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.

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.

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.

The Impact of Ulmus macrocarpa Extracts on a Model of Sarcopenia-Induced C57BL/6 Mice.

Aging leads to tissue and cellular changes, often driven by oxidative stress and inflammation, which contribute to age-related diseases. Our research focuses on harnessing the potent anti-inflammatory and antioxidant properties of Korean Ulmus macrocarpa Hance, a traditional herbal remedy, to address muscle loss and atrophy. We evaluated the effects of Ulmus extract on various parameters in a muscle atrophy model, including weight, exercise performance, grip strength, body composition, muscle mass, and fiber characteristics. Additionally, we conducted Western blot and RT-PCR analyses to examine muscle protein regulation, apoptosis factors, inflammation, and antioxidants. In a dexamethasone-induced muscle atrophy model, Ulmus extract administration promoted genes related to muscle formation while reducing those associated with muscle atrophy. It also mitigated inflammation and boosted muscle antioxidants, indicating a potential improvement in muscle atrophy. These findings highlight the promise of Ulmus extract for developing pharmaceuticals and supplements to combat muscle loss and atrophy, paving the way for clinical applications.

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.

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.

The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy.

Autophagy is a lysosomal degradation pathway that is important in cellular homeostasis. Prior work showed a key role for the autophagy related 5 (Atg5) in resistance to Toxoplasma gondii. Here we show that the cassette of autophagy proteins involved in the conjugation of microtubule-associated protein 1 light chain 3 (LC3) to phosphatidylethanolamine, including Atg7, Atg3, and the Atg12-Atg5-Atg16L1 complex play crucial roles in the control of T. gondii in vitro and in vivo. In contrast, pharmacologic modulation of the degradative autophagy pathway or genetic deletion of other essential autophagy genes had no substantial effects. Rather the conjugation system was required for targeting of LC3 and interferon-γ effectors onto the vacuolar membrane of T. gondii and its consequent disruption. These data suggest that the ubiquitin-like conjugation systems that reorganize intracellular membranes during canonical autophagy are necessary for proper targeting of immune effectors to the intracellular vacuole membranes utilized by pathogens.

Interaction of polygenetic variants related to inflammation with carbohydrate and vitamin D intakes in middle-aged and older adults in a large hospital-based cohort.

Low-grade subclinical inflammation is interrelated with metabolic diseases, and its susceptibility interacts with genetic and environmental factors. We aimed to examine genetic variants related to a high risk for inflammation using serum C-reactive protein (CRP) concentration, interactions among the genetic variants and the genetic variant interaction with dietary and lifestyle factors in adults. The participants were divided into case and control by serum CRP concentrations: ≥ 0·5 mg/dl (case; n 2018) and < 0·5 mg/dl (control; n 47 185). Genetic variants contributing to high inflammation risk were selected using GWAS after adjusting covariates to influence inflammation, and genetic variant-genetic variant interactions were identified by generalised multifactor dimensionality reduction analysis. Polygenetic-risk scores (PRS) were constructed from the selected genetic variants, and PRS-nutrient interactions for the high inflammation risk were determined. The PRS included CRP_rs1205, OASL_rs3213545, APOE_rs429358, HNF1A_rs1169286, APOC1_rs7256200 and SLC13A3_rs424697. The PRS was positively associated with serum CRP concentration by 2·0 times after adjusting for covariates. The PRS interacted with age: older participants with High-PRS had much higher serum CRP concentrations than those with Low-PRS. Intake of carbohydrates, MUFA and vitamin D exhibited an interaction with PRS for inflammation risk (P < 0·05). In participants with high-carbohydrate/low-fat diets and low vitamin D intakes, those with High-PRS had a higher risk of serum CRP concentrations than those with Low-PRS. In conclusion, the participants with inflammation-related PRS potentially worsened inflammation status, especially in diets with high carbohydrates, low fat (especially MUFA) and low vitamin D. These results can be applied to personalised nutrition to reduce inflammation risk.

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.

Interaction of environmental factors with the polygenic risk scores of thinness-related genes in preventing obesity risk in middle-aged adults: The KoGES.

BACKGROUND: Some persons are genetically resistant to obesity, but only a few studies have evaluated thinness genes for preventing obesity. We aimed to investigate the association of polygenic variants with being underweight and their interaction with the lifestyles of middle-aged and elderly persons and identify potential new genetic approaches for managing body weight. METHODS: In total, 58,701 participants aged 40-77 years were recruited from urban hospitals in Korea. Underweight (case) was defined as body mass index (BMI) < 18.5 kg m2 (n = 991) and normal weight (control, n = 21,921) was defined as 18.5 ≤ BMI < 23 kg m2 . A genome-wide association study was run to identify thinness-related single nucleotide polymorphisms (SNPs) after adjustment for compound factors using Gplink. The generalised multifactor dimensionality reduction program was used to identify the genetic variants with SNP-SNP interactions. The polygenic risk score (PRS) was calculated by summing up the number of risk alleles in each SNP and classifying them into low-, medium- and high-PRS. RESULTS: The best model included the ANK2_rs7656666, CAST_rs28042, SLC1A3_rs928431867, CHST12_rs2906173, ALOX5_rs1051713, RGS6_rs17180754, ST8SIA5_rs79491311 and DCC_rs35721894 alleles. The participants with high-PRS had a lower BMI (p < 0.0001) than those with low-PRS and were 3.834 (2.58-5.70) times more likely to be underweight after multivariate adjustment (p < 0.001). The selected SNPs were correlated with each other and highly expressed in brain-related genes. The genes with minor alleles of CAST_rs28042 and CHST12_rs2906173 exhibited a higher expression frequency in brain-related tissues. PRS had significant interactions with protein, sodium, indigestible carbohydrates, calcium intake and exercise (p < 0.05), influencing the underweight state. People with a high-PRS were more underweight than those with low-PRS under high protein, sodium, high calcium, low indigestible carbohydrate intake and low exercise by 3.75, 3.88, 7.05, 3.18 and 3.80 times, respectively (p < 0.0001). CONCLUSIONS: In conclusion, adults having a high-PRS were significantly correlated with being underweight, especially in combination with a particular nutritional status. These results show the potential for thinness genes to be applied to personalised nutrition for preventing obesity through targeted gene therapy.

A Prediction Model for Osteoporosis Risk Using a Machine-Learning Approach and Its Validation in a Large Cohort.

BACKGROUND: Osteoporosis develops in the elderly due to decreased bone mineral density (BMD), potentially increasing bone fracture risk. However, the BMD is not regularly measured in a clinical setting. This study aimed to develop a good prediction model for the osteoporosis risk using a machine learning (ML) approach in adults over 40 years in the Ansan/Anseong cohort and the association of predicted osteoporosis risk with a fracture in the Health Examinees (HEXA) cohort. METHODS: The 109 demographic, anthropometric, biochemical, genetic, nutrient, and lifestyle variables of 8,842 participants were manually selected in an Ansan/Anseong cohort and included in the ML algorithm. The polygenic risk score (PRS) of osteoporosis was generated with a genome-wide association study and added for the genetic impact of osteoporosis. Osteoporosis was defined with < -2.5 T scores of the tibia or radius compared to people in their 20s-30s. They were divided randomly into the training (n = 7,074) and test (n = 1,768) sets-Pearson's correlation between the predicted osteoporosis risk and fracture in the HEXA cohort. RESULTS: XGBoost, deep neural network, and random forest generated the prediction model with a high area under the curve (AUC, 0.86) of the receiver operating characteristic (ROC) with 10, 15, and 20 features; the prediction model by XGBoost had the highest AUC of ROC, high accuracy and k-fold values (> 0.85) in 15 features among seven ML approaches. The model included the genetic factor, genders, number of children and breastfed children, age, residence area, education, seasons to measure, height, smoking status, hormone replacement therapy, serum albumin, hip circumferences, vitamin B6 intake, and body weight. The prediction models for women alone were similar to those for both genders, with lower accuracy. When the prediction model was applied to the HEXA study, the correlation between the fracture incidence and predicted osteoporosis risk was significant but weak (r = 0.173, P < 0.001). CONCLUSION: The prediction model for osteoporosis risk generated by XGBoost can be applied to estimate osteoporosis risk. The biomarkers can be considered for enhancing the prevention, detection, and early therapy of osteoporosis risk in Asians.

Fecal Microbiota Composition, Their Interactions, and Metagenome Function in US Adults with Type 2 Diabetes According to Enterotypes.

T2DM etiology differs among Asians and Caucasians and may be associated with gut microbiota influenced by different diet patterns. However, the association between fecal bacterial composition, enterotypes, and T2DM susceptibility remained controversial. We investigated the fecal bacterial composition, co-abundance network, and metagenome function in US adults with T2DM compared to healthy adults based on enterotypes. We analyzed 1911 fecal bacterial files of 1039 T2DM and 872 healthy US adults from the Human Microbiome Projects. Operational taxonomic units were obtained after filtering and cleaning the files using Qiime2 tools. Machine learning and network analysis identified primary bacteria and their interactions influencing T2DM incidence, clustered into enterotypes, Bacteroidaceae (ET-B), Lachnospiraceae (ET-L), and Prevotellaceae (ET-P). ET-B showed higher T2DM incidence. Alpha-diversity was significantly lower in T2DM in ET-L and ET-P (p < 0.0001), but not in ET-B. Beta-diversity revealed a distinct separation between T2DM and healthy groups across all enterotypes (p < 0.0001). The XGBoost model exhibited high accuracy and sensitivity. Enterocloster bolteae, Facalicatena fissicatena, Clostridium symbiosum, and Facalibacterium prausnitizii were more abundant in the T2DM group than in the healthy group. Bacteroides koreensis, Oscillibacter ruminantium, Bacteroides uniformis, and Blautia wexlerae were lower in the T2DM than in the healthy group regardless of the enterotypes in the XGBoost model (p < 0.0001). However, the patterns of microbial interactions varied among different enterotypes affecting T2DM risk. The interaction between fecal bacteria was more tightly regulated in the ET-L than in the ET-B and ET-P groups (p < 0.001). Metagenomic analysis revealed an inverse association between bacteria abundance in T2DM, energy utility, butanoate and propanoate metabolism, and the insulin signaling pathway (p < 0.0001). In conclusion, fecal bacteria play a role in T2DM pathogenesis, particularly within different enterotypes, providing valuable insights into the link between gut microbiota and T2DM in the US population.

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.

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.

Association between IL-10 rs3024505 and susceptibility to inflammatory bowel disease: A systematic review and meta-analysis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the small intestine, colon, and rectum. We evaluated associations between the interleukin 10 (IL-10) rs3024505 polymorphism and IBD, ulcerative colitis (UC), and Crohn's disease (CD) by meta-analysis. All peer-reviewed manuscripts concerning the relationship between IL-10_rs3024505 and IBD identified by searing the PubMed, Cochrane Library, EMBASE, and Chinese Medical Database were examined. The association between IL-10_rs3024505 and IBD was evaluated in allele (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Associations were also conducted on IBD subtypes, CD and UC, and ethnicity (Non-Europeans and Europeans) subgroups. The meta-analysis included 13 studies, 8552 cases (IBD patients), and 12,830 healthy controls. Subgroup analysis of IBD (UC and CD) revealed heterogeneity in AG, DG, and HTG but no heterogeneity in RG or HMG. Moreover, AG, DG, and HTG did not show publication bias in IBD, CD, or UC, but RG and HMG exhibited publication bias. No heterogeneity and no publication bias were found among the five genetic models by a subgroup analysis of Non-Europeans and European ethnicities. The minor allele(T) of rs3024505 was significantly related to IBD: 1.37 (1.30-1.45) for AG, 2.06 (1.74-2.45) for RG, 1.39 (1.27-1.52) for DG, 2.25 (1.89-2.67) for HMG, and 1.32 (1.23-1.40) for HTG (all P < 0.00001). In the subgroup analysis of ethnicity, there was a significant effect of rs3024505 on IBD in Europeans but not non-Europeans: 1.38 (1.31-1.46) for AG, 2.07 (1.73-2.48) for RG, 1.39 (1.31-1.49) for DG, 2.26 (1.89-2.71) for HMG, and 1.33 (1.24-1.42) for HTG in Europeans (all P < 0.00001). Sensitivity analysis showed no dominant study in Europeans, but one study had a dominant impact in Non-Europeans. In conclusion, IL-10_rs3024505 polymorphism confers susceptibility to CD and UC in Europeans, but its impact should have conducted more studies in Non-Europeans.

Coffee Intake Interacted with the Bcl-2 rs1944420, rs7236090, and rs2849382 Haplotype to Influence Breast Cancer Risk in Middle-Aged Women.

We hypothesized that the haplotype of Bcl-2 genetic variants increases breast cancer risk and interacts with lifestyles in Korean women. We identified single nucleotide polymorphism (SNPs) of Bcl-2 associated with breast cancer risk after adjusting for covariates in 390 breast cancer patients and 36,726 women without any cancer that participated in the Korean Genomic Epidemiology Study (KoGES). An allelic genetic model showed that three SNPs (rs1944420, rs7236090, and rs2849382) in the Bcl-2 gene were significantly associated with breast cancer (ORs = 1.28, 0.84, and 0.79, respectively). The participants with the minor allele of the haplotype with three SNPs had 1.65-fold higher breast cancer risk than those with the major allele, after adjusting for covariates. Serum C-reactive protein concentration had a positive association with breast cancer risk. A significant interaction was also observed between the minor allele of the Bcl-2 haplotype and coffee intake (P = 0.03). A low coffee intake in women with the minor allele presented a higher breast cancer risk than a low coffee intake in those with the major allele. In conclusion, the risk of breast cancer risk was higher in post-menopausal women with the minor allele of the Bcl-2 haplotype, and consuming more than 1 cup of coffee per day reduced the risk. The results of this study could be applied to reduce the risk of breast cancer.

Intermittent fasting with a high-protein diet mitigated osteoarthritis symptoms by increasing lean body mass and reducing inflammation in osteoarthritic rats with Alzheimer's disease-like dementia.

Menopausal women are susceptible to osteoarthritis(OA) and memory impairment. We hypothesised that Alzheimer's-like disease(AD) exacerbates OA and that intermittent fasting(IMF) with a high-protein(H-P) diet would enhance memory function and relieve OA symptoms in oestrogen-deficient animals induced AD and OA. The action mechanism was also explored. Ovariectomised Sprague-Dawley rats were fed high-fat(H-F) or H-P diets for 2 weeks, and then they had a hippocampal infusion of ß-amyloid(25-35) for 4 weeks to induce AD and an injection of monoidoacetate(MIA) into the articular cartilage to induce OA. Non-AD groups had non-AD symptoms by hippocampal amyloid-ß(35-25) infusion. IMF suppressed memory impairment in AD rats, especially those fed H-P diets. Compared with non-AD, AD exacerbated OA symptoms, including swelling, limping, slowed treadmill running speed, and uneven weight distribution in the left leg. The exacerbations were linked to increased inflammation and pain, but IMF and H-P lessened the exacerbation. Lean body mass(LBM) decreased with AD, but H-P protected against LBM loss. Histological examination of the knee joint revealed the degree of the cellular invasion into the middle zone, and the changes in the tidemark plateau were greatest in the AD-AL with H-F, while non-AD-IMF improved the cellular invasion to as much as non-AD-AL. H-P reduced the infiltration into the middle zone of the knee and promoted collagen production. In conclusion, AD exacerbated the articular cartilage deterioration and memory impairment, and IMF with H-P alleviated the memory impairment and osteoarthritic symptoms by decreasing hippocampal amyloid-ß deposition and proinflammatory cytokine expressions and by increasing LBM.

Isolation and identification of mucin-degrading bacteria originated from human faeces and their potential probiotic efficacy according to host-microbiome enterotype.

AIM: Mucin-degrading bacteria are known to be beneficial for gut health. We aimed to isolate human-derived mucin-degrading bacteria and identify potential probiotic characteristics and their effects on the bacterial community and short-chain fatty acid (SCFA) production according to three different enterotypes of the host. METHODS AND RESULTS: Bacteria with mucin decomposition ability from human faeces were isolated and identified by 16S rRNA sequencing and MALDI-TOF. Heat resistance, acid resistance, antibiotic resistance, and antibacterial activity were analysed in the selected bacteria. Their adhesion capability to the Caco-2 cell was determined by scanning electron microscopy. Their ability to alter the bacterial community and SCFA production of the isolated bacteria was investigated in three enterotypes. The three isolated strains were Bifidobacterium(Bif.) animalis SPM01 (CP001606.1, 99%), Bif. longum SPM02 (NR_043437.1, 99%), and Limosilactobacillus(L.) reuteri SPM03 (CP000705.1, 99%) deposited in Korean Collection for Type Culture (KCTC-18958P). Among them, Bif. animalis exhibited the highest mucin degrading ability. They exhibited strong resistance to acidic conditions, moderate resistance to heat, and the ability to adhere tightly to Caco-2 cells. Three isolated mucin-degrading bacteria incubation increased Lactobacillus in the faecal bacteria from Bacteroides and Prevotella enterotypes. However, only L. reuteri elevated Lactobacillus in the faecal bacteria from the Ruminococcus enterotype. B. longum and B. animalis increased the α-diversity in the Ruminococcus enterotype, while their incubation with other intestinal types decreased the α-diversity. Bifidobacterium animalis and L. reuteri increased the butyric acid level in faecal bacteria from the Prevotella enterotype, and L. reuteri elevated the acetic acid level in those from the Ruminococcus enterotype. However, the overall SCFA changes were minimal. CONCLUSIONS: The isolated mucin-degrading bacteria act as probiotics and modulate gut microbiota and SCFA production differently according to the host's enterotypes. SIGNIFICANCE AND IMPACT OF STUDY: Probiotics need to be personalized according to the enterotypes in clinical application.

Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells.

Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP, as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE.