group showed an increased relative abundance of specific genera, such as Mediterraneibacter, Blautia, Bifidobacterium, and Clostridium. Within ET-L, Bifidobacterium, Blautia, Clostridium, Collinsella, and Corynebacterium were significantly higher in the DP group in the LDA and ANOVA-like differential expression-2 (ALDEx2) analyses. At the species level of ET-L, Blautia luti, Blautia provencensis, Blautia glucerasea, Clostridium innocuum, Clostridium porci, and Clostridium leptum were the primary bacteria in the DP group identified using the machine learning approach. A network analysis revealed a more tightly interconnected microbial community within ET-L than within ET-B. This suggests a potentially stronger functional relationship among the gut microbiota in ET-L. The metabolic pathways related to glucose metabolism, tryptophan and tyrosine metabolism, neurotransmitter metabolism, and immune-related functions showed strong negative associations with depression, particularly within ET-L. These findings provide insights into the gut-brain axis and its role in the pathogenesis of depression, thus contributing to our understanding of the underlying mechanisms in Asian individuals. Further research is warranted to explain the mechanistic links between gut microbiota and depression and to explore their potential for use in precision medicine interventions.

Interactions between Polygenetic Variants and Lifestyle Factors in Hypothyroidism: A Hospital-Based Cohort Study.

Hypothyroidism is a prevalent endocrine disorder and is associated with a variety of metabolic disturbances. This study aimed to investigate the polygenic variants associated with hypothyroidism risk and the interaction of polygenic risk scores (PRS) with dietary patterns in influencing disease risk in 56,664 participants aged >40 in a hospital-based cohort. The participants were classified as having hypothyroidism (n = 870) diagnosed by a physician and no hypothyroidism (n = 55,794). Genetic variants associated with hypothyroidism were identified using a genome-wide association study (GWAS). Genetic variants interacting with each other were selected using a generalized multifactor dimensionality reduction analysis, and the PRS generated was evaluated for interaction with lifestyle parameters. Coffee, alcohol, meat intake, and a Korean balanced diet were inversely associated with hypothyroidism risk, as were selenium, copper, and manganese intakes. White blood cell (WBC) counts and serum alkaline phosphatase and triglyceride concentrations were positively associated with hypothyroidism risk, as were osteoporosis and thyroid cancer. The GMDR analysis generated a three-single nucleotide polymorphism (SNP) model comprising dual oxidase-1 (DUOX1)_rs1648314; thyroid-stimulating hormone receptor (TSHR)_rs75664963; and major histocompatibility complex, class-II, DQ Alpha-1 (HLA-DQA1)_rs17426593. The PRS derived from the three- and seven-SNP models were associated with a 2.11- and 2.32-fold increase in hypothyroidism risk, respectively. Furthermore, the PRS from the three-SNP model showed interactions with WBC counts, wherein the positive association with hypothyroidism risk was more pronounced in participants with low WBC counts than those with high WBC counts (≥4 × 109 /L). Dietary patterns, such as the plant-based diet (PBD) and the Western-style diet (WSD), along with smoking status, exhibited interactions with the PRS, influencing hypothyroidism risk. In participants with a high PRS, those in the high-PBD, low-WSD, and smoker groups had a higher proportion of hypothyroidism than those in the low-PBD, high-WSD, and non-smoker groups. In conclusion, genetic variants related to immunity and thyroid hormone secretion were linked to hypothyroidism risk, and their PRS interacted with PBD and WSD intake and smoking status. These results contribute to a better understanding of hypothyroidism and its prevention strategies for precision medicine intervention.

Association of Pooled Fecal Microbiota on Height Growth in Children According to Enterotypes.

OBJECTIVES: The association between fecal microbiota and height in children has yielded conflicting findings, warranting further investigation into potential differences in fecal bacterial composition between children with short stature and those of standard height based on enterotypes (ETs). METHODS: According to the height z score for age and gender, the children were categorized into normal-stature (NS; n = 335) and short-stature (SS; n = 152) groups using a z score of -1.15 as a separator value. The human fecal bacterial FASTA/Q files (n = 487) were pooled and analyzed with the QIIME 2 platform with the National Center for Biotechnology Information alignment search tool. According to ETs, the prediction models by the machine learning algorithms were used for explaining SS, and their quality was validated. RESULTS: The proportion of SS was 16.4% in ET Enterobacteriaceae (ET-E) and 68.1% in Prevotellaceae (ET-P). The Chao1 and Shannon indexes were significantly lower in the SS than in the NS groups only in ET-P. The fecal bacteria related to SS from the prediction models were similar regardless of ETs. However, in network analysis, the negative correlations between fecal bacteria in the NS and SS groups were much higher in the ET-P than in the ET-E. In the metagenome function, fecal bacteria showed an inverse association of biotin and secondary bile acid synthesis and downregulation of insulin/insulin-like growth factor-1-driven phosphoinositide 3-kinase Akt signaling and AMP-kinase signaling in the SS group compared with the NS group in both ETs. CONCLUSION: The gut microbial compositions in children were associated with height. Strategies to modify and optimize the gut microbiota composition should be investigated for any potential in promoting height in children.

Protective Effect of Long-Term Fermented Soybeans with Abundant Bacillus subtilis on Glucose and Bone Metabolism and Memory Function in Ovariectomized Rats: Modulation of the Gut Microbiota.

We investigated the effects of different types of long-term fermented soybeans (traditionally made doenjang; TMD) on glucose and bone metabolism and memory function in ovariectomized (OVX) rats. The rats were categorized into six groups: Control, cooked unfermented soybeans (CSB), and four TMDs based on Bacillus subtilis (B. subtilis) and biogenic amine contents analyzed previously: high B. subtilis (HS) and high biogenic amines (HA; HSHA), low B. subtilis (LS) and HA (LSHA), HS and low biogenic amines (LA; HSLA), and LS and LA (LSLA). The rats in the CSB and TMD groups fed orally had a 4% high-fat diet for 12 weeks. Rats in the Control (OVX rats) and Normal-control (Sham-operated rats) groups did not consume CSB or TMD, although macronutrient contents were the same in all groups. Uterine weight and serum 17ß-estradiol concentrations were much lower in the Control than the Normal-control group, but CSB and TMD intake did not alter them regardless of B. subtilis and biogenic amine contents. HOMA-IR, a measure of insulin resistance, decreased with TMD with high B. subtilis (HSLA and HSHA) compared to the Control group. In OGTT and IPGTT, serum glucose concentrations at each time point were higher in the Control than in the Normal-control, and HSLA and HSHA lowered them. Memory function was preserved with HSHA and HSLA administration. Bone mineral density decline measured by DEXA analysis was prevented in the HSHA and HSLA groups. Bone metabolism changes were associated with decreased osteoclastic activity, parathyroid hormone levels, and osteoclastic activity-related parameters. Micro-CT results demonstrated that TMD, especially HSLA and HSHA, preserved bone structure in OVX rats. TMD also modulated the fecal bacterial community, increasing Lactobacillus, Ligalactobacillus, and Bacillus. In conclusion, through gut microbiota modulation, TMD, particularly with high B. subtilis content, acts as a synbiotic to benefit glucose, bone, and memory function in OVX rats. Further research is needed to make specific recommendations for B. subtilis-rich TMD for menopausal women.

A Positive Causal Relationship between Noodle Intake and Metabolic Syndrome: A Two-Sample Mendelian Randomization Study.

The controversy over the link between noodle consumption and metabolic syndrome (MetS) persists. Using a two-sample Mendelian randomization (MR) approach, we aimed to examine the potential causal relationship between noodle consumption and the risk of MetS and its components in adult populations of city hospital-based (n = 58,701) and Ansan/Ansung plus rural (AAR; n = 13,598) cohorts. The instrumental variables were assigned with genetic variants associated with low- and high-noodle intake (cutoff: 130 g/day) by a genome-wide association study (GWAS) with p < 5 × 10-5 and linkage disequilibrium (r2 = 0.001), following adjustment for covariates related to MetS, in the city cohort. MR-Egger, inverse-variance weighted (IVW), and weighted median were applied to investigate the causal association of noodle intake with MetS risk in the AAR. The quality of the MR results was checked with leave-one-out sensitivity and heterogeneity analyses. A higher energy intake with lower carbohydrates and higher fats, proteins, and higher sodium and a lower intake of calcium, vitamin D, vitamin C, and flavonoids were shown in the high-noodle group, indicating poor diet quality. The glycemic index and glycemic load of daily meals were much higher in the high-noodle intake group than in the low-noodle intake group. In the observational studies, not only the total noodle intake but also the different types of noodle intake were also positively associated with MetS risk. In the MR analysis, high-noodle intake elevated MetS, hypertension, dyslipidemia, hyperglycemia, hypertriglyceridemia, and abdominal obesity in an IVW model (p < 0.05) but not the MR-Egger model. No single genetic variant among the instrumental variables changed their relationship in the leave-one-out sensitivity analysis. No likelihood of horizontal pleiotropy and heterogeneity was exhibited in the association between noodle intake and MetS. In conclusion, noddle intake had a positive causal association with MetS and its components in Asian adults.

Association of Fried Food Intake with Gastric Cancer Risk: A Systemic Review and Meta-Analysis of Case-Control Studies.

Gastric cancer is one of the most prevalent cancers in Asia, and has a significant global incidence. However, the impact of fried food consumption on gastric cancer risk remains uncertain, mainly due to the limited number of participants in previous studies. To address this knowledge gap, we aimed to examine the association between fried food intake and gastric cancer incidence through a comprehensive meta-analysis. We conducted a thorough search across multiple databases, including PubMed, EMBASE, Google Scholar, Cochrane Library, China National Knowledge Infrastructure (CNKI), Korean Information Service System (KISS), and Research Information Service System (RISS), to collect studies. The newly analyzed results of the Korean Genome and Epidemiology Study (KoGES) findings were added. We assessed integrated odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) from the selected studies using Cochrane RevMan 5.0 for the meta-analysis. The quality of the studies included in the meta-analysis was assessed using the Study Quality Assessment Tool of the National Heart, Lung, and Blood Institute (NHLBI). We included 18 studies in the analysis, which compared the impact of fried food intake in gastric cancer patients (n = 5739) and healthy adults (control, n = 70,933). There was a significant positive association between gastric cancer risk and fried food intake (OR = 1.52, 95% CI = 1.23-1.87, I2 = 76%, p = 0.0001). The relationship was found to be significant in both non-East Asians (OR = 1.48, 95% CI = 1.18-1.85, I2 = 31%, p = 0.0006) and East Asians (OR = 1.54, 95% CI = 1.14-2.08, I2 = 83%, p = 0.005). In conclusion, this meta-analysis supports the notion that fried food intake is associated with an increased risk of gastric cancer in both non-Asians and Asians. Promoting a reduction in fried food consumption as a measure against gastric cancer risk is recommended.