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Recent investigations have revealed that the human microbiome plays an essential role in the occurrence of type 2 diabetes (T2D). However, despite the importance of understanding the involvement of the microbiota throughout the body in T2D, most studies have focused specifically on the intestinal microbiota. Extracellular vesicles (EVs) have been recently found to provide important evidence regarding the mechanisms of T2D pathogenesis, as they act as key messengers between intestinal microorganisms and the host. Herein, we explored microorganisms potentially associated with T2D by tracking changes in microbiota-derived EVs from patient urine samples collected three times over four years. Mendelian randomization analysis was conducted to evaluate the causal relationships among microbial organisms, metabolites, and clinical measurements to provide a comprehensive view of how microbiota can influence T2D. We also analyzed EV-derived metagenomic (N = 393), clinical (N = 5032), genomic (N = 8842), and metabolite (N = 574) data from a prospective longitudinal Korean community-based cohort. Our data revealed that GU174097_g, an unclassified Lachnospiraceae, was associated with T2D (β = −189.13; p = 0.00006), and it was associated with the ketone bodies acetoacetate and 3-hydroxybutyrate (r = −0.0938 and −0.0829, respectively; p = 0.0022 and 0.0069, respectively). Furthermore, a causal relationship was identified between acetoacetate and HbA1c levels (β = 0.0002; p = 0.0154). GU174097_g reduced ketone body levels, thus decreasing HbA1c levels and the risk of T2D. Taken together, our findings indicate that GU174097_g may lower the risk of T2D by reducing ketone body levels.

Background and aims Bile acid (BA) dysregulation is related to not only metabolic diseases but also nonalcoholic fatty liver disease (NAFLD). We investigated whether circulating BA levels are altered according to the histological severity of NAFLD independent of metabolic derangements. Methods Global metabolic profiling and targeted BA analysis using sera collected from biopsy-proven no-NAFLD (n = 67), nonalcoholic fatty liver (NAFL) (n = 99), and nonalcoholic steatohepatitis (NASH, n = 75) subjects were performed sequentially. Circulating metabolome analysis integrated with the hepatic transcriptome was performed to elucidate the mechanistic basis of altered circulating BA profiles after stratification by obesity (body mass index ≤ 25 kg/m2 ). Circulating BA alterations were also validated in an independent validation cohort (29 no-NAFLD, 70 NAFL and 37 NASH). Results Global profiling analysis showed that BA was the metabolite significantly altered in NASH compared to NAFL. Targeted BA analysis demonstrated that glyco-/tauro-conjugated primary BAs were commonly increased in nonobese and obese NASH, while unconjugated primary BAs increased only in nonobese NASH. These characteristic primary BA level changes were maintained even after stratification according to diabetes status and were replicated in the independent validation cohort. Compared to nonobese NAFL patients, nonobese NASH patients exhibited upregulated hepatic expression of CYP8B1. Conclusions BA metabolism is dysregulated as the histological severity of NAFLD worsens, independent of obesity and diabetes status; dysregulation is more prominent in nonobese NAFLD patients. Metabolome-driven omics approach provides new insight into our understanding of altered BA metabolism associated with individual phenotypes of NAFLD.

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Yellow yeast rice (YYR) is a Korean functional food fermented with

To explore how bariatric surgery (BS) modified the obesity-associated gut microbiome, the host metabolome, and their interactions in obese Korean patients.Stool and fasting blood samples were obtained before and 1, 3, 6, and 12 months after BS from 52 patients enrolled in the Korean Obesity Surgical Treatment Study. We analysed the gut microbiome by 16S rRNA gene sequencing and the serum metabolome, including bile acids, by nuclear magnetic resonance spectroscopy and ultrahigh-performance liquid chromatography/triple quadrupole mass spectrometry.Stool metagenomics showed that 27 microbiota were enriched and 14 microbiota were reduced after BS, whereas the abundances and diversity of observed features were increased. The levels of branched-chain amino acids and metabolites of energy metabolism in serum were decreased after surgery, whereas the levels of metabolites related to microbial metabolism, including dimethyl sulphone, glycine, and secondary bile acids, were increased in the serum samples. In addition, we found notable mutual associations among metabolites and gut microbiome changes attributed to BS.Changes in the gut microbiome community and systemic levels of amino acids and sugars were directly derived from anatomical changes in the gastrointestinal tract after BS. We hypothesized that the observed increases in microbiome-related serum metabolites were a result of complex and indirect changes derived from BS. Ethnic-specific environmental or genetic factors could affect Korean-specific postmetabolic modification in obese patients who undergo BS.

Persistent organic pollutants (POPs) are lipophilic environmental toxins, and the level of chemicals accumulated in the body through the food chain has been linked to the incidence of diseases such as type 2 diabetes, cardiovascular disease, and cancer. We analyzed the concentration of POPs and circulating metabolites and investigated the associations between the concentration of plasma metabolites and the levels of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) to determine the effect of the accumulation of POPs in human samples. Metabolic profiling of plasma from 276 Korean participants was performed using

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) affects obese and non-obese individuals. However, mechanisms underlying non-obese non-alcoholic steatohepatitis (NASH) remain unclear. AIMS To attempt to identify metabolic perturbations associated with non-obese and obese NAFLD using a lipidomics approach. METHODS A cross-sectional analysis of 361 subjects with biopsy-proven NAFLD (157 NAFL and 138 NASH) and healthy controls (n = 66) was performed. Individuals were categorised as obese or non-obese based on the Asian cut-off for body mass index. Circulating lipidomic profiling of sera was performed based on the histological severity of NAFLD. Circulating lipidomic alterations were validated with an independent validation set (154 NAFLD subjects [93 NAFL and 61 NASH] and 21 healthy controls). RESULTS Saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in non-obese NAFLD (SM d38:0; P

Metabolomics is a powerful tool for the investigation of interactions between diet, nutrients, and human metabolism. Ecklonia cava is an edible brown alga that is abundantly found in Korea and Japan and contains unique polyphenols referred to as phlorotannins. However, there are few metabolomics studies related to the effects of polyphenols in humans. In this study, we performed a mass spectrometry-based metabolomics analysis of urine samples from participants with a body mass index (BMI) higher than 25 kg/m2 and lower than 30 kg/m2 to investigate the effects of the intake of seapolynol isolated from E. cava. Metabolomic profiling showed that the levels of riboflavin, urocanic acid, 5-hydroxy-6-methoxyindole glucuronide, and guanidino valeric acid were significantly increased in the seapolynol intake group compared with the placebo group. A correlation analysis was performed to identify the association between the metabolites’ levels and clinical characteristics related to body fat. Among the metabolites whose concentrations changed in the seapolynol intake group, riboflavin was associated with BMI, body weight, fat mass, and percent body fat. These findings suggest that the decreased body fat induced by the intake of seapolynol is related to an increase in the antioxidant effect of riboflavin.

In the current study, the metabolic effects of atorvastatin dose escalation versus atorvastatin/fenofibric acid combination were compared using metabolomics analyses. Men and women with combined hyperlipidaemia were initially prescribed atorvastatin (10 mg, ≥4 weeks). Patients who reached low-density lipoprotein-cholesterol targets, but had triglyceride and high-density lipoprotein-cholesterol levels ≥150 mg/dL and l-carnitine remarkably increased in the combination group. In conclusion, the atorvastatin/fenofibric acid combination induced distinct metabolite clustering. Our results provide comprehensive information regarding metabolic changes beyond conventional lipid profiles for this combination therapy.

We have designed and synthesized linear polymer-based nanoconjugates and nanocomplexes bearing multivalent immunostimulatory ligands and also demonstrated that the synthetic multivalent nanocomplexes led to an enhanced stimulation of immune cells in vitro and antitumor and systemic immune memory response in vivo. We have developed hyaluronic acid (HA)-based multivalent nanoconjugates and nanocomplexes for enhanced immunostimulation through the combination of multivalent immune adjuvants with CpG ODNs (as a TLR9 ligand) and cationic poly(L-lysine) (PLL; for the enhancement of cellular uptake). The multivalent HA-CpG nanoconjugate efficiently stimulated the antigen-presenting cells and the multivalent PLL/HA-CpG nanocomplex also led to an enhanced cellular uptake as well as continuous stimulation of endosomal TLR9. The mice vaccinated with dendritic cells treated with the multivalent nanocomplex exhibited tumor growth inhibition as well as a strong antitumor memory response.

Inflammation is a common cause of cardiac arrhythmia. Angiotensin ІІ (Ang ІІ) is a major contributing factor in the pathogenesis of cardiac inflammation; however, its underlying molecular mechanism remains unclear. Here, we explored the effect of Ang ІІ on inflammatory mechanisms and oxidative stress using HL-1 atrial myocytes. We showed that Ang ІІ activated c-Jun N-terminal kinase (JNK) phosphorylation and other inflammatory markers, such as transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α). Ang ІІ decreased oxygen consumption rate, which resulted in reactive oxygen species (ROS) generation and inhibition of ROS blocked Ang II-mediated JNK phosphorylation and TGF-β1 induction. Ang ІІ induced the expression of its specific receptor, AT1R. Ang II-induced intracellular calcium production associated with Ang ІІ-mediated signalling pathways. In addition, the generated ROS and calcium stimulated AMPK phosphorylation. Inhibiting AMPK blocked Ang II-mediated JNK and TGF-β signalling pathways. Ang ІІ concentration, along with TGF-β1 and tumor necrosis factor-α levels, was slightly increased in plasma of patients with atrial fibrillation. Taken together, these results suggest that Ang ІІ induces inflammation mechanisms through an AMPK-related signalling pathway. Our results provide new molecular targets for the development of therapeutics for inflammation-related conditions, such as atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is increasing worldwide. One method used to restore sinus rhythm is direct current cardioversion (DCCV). Despite the high success rate of DCCV, AF typically recurs within the first 2 weeks. However, our understanding of the pathophysiology of AF recurrence, incidence, and progression are highly limited. Lipidomic profiling was applied to identify altered lipids in plasma from patients with AF using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry coupled with multivariate statistical analysis. Partial least-squares discriminant analysis revealed a clear separation between AF patients and healthy controls. The levels of several lipid species, including fatty acids and phospholipids, were different between AF patients and healthy controls, indicating that oxidative stress and inflammation are associated with the pathogenesis of AF. Similar patterns were also detected between recurrent and non-recurrent AF patients. These results suggest that the elevated saturated fatty acid and reduced polyunsaturated fatty acid levels in AF patients may be associated with enhanced inflammation and that free fatty acid levels may play a crucial role in the development and progression of AF.

Myocardial infarction (MI), a leading cause of death worldwide, results from prolonged myocardial ischemia with necrosis of myocytes due to a blood supply obstruction to an area of the heart. Many studies have reported gender-related differences in the clinical features of MI, but the reasons for these differences remain unclear. In this study, we applied ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) and various statistical methods-such as multivariate, pathway, and correlation analyses-to identify gender-specific metabolic patterns in polar metabolites in serum from healthy individuals and patients with MI. Patients with diagnosed MI (n=68), and age- and body mass index-matched healthy individuals (n=68), were included in this study. The partial least-squares discriminant analysis (PLS-DA) model was generated from metabolic profiling data, and the score plots showed a significant gender-related difference in patients with MI. Many pathways were associated with amino acids and purines; amino acids, acylcarnitines, and purines differed significantly between male and female patients with MI. This approach could be utilized to observe gender-specific metabolic pattern differences between healthy controls and patients with MI.

Mass screening for gastric cancer (GC), particularly using endoscopy, may not be the most practical approach as a result of its high cost, lack of acceptance, and poor availability. Thus, novel markers that can be used in cost-effective diagnosis and noninvasive screening for GC are needed.A total of 154 urine samples from GC patients and healthy individuals and 30 pairs of matched tumor and normal stomach tissues were collected. Multivariate analysis was performed on urinary and tissue metabolic profiles acquired using (1)H nuclear magnetic resonance and (1)H high-resolution magic angle spinning spectroscopy, respectively. In addition, metabolic profiling of urine from GC patients after curative surgery was performed.Multivariate statistical analysis showed significant separation in the urinary and tissue data of GC patients and healthy individuals. The metabolites altered in the urine of GC patients were related to amino acid and lipid metabolism, consistent with changes in GC tissue. In the external validation, the presence of GC (early or advanced) from the urine model was predicted with high accuracy, which showed much higher sensitivity than carbohydrate antigen 19-9 and carcinoembryonic antigen. Furthermore, 4-hydroxyphenylacetate, alanine, phenylacetylglycine, mannitol, glycolate, and arginine levels were significantly correlated with cancer T stage and, together with hypoxanthine level, showed a recovery tendency toward healthy controls in the postoperative samples compared to the preoperative samples.An urinary metabolomics approach may be useful for the effective diagnosis of GC.

Kimchi is a well-known traditional Korean food. Its geographical origins can be determined by its biochemical composition. This study identified the biochemical compositions of kimchi extracts from Korea and China by (1)H nuclear magnetic resonance (NMR) spectroscopy followed by multivariate data analysis. Principal component analyses (PCA) clearly discriminated between extracts prepared in the two countries. The identified metabolites, including amino acids, organic acids, sugars, and ethanol, contributed to discriminating the geographical origin of kimchi extracts. Furthermore, differences in composition by origin were predicted with high accuracy in external validation models. These results establish biochemical profiles for kimchi extracts, and indicate that metabolomics can be used in the discrimination of food origins.

The total synthesis and anticancer activity of several novel derivatives based on a dauer effect-inducing glycolipid are presented. A versatile and convergent synthesis was accomplished through stereospecific alpha-glycosylation, which produced di- and tri-rhamnoside daumone derivatives. Most of the synthetic derivatives possessed potent anticancer activity against human cancer cell lines. Daumone and deoxyrhamnose trisaccharides with amide side chains had the most potent anticancer activity among all other known glycolipids, with an effective concentration of 20 nM, which is comparable to that of doxorubicin. Conversely, acyclic and macrocyclic daumone derivatives had drastically decreased anticancer activity. Due to the high lipophilic nature of the novel glycolipid derivatives, we propose that the observed anticancer activity is due to their potential to inhibit cell differentiation and proliferation via interaction with the membranes of cancer cells.