Adaptive Perturbation for Adversarial Attack.

In recent years, the security of deep learning models achieves more and more attentions with the rapid development of neural networks, which are vulnerable to adversarial examples. Almost all existing gradient-based attack methods use the sign function in the generation to meet the requirement of perturbation budget on L∞ norm. However, we find that the sign function may be improper for generating adversarial examples since it modifies the exact gradient direction. Instead of using the sign function, we propose to directly utilize the exact gradient direction with a scaling factor for generating adversarial perturbations, which improves the attack success rates of adversarial examples even with fewer perturbations. At the same time, we also theoretically prove that this method can achieve better black-box transferability. Moreover, considering that the best scaling factor varies across different images, we propose an adaptive scaling factor generator to seek an appropriate scaling factor for each image, which avoids the computational cost for manually searching the scaling factor. Our method can be integrated with almost all existing gradient-based attack methods to further improve their attack success rates. Extensive experiments on the CIFAR10 and ImageNet datasets show that our method exhibits higher transferability and outperforms the state-of-the-art methods.

LINC MIR503HG Controls SC-ß Cell Differentiation and Insulin Production by Targeting CDH1 and HES1.

Stem cell-derived pancreatic progenitors (SC-PPs), as an unlimited source of SC-derived ß (SC-ß) cells, offers a robust tool for diabetes treatment in stem cell-based transplantation, disease modeling, and drug screening. Whereas, PDX1+/NKX6.1+ PPs enhances the subsequent endocrine lineage specification and gives rise to glucose-responsive SC-ß cells in vivo and in vitro. To identify the regulators that promote induction efficiency and cellular function maturation, single-cell RNA-sequencing is performed to decipher the transcriptional landscape during PPs differentiation. The comprehensive evaluation of functionality demonstrated that manipulating LINC MIR503HG using CRISPR in PP cell fate decision can improve insulin synthesis and secretion in mature SC-ß cells, without effects on liver lineage specification. Importantly, transplantation of MIR503HG-/- SC-ß cells in recipients significantly restored blood glucose homeostasis, accompanied by serum C-peptide release and an increase in body weight. Mechanistically, by releasing CtBP1 occupying the CDH1 and HES1 promoters, the decrease in MIR503HG expression levels provided an excellent extracellular niche and appropriate Notch signaling activation for PPs following differentiation. Furthermore, this exhibited higher crucial transcription factors and mature epithelial markers in CDH1High expressed clusters. Altogether, these findings highlighted MIR503HG as an essential and exclusive PP cell fate specification regulator with promising therapeutic potential for patients with diabetes.

Identification of changes in bile composition in pancreaticobiliary reflux based on liquid chromatography/mass spectrometry metabolomics.

INTRODUCTION: Pancreaticobiliary reflux (PBR) can induce gallstone formation; however, its pathogenic mechanism remains unclear. In this study, we explored the mechanism of PBR by the non-targeted metabolomic analysis of bile in patients with PBR. OBJECTIVE: The aim of this study was to investigate the pathogenic mechanism in PBR by the non-targeted metabolomic analysis of bile collected during surgery. METHODS: Sixty patients who underwent gallstone surgery at our center from December 2020 to May 2021 were enrolled in the study. According to the level of bile amylase, 30 patients with increased bile amylase ( > 110 U/L) were classified into the PBR group, and the remaining 30 patients were classified into the control group (≤ 110 U/L). The metabolomic analysis of bile was performed. RESULTS: The orthogonal projections to latent structure-discriminant analysis of liquid chromatography mass spectrometry showed significant differences in bile components between the PBR and control groups, and 40 metabolites were screened by variable importance for the projection value (VIP > 1). The levels of phosphatidylcholine (PC) and PC (20:3(8Z,11Z,14Z)/14:0) decreased significantly, whereas the levels of lysoPC (16:1(9z)/0:0), lysoPC (15:0), lysoPC (16:0), palmitic acid, arachidonic acid, leucine, methionine, L-tyrosine, and phenylalanine increased. CONCLUSIONS: Significant differences in bile metabolites were observed between the PBR and control groups. Changes in amino acids and lipid metabolites may be related to stone formation and mucosal inflammation.

Silencing hsa_circ_0032449 inhibits the pancreatic differentiation of human embryonic stem cells via the hsa_miR-195-5p/CCND1/PI3K/AKT signaling pathway.

Stem cell-derived ß cells (SC-ß cells) differentiated from stem cell-derived pancreatic progenitor (PP) cells are promising tools for enabling normal glucose control of islet transplants and have therapeutic potential for type 1 diabetes treatment. Pancreatic specification is essential for SC-ß cell induction in vitro and low-quality PP cells may convert into derivatives of non-pancreatic lineages both in vivo and in vitro, impeding PP-derived ß cell safety and differentiation efficiency. Circular RNA (circRNA) commonly determines the fate of stem cells by acting as competing endogenous RNA (ceRNA). Currently, the relationships between endogenous circRNA and pancreatic specification remain elusive. Herein, we used whole transcriptome sequencing analysis and functional experiments to reveal that deficiency of hsa_circ_0032449 resulted in posterior foregut-derived PP cells with a weakened the progenitor state with decreased expression of PDX1, NKX6.1 and CCND1. As differentiation processed into maturation, silencing of hsa_circ_0032449 suppressed PP cell development into functionally mature and glucose-responsive SC-ß cells. These SC-ß cells exhibited lower serum C-peptide levels compared with those of control groups in nude mice and had difficulties in reversing hyperglycemia in STZ-induced diabetic nude mice. Mechanistically, loss of hsa_circ_0032449 participated in PI3K-AKT signaling transduction by acting as a ceRNA to sponge miR-195-5p and by influencing the expression of the downstream target CCND1 at transcription and translation levels. Overall, our findings identified hsa_circ_0032449 as an essential PP cell-fate specification regulator, indicating a promising potential in clinical applications and basic research.

PPARα Senses Bisphenol S to Trigger EP300-Mediated Autophagy Blockage and Hepatic Steatosis.

The internal exposure dose of bisphenol S (BPS) is increasing since its use as a substitute for BPA. The relationship between BPS and nonalcoholic liver disease (NAFLD) and the underlying mechanism remain unclarified. In this study, we evaluated the correlation of BPS with NAFLD in populations from the Jiangsu Survey and the 2013-2016 National Health Nutrition Examination Survey and unraveled the molecular pathway by which BPS blocked hepatic autophagy, contributing to lipid accumulation. The study found that serum and urine BPS were associated with NAFLD risks in both the Chinese and US populations. For each additional unit of the BPS level, the NAFLD risk increased by 3.163-fold (serum) and 3.979-fold (urine) in the Chinese population. In addition, after BPS exposure at a dose equivalent to human exposure for 20 weeks, mice developed liver lipid accumulation. BPS could trigger PPARα-mediated transcriptional activation of EP300 expression. BPS promoted the translocation of EP300 from the nucleus to the cytoplasm to regulate the acetylation of Raptor and the activation of mTORC1, which in turn induced autophagy blockage and interfered with lipid degradation in hepatocytes. Conversely, knockdown of EP300 reduced Raptor acetylation and ameliorated autophagy blockage. This study demonstrated that EP300 was a key enzyme for the development of BPS-related NAFLD and provided novel evidence that BPS causes NAFLD.

Dietary diosgenin transcriptionally down-regulated intestinal NPC1L1 expression to prevent cholesterol gallstone formation in mice.

BACKGROUND: Cholesterol gallstone disease is a common disease. Reducing cholesterol burden is important to prevent/treat gallstone. In this study, we investigated the application of diosgenin (DG) to prevent the formation of gallstone in mice. METHODS: Adult male C57BL/6J mice were fed with the lithogenic diet (LD) only or LD supplemented with DG or ezetimibe for 8 weeks. Incidences of gallstone formation were documented. Intestine and liver tissues were collected to measure the lipid contents and expression of genes in cholesterol metabolism. Caco2 cells were treated with DG to monitor the regulation on cholesterol absorption and the transcriptional regulation of Npc1l1 gene. Changes of gut microbiota by DG was analyzed. Intraperitoneal injection of LPS on mice was performed to verify its effects on STAT3 activation and Npc1l1 expression in the small intestine. RESULTS: LD led to 100% formation of gallstones in mice. In comparison, dietary DG or ezetimibe supplementary completely prevents gallstones formation. DG inhibited intestinal cholesterol absorption in mice as well as in Caco2 cells by down-regulation of Npc1l1 expression. DG could directly inhibit phosphorylation of STAT3 and its transcriptional regulation of Npc1l1 expression. Furthermore, DG could modulate gut microbiota profiles and LPS mediated STAT3 activation and Npc1l1 expression. CONCLUSION: Our results demonstrated that dietary DG could inhibit intestinal cholesterol absorption through decreasing NPC1L1 expression to prevent cholesterol gallstone formation.

Insulin-like growth factor-2 mRNA-binding protein 3 promotes cell migration, invasion, and epithelial-mesenchymal transition of esophageal squamous cell carcinoma cells by targeting zinc finger E-box-binding homeobox 1 mRNA.

The role and mechanism of insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) in the metastasis of esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, IGF2BP3 mRNA and protein expression levels were evaluated in ESCC tissues. Small interfering RNAs (siRNAs), plasmid overexpression, and stable lentivirus transfection were used to manipulate intracellular IGF2BP3 expression levels. The role of IGF2BP3 in ESCC tumorigenesis was investigated in vitro and in vivo. IGF2BP3 target transcripts were detected, and the acetylation effect ratios of the IGF2BP3 promoter region by H3K27ac were determined. IGF2BP3 mRNA expression levels were significantly higher in ESCC tissues than in normal esophageal tissues. Increased IGF2BP3 expression levels were detected in node-negative ESCC tissues and correlated with greater lesion depth in ESCC. Overexpression of IGF2BP3 promoted ESCC development in vitro and in vivo, and IGF2BP3 knockdown caused an opposite effect. IGF2BP3 was found to directly bind to the zinc finger E-box-binding homeobox 1 (Zeb1) mRNA, and the downregulation of IGF2BP3 reduced the stability of Zeb1 mRNA. IGF2BP3 induced epithelial-mesenchymal transition in ESCC cells in a Zeb1-dependent manner. IGF2BP3 was transcriptionally activated in ESCC cell lines via H3K27 acetylation. Our results demonstrate that IGF2BP3 plays a vital role in ESCC cell proliferation, invasion, and metastasis and is a potential therapeutic target for treating ESCC.

An artificial LAMA2-GelMA hydrogel microenvironment for the development of pancreatic endocrine progenitors.

The biomimetic pancreatic microenvironment improves the differentiation efficiency and function of human embryonic stem cell-derived ß-cells (SC-ß cells). Thus, a laminin subunit alpha 2-gelatin methacrylate (LAMA2-GelMA) hybrid hydrogel as a bionics carrier for the formation and maturation of endocrine lineage was developed in our research, based on pancreas proteomics analysis of postnatal mice. Pancreatic endocrine cells cultured on the hybrid hydrogel in vitro, which was composed of 0.5 µg/mL LAMA2 protein and 4% GelMA, the expression of transcription factors (TFs), including NKX6.1, NKX6.2, and NEUROD1 were upregulated. Single-cell transcriptomics was performed after LAMA2 knockdown during the early differentiation of pancreatic progenitor (PP) cells, a marked decrease in the forkhead box protein A2 (FOXA2+)/GATA-binding factor 6 (GATA6+) cluster was detected. Also, we clarified that as a receptor of LAMA2, integrin subunit alpha 7 (ITGA7) participated in Integrin-AKT signaling transduction and influenced the protein levels of FOXA2 and PDX1. In vivo experiments showed that, PP cells encapsulated in the LAMA2-GelMA hydrogel exhibited higher serum C-peptide levels compared to the GelMA and Matrigel groups in nude mice and reversed hyperglycemia more quickly in STZ-induced diabetic nude mice. Taken together, our findings highlighted the feasibility of constructing a pancreas-specific microenvironment based on proteomics and tissue engineering for the treatment of diabetes.

Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion.

Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.

Risk Factors for Early Recurrence of Gallstones in Patients Undergoing Laparoscopy Combined With Choledochoscopic Lithotomy: A Single-Center Prospective Study.

Objective: For patients with gallstones, laparoscopy combined with choledochoscopic lithotomy is a therapeutic surgical option for preservation rather than the removal of the gallbladder. However, postoperative recurrence of gallstones is a key concern for both patients and surgeons. This prospective study was performed to investigate the risk factors for early postoperative recurrence of gallstones. Methods: The clinical data of 466 patients were collected. Each patient was followed up for up to 2 years. The first follow-up visit occurred 4 months after the operation, and a follow-up visit was carried out every 6 months thereafter. The main goal of each visit was to confirm the presence or absence of gallbladder stones. The factors associated with gallstone recurrence were analyzed by univariate analysis and Cox regression. Results: In total, 466 eligible patients were included in the study, and 438 patients (180 men and 258 women) completed the 2-year postoperative follow-up. The follow-up rate was 94.0%. Recurrence of gallstones was detected in 5.71% (25/438) of the patients. Univariate analysis revealed five risk factors for the recurrence of gallstones. Multivariate Cox regression analysis showed that multiple gallstones, a gallbladder wall thickness of ≥4 mm, and a family history of gallbladder stones were the three predictive factors for postoperative recurrence of gallstones (P < 0.05). Conclusion: The overall 2-year recurrence rate of gallstones after the operation was 5.71%. Multiple gallstones, a gallbladder wall thickness of ≥4 mm, and a family history of gallstones were the three risk factors associated with early postoperative recurrence of gallstones.

Circadian Rhythm Disruption Influenced Hepatic Lipid Metabolism, Gut Microbiota and Promoted Cholesterol Gallstone Formation in Mice.

Background: Hepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation. Methods: Adult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed. Results: TRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice. Conclusion: Disordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.

Dietary plant sterols prevented cholesterol gallstone formation in mice.

Cholesterol gallstone disease is a common global condition. This study investigated the role of plant sterols (PS) in the prevention of gallstone formation and the underlying mechanisms. Adult male mice were fed a lithogenic diet (LD) alone or supplemented with PS (LD-ps), phospholipids (LD-pl) or both PS and phospholipids (LD-ps/pl) for 8 weeks. Incidences of gallstone formation were compared among the groups. Lipids in the bile, liver and serum were analyzed. The expression of genes involved in cholesterol absorption, transport and metabolism in the liver and small intestine was determined. The incidences of gallstone formation were 100% (10/10), 20% (2/10), 100% (10/10) and 40% (4/10) in the LD, LD-ps, LD-pl and LD-ps/pl groups, respectively. Serum cholesterol and intestinal cholesterol absorption were decreased in PS-supplemented mice. The expression of genes related to cholesterol transport and metabolism in the liver was down-regulated by dietary PS. PS supplementation decreased Niemann-Pick C1-like 1 expression in the small intestine and reduced intestinal cholesterol absorption. Our results demonstrated that PS could inhibit intestinal cholesterol absorption and thus prevent cholesterol gallstone formation.

Single Cell RNA-Sequencing Reveals a Murine Gallbladder Cell Transcriptome Atlas During the Process of Cholesterol Gallstone Formation.

Gallstone disease is a worldwide common disease. However, the knowledge concerning the gallbladder in the pathogenesis of cholesterol gallstone formation remains limited. In this study, using single-cell RNA sequencing (scRNA-seq) to obtain the transcriptome of gallbladder cells, we showed cellular heterogeneity and transcriptomic dynamics in murine gallbladder cells during the process of lithogenesis. Our results indicated gallbladder walls were subjected to remodeling during the process of lithogenesis. The major molecular events that happened included proliferation of epithelial cells, infiltration of immune-cells, activation of angiogenesis, and extracellular matrix modulation. Furthermore, we observed partial reversal of gallbladder cell transcriptomes by ursodeoxycholic acid treatment. This work thus provides novel and integral knowledges on the cellular changes during lithogenesis, which is of great significance to the understanding of pathogenesis and treatment of cholesterol gallstone.

Maternal smoking during pregnancy is risk factor for gallbladder disease in offspring during adulthood: a prospective study from UK Biobank.

INTRODUCTION AND OBJECTIVES: Gallbladder disease is a common disease with high prevalence. Majority of gallbladder disease is due to gallstone. Though genetics are believed to play a role in its pathogenesis, the contribution of environmental pressures in early life to the development of this disease in adulthood has not been ever investigated. This study aimed to clarify the risk of maternal smoking exposure in association with gallbladder disease in adulthood. The interaction of maternal smoking and own smoking during adulthood on this association was studied as well. PATIENTS AND METHODS: A total of 286,731 eligible participants from the UK Biobank population-based cohort were included. Multivariable Cox regression analysis were used to examine the HR and 95% CI with adjustment for covariates. RESULT: During a median of 8.8 years follow-up, 7110 incident cases of gallbladder disease including 6800 (95.6%) gallstone were identified. Maternal smoking was associated with increased risk of incident total gallbladder disease (HR = 1.13; 95%CI: 1.06 - 1.21; P = 0.0002) as well as gallstones (HR = 1.13; 95%CI: 1.06 -1.21; P = 0.0003) in adulthood. Compared with those who were neither exposed to maternal smoking nor own smoking, subjects adherence to no smoking during adulthood but having maternal smoking exposure still had increased risk of total gallbladder disease (HR = 1.21; 95%CI: 1.1-1.34, P=0.0001) and gallstones (HR = 1.21; 95%CI: 1.1-1.35, P=0.0001). CONCLUSION: The present study using large prospective cohort data from UK Biobank, for the first time, demonstrated maternal smoking exposure bringing elevated risk of incident total gallbladder disease/gallstone in adulthood.

Comparison of a new gasless method and the conventional CO2 pneumoperitoneum method in laparoendoscopic single-site cholecystectomy: a prospective randomized clinical trial.

To avoid CO2 pneumoperitoneum-associated cardiopulmonary side-effects during conventional laparoscopic surgeries, we have developed a gasless laparoscopic operation field formation (LOFF) device for laparoendoscopic single-site surgery. The aim of this study is to analyze the safety and efficacy of the LOFF device for laparoendoscopic single-site cholecystectomy and to verify its advantage of avoiding CO2 pneumoperitoneum-associated complications. In this prospective, randomized, observer-blinded clinical trial, eligible participants were randomized in a 1:1 ratio to undergo either conventional CO2 pneumoperitoneum assisted laparoendoscopic single-site cholecystectomy (LESS) or the new gasless LOFF device assisted laparoendoscopic single-site cholecystectomy (LOFF-LESS). Outcomes including intra-operative respiratory and hemodynamic parameters, operation time, conversion rate, complication rate, et al were compared between the two groups. A total of 100 patients were randomized to the LESS group [n = 50; mean (SD) age, 49.5 (13.9) years; 24 (48.0%) women] and the LOFF-LESS group [n = 50, mean (SD) age, 47.4 (13.3) years; 27 (54.0%) women]. Compared with the LOFF-LESS group, the LESS group witnessed significant fluctuations in intra-operative respiratory and hemodynamic parameters. The tracheal extubation time of the LESS group was significantly longer (P = 0.001). The gasless LOFF device is safe and feasible for simple laparoscopic cholecystectomy and has a predominance of avoiding CO2 pneumoperitoneum-associated cardiopulmonary side-effects. Trial registration number: ChiCTR2000033702.

Dysbiosis of gut microbiota after cholecystectomy is associated with non-alcoholic fatty liver disease in mice.

Increasing evidence suggests that cholecystectomy is an independent risk factor for non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms that lead to hepatic lipid deposition after cholecystectomy are unclear. In this study, adult male C57BL/6J mice that underwent a cholecystectomy or sham operation were fed either a high-fat diet (HFD) or a chow diet for 56 days. Significantly increased steatohepatitis, liver/body weight ratio, hepatic triglycerides, and glucose intolerance were observed in postcholecystectomy mice fed the HFD. Notable alterations in the composition of gut microbiota after cholecystectomy were observed in both HFD- and chow-diet-fed mice. Our results indicate that cholecystectomy alters the gut microbiota profile, which might contribute to the development of NAFLD in mice.

Urinary biomarkers of polycyclic aromatic hydrocarbons and their associations with liver function in adolescents.

Associations between polycyclic aromatic hydrocarbons (PAHs) and respiratory diseases have been widely studied, but the effects of PAH on liver toxicity in adolescents are unclear. Here, 3194 adolescents with NHANES data from 2003 to 2016 were selected. PAH exposure was assessed by measuring PAH metabolites in urine. The outcome variables were the levels of alanine aminotransferase (ALT), aspartate amino transferase (AST) and gamma-glutamyl transpeptidase (GGT). The association between PAH exposure and liver function was evaluated by the weighted quantile sum (WQS) and logistic regression, and the associations between PAHs and inflammation and blood lipids were evaluated by linear regression. Covariates were adjusted for age, ethnicity, BMI, physical activity, family income, cotinine, and urinary creatinine. The results showed that for females, mixed PAH exposure was related to an increased ALT level (OR = 2.33, 95% CI 1.15, 4.72), and 2-fluorene contributed the most (38.6%). Urinary 2-fluorene was positively associated with an elevated ALT level (OR = 2.19 95% 1.12, 4.27, p for trend = 0.004). Mechanistically, 2-fluorene can cause a 3.56% increase in the white blood cell count, a 6.99% increase in the triglyceride level, and 1.70% increase in the total cholesterol level. PAHs may have toxic effects, possibly mediated by inflammation and blood lipids, on the adolescent female liver. Additional confirmatory studies are needed.

Association of urinary caffeine and caffeine metabolites with cardiovascular disease risk in adults.

OBJECTIVES: Studies have shown that the consumption of a moderate amount of caffeine is associated with a reduced risk of cardiovascular disease (CVD) and may even be protective against CVD. The purpose of the current study was to evaluate the association between urinary caffeine and its related metabolites and CVD risk in a national representative sample of US adults. METHODS: We analyzed cross-sectional data from the US National Health and Nutrition Examination Survey from 2009 and 2010. The associations between the levels of urinary caffeine metabolites and self-reported CVD, including congestive heart failure, coronary heart disease, angina, heart attack, and stroke, were examined separately in men and women using multivariate logistic regression models adjusted for covariates. RESULTS: In total, 1916 participants (910 men and 1006 women) were included in the analysis. Among women, the odds ratios of CVD in the highest quartiles of 1,3-dimethylxanthine and 1,3,7-trimethylxanthine were 0.33 (95% confidence interval [CI], 0.12-0.92) and 0.35 (95% CI, 0.13-0.93), respectively, compared with the lowest quartiles. Each one-unit (µmol/L) increase in theophylline concentration was associated with a 0.24-mg/dL increase in high-density lipoprotein cholesterol in the fully adjusted model. Among men, no significant association was observed between urinary caffeine metabolites and CVD. Regarding the subtypes of CVD, compared with women in the lowest quartile for 1,3-dimethylxanthine and 1,3,7-trimethylxanthine, the odds of coronary heart disease decreased by 90% (95% CI, -99% to -11%) and 97% (95% CI, -99% to -47%), respectively, in those in the highest quartile. CONCLUSIONS: Urinary 1,3-dimethylxanthine and 1,3,7-trimethylxanthine were significantly and inversely associated with CVDs in women. Additional studies are needed to further confirm the results of this study and explore the underlying mechanisms..

The effect of Tauroursodeoxycholic acid (TUDCA) and gut microbiota on murine gallbladder stone formation.

INTRODUCTION AND OBJECTIVES: The incidence of gallstone-related disease steadily increased in the last few years. Here, we aimed to investigate the effect of tauroursodeoxycholic acid1 (TUDCA) on preventing cholesterol gallstones formation in high-fat fed (HFD) mice. MATERIAL AND METHODS: Specific pathogen-free male C57Bl/6 mice were fed a lithogenic diet2 (LD group) alone or in combination with TUDCA (5g/kg diet) for 8 weeks. Upon sacrifice, serum, gallbladder, liver and small intestine were collected and the formation of gallstones or crystals in the gallbladder was analyzed. Additionally, the intestinal microbiota, and bile acid composition, serum lipids and hepatic lipids were studied. RESULTS: Cholesterol gallstones with cholesterol crystals formed in mice of the LD-fed group (15/15, 100%). However, only cholesterol crystals were found in three mice without the presence of any gallstone in the TUDCA-treated group. Both serum and hepatic total cholesterol levels in the TUDCA group were significantly decreased compared with the LD group. Concomitantly, mRNA expression of Abcg5 and Abcg8 was significantly lower in the liver of the TUDCA group whilst mRNA transcripts for Abcb11, Acat2, and Cyp27 were significantly increased compared with the LD group. Additionally, the gallbladder cholesterol saturation index (1.06±0.15) in the TUDCA group was significantly decreased compared with the LD group. Interestingly, the ratio of Firmicutes/Bacteroides in the TUDCA group was increased 3x fold. CONCLUSIONS: TUDCA can inhibit the absorption and synthesis of lipids in the small intestine by improving the intestinal microbiota in HFD-fed mice, thus reducing gallstone formation.

Early-life perfluorooctanoic acid exposure induces obesity in male offspring and the intervention role of chlorogenic acid.

Perfluorooctanoic acid (PFOA) is an emerging organic pollutant (EOP) hazardous to human health. Effects of maternal PFOA exposure on offspring as well as the underlying mechanisms remain unclear. In this study, ICR mouse models of gestational low PFOA exposure (0.05 mg/kg/day) were established to investigate the roles on metabolic disorders of offspring. Body weight, body composition, hepatic lipid levels, transcriptome and metabolome were analyzed. Expression of genes related to lipid metabolism, inflammasome formation and gut barrier integrity were measured. Furthermore, oral administration of chlorogenic acid (CGA) (100 mg/kg/day) was performed to observe the rescue effect on lipid disorders caused by PFOA exposure. Our findings demonstrated that gestational exposure to PFOA resulted in obesity, hepatic inflammation, disorders of lipid metabolism, and disruption of gut barrier integrity in male offspring. Notably, these adverse effects were attenuated by CGA supplementation. These data suggested that PFOA exposure during early life stage induced potential risks for later onset of obesity and metabolic disorder which could be ameliorated by CGA treatment.