The First Domesticated 'Cheongju Sorori Rice' Excavated in Korea.

Archaeological excavations led by Yung-jo Lee and Jong-yoon Woo were carried out twice at the Sorori paleolithic site, Cheongju, in the Republic of Korea, at the upper stream of the Geumgang river, the Miho riverside. A total of 127 rice seeds were excavated, including 18 ancient rice and 109 Quasi-rice, in 1998 and 2001. At the first excavation, eleven short japonica-type ancient rice and one slender smooth ancient rice with two kinds of Quasi-rice were excavated. The average length of the 11 short rice grains obtained from the first and second excavation was 7.19 mm and the average width was 3.08 mm, respectively. The Quasi-rice are apparently different from the rice and do not have bi-peak protuberances on their glume surface. At the second excavation, six short ancient rice chaffs and some Quasi-rice 2 were found. These short-grained ancient rice were comparable to the ancient rice that were excavated at the Illsan Neolithic site. Geologists and radiologists confirmed that the peat layer in which the rice found was older than 15,000 years. In this study, the morphological characteristics, crushing, and DNA band patterns related to the genetic polymorphism of rice grains in Cheongju Sorori were compared and analyzed for genetic similarities and differences with wild rice, weed rice, and modern rice. The morphological, ecological, and physiological variations in rice grains excavated from the Sorori site were presumed to denote the origin of rice domestication in Korea. It is also suggested that the results of the DNA sequencing of excavated rice are very important clues in estimating the origin of the early domestication of rice.

Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its prevalence has increased worldwide in recent years. Additionally, there is a close relationship between MASLD and gut microbiota-derived metabolites. However, the mechanisms of MASLD and its metabolites are still unclear. We demonstrated decreased indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA) in the feces of patients with hepatic steatosis compared to healthy controls. Here, IPA and IAA administration ameliorated hepatic steatosis and inflammation in an animal model of WD-induced MASLD by suppressing the NF-κB signaling pathway through a reduction in endotoxin levels and inactivation of macrophages. Bifidobacterium bifidum metabolizes tryptophan to produce IAA, and B. bifidum effectively prevents hepatic steatosis and inflammation through the production of IAA. Our study demonstrates that IPA and IAA derived from the gut microbiota have novel preventive or therapeutic potential for MASLD treatment.

Systemic multiomics evaluation of the therapeutic effect of Bacteroides species on liver cirrhosis in male mice.

IMPORTANCE: The human gut microbiome mediates bidirectional interaction within the gut-liver axis, while liver diseases, including liver cirrhosis, are very closely related to the state of the gut environment. Thus, improving the health of the gut-liver axis by targeting the intestinal microbiota is a potential therapeutic approach in hepatic diseases. This study examines changes in metabolomics and microbiome composition by treating bacteria derived from the human gut in mice with liver cirrhosis. Interorgan-based multiomics profiling coupled with functional examination demonstrated that the treatment of Bacteroides dorei pertained to protective effects on liver cirrhosis by normalizing the functional, metabolic, and metagenomic environment through the gut-liver axis. The study provides the potential value of a multiomics-based and interorgan-targeted evaluation platform for the comprehensive examination and mechanistic understanding of a wide range of biologics, including gut microbes. Furthermore, the current finding also suggests in-depth future research focusing on the discovery and validation of next-generation probiotics and products (postbiotics).

Bifidobacterium-derived short-chain fatty acids and indole compounds attenuate nonalcoholic fatty liver disease by modulating gut-liver axis.

Emerging evidences about gut-microbial modulation have been accumulated in the treatment of nonalcoholic fatty liver disease (NAFLD). We evaluated the effect of Bifidobacterium breve and Bifidobacterium longum on the NAFLD pathology and explore the molecular mechanisms based on multi-omics approaches. Human stool analysis [healthy subjects (n = 25) and NAFLD patients (n = 32)] was performed to select NAFLD-associated microbiota. Six-week-old male C57BL/6 J mice were fed a normal chow diet (NC), Western diet (WD), and WD with B. breve (BB) or B. longum (BL; 109 CFU/g) for 8 weeks. Liver/body weight ratio, histopathology, serum/tool analysis, 16S rRNA-sequencing, and metabolites were examined and compared. The BB and BL groups showed improved liver histology and function based on liver/body ratios (WD 7.07 ± 0.75, BB 5.27 ± 0.47, and BL 4.86 ± 0.57) and NAFLD activity scores (WD 5.00 ± 0.10, BB 1.89 ± 1.45, and BL 1.90 ± 0.99; p < 0.05). Strain treatment showed ameliorative effects on gut barrier function. Metagenomic analysis showed treatment-specific changes in taxonomic composition. The community was mainly characterized by the significantly higher composition of the Bacteroidetes phylum among the NC and probiotic-feeding groups. Similarly, the gut metabolome was modulated by probiotics treatment. In particular, short-chain fatty acids and tryptophan metabolites were reverted to normal levels by probiotics, whereas bile acids were partially normalized to those of the NC group. The analysis of gene expression related to lipid and glucose metabolism as well as the immune response indicated the coordinative regulation of ß-oxidation, lipogenesis, and systemic inflammation by probiotic treatment. BB and BL attenuate NAFLD by improving microbiome-associated factors of the gut-liver axis.

The effect of nicorandil on cardiac function and clinical outcomes in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: a randomised trial.

BACKGROUND: We investigated the effect of nicorandil on infarct size, cardiac function assessed by cardiac magnetic resonance imaging (CMR) and outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). METHODS: In a prospective, randomised, controlled trial, 83 patients with STEMI receiving primary PCI were randomised into the nicorandil (n =  40) or placebo (n  =  43) groups. Nicorandil was administered in the emergency room before primary PCI as an intravenous bolus of 4 mg followed by a continuous infusion of 6 mg/h for 24 h and as 2-mg intracoronary injections prior to balloon dilatation and coronary stenting. Nicorandil was continued orally at 10-20 mg/d for 6 months. Infarct size and cardiac function were measured by CMR at 5 d and 6 months after primary PCI. Furthermore, major adverse cardiac events (MACEs) including all-cause death, nonfatal myocardial infarction (MI), any revascularisation, stroke, and definite/probable stent thrombosis (ST) were compared. RESULTS: There were no significant differences in baseline clinical characteristics between the groups. Infarct size at baseline and 6 months as well as infarct size changes during 6 months as measured by CMR were similar between the groups. Similarly, other CMR parameters were comparable at baseline and 6 months between the groups. MACEs occurred in four patients (4.8%) during 6 months. No significant difference in the risk of MACEs was observed between the groups. CONCLUSIONS: Treatment with nicorandil for 6 months after primary PCI was not associated with any improvement in infarct size, CMR-determined cardiac function, and outcomes in STEMI patients.

De Novo Sphingolipid Biosynthesis in Atherosclerosis.

Atherosclerosis is the formation of fibrofatty lesions in the arterial wall, and this inflammatory state of the artery is the main cause of advanced pathological processes, including myocardial infarction and stroke. Dyslipidemic conditions with excess cholesterol accumulate within the arterial vessel wall and initiate atherogenic processes. Following vascular reaction and lipid accumulation, the vascular wall gradually thickens. Together with the occurrence of local inflammation, early atherosclerotic lesions lead to advanced pathophysiological events, plaque rupture, and thrombosis. Ceramide and sphingomyelin have emerged as major risk factors for atherosclerosis and coronary artery disease. Currently, the clinical association between de novo sphingolipid biosynthesis and coronary artery disease has been established. Furthermore, therapeutic strategies to modulate this pathway, especially those involving serine palmitoyltransferase and sphingomyelin synthase, against atherosclerosis, cancer, type 2 diabetes, and non-alcoholic fatty liver disease are actively under development. In this chapter, we focus on the relationship between de novo sphingolipid biosynthesis and coronary artery disease.

Upregulation of the serine palmitoyltransferase subunit SPTLC2 by endoplasmic reticulum stress inhibits the hepatic insulin response.

Endoplasmic reticulum (ER) stress is induced by various conditions, such as inflammation and the presence of excess nutrients. Abnormal accumulation of unfolded proteins leads to the activation of a collective signaling cascade, termed the unfolded protein response (UPR). ER stress is reported to perturb hepatic insulin response metabolism while promoting insulin resistance. Here, we report that ER stress regulates the de novo biosynthesis of sphingolipids via the activation of serine palmitoyltransferase (SPT), a rate-limiting enzyme involved in the de novo biosynthesis of ceramides. We found that the expression levels of Sptlc1 and Sptlc2, the major SPT subunits, were upregulated and that the cellular concentrations of ceramide and dihydroceramide were elevated by acute ER stress inducers in primary hepatocytes and HepG2 cells. Sptlc2 was upregulated and ceramide levels were elevated by tunicamycin in the livers of C57BL/6J wild-type mice. Analysis of the Sptlc2 promoter demonstrated that the transcriptional activation of Sptlc2 was mediated by the spliced form of X-box binding protein 1 (sXBP1). Liver-specific Sptlc2 transgenic mice exhibited increased ceramide levels in the liver and elevated fasting glucose levels. The insulin response was reduced by the inhibition of the phosphorylation of insulin receptor ß (IRß). Collectively, these results demonstrate that ER stress induces activation of the de novo biosynthesis of ceramide and contributes to the progression of hepatic insulin resistance via the reduced phosphorylation of IRß in hepatocytes.

Comprehensive Transcriptomic Analysis of Cordyceps militaris Cultivated on Germinated Soybeans.

The ascomycete fungus Cordyceps militaris infects lepidopteran larvae and pupae and forms characteristic fruiting bodies. Owing to its immune-enhancing effects, the fungus has been used as a medicine. For industrial application, this fungus can be grown on geminated soybeans as an alternative protein source. In our study, we performed a comprehensive transcriptomic analysis to identify core gene sets during C. militaris cultivation on germinated soybeans. RNA-Seq technology was applied to the fungal cultures at seven-time points (2, 4, and 7-day and 2, 3, 5, 7-week old cultures) to investigate the global transcriptomic change. We conducted a time-series analysis using a two-step regression strategy and chose 1460 significant genes and assigned them into five clusters. Characterization of each cluster based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases revealed that transcription profiles changed after two weeks of incubation. Gene mapping of cordycepin biosynthesis and isoflavone modification pathways also confirmed that gene expression in the early stage of GSC cultivation is important for these metabolic pathways. Our transcriptomic analysis and selected genes provided a comprehensive molecular basis for the cultivation of C. militaris on germinated soybeans.

Lactobacillus lactis and Pediococcus pentosaceus-driven reprogramming of gut microbiome and metabolome ameliorates the progression of non-alcoholic fatty liver disease.

BACKGROUND: Although microbioa-based therapies have shown putative effects on the treatment of non-alcoholic fatty liver disease (NAFLD), it is not clear how microbiota-derived metabolites contribute to the prevention of NAFLD. We explored the metabolomic signature of Lactobacillus lactis and Pediococcus pentosaceus in NAFLD mice and its association in NAFLD patients. METHODS: We used Western diet-induced NAFLD mice, and L. lactis and P. pentosaceus were administered to animals in the drinking water at a concentration of 109 CFU/g for 8 weeks. NAFLD severity was determined based on liver/body weight, pathology and biochemistry markers. Caecal samples were collected for the metagenomics by 16S rRNA sequencing. Metabolite profiles were obtained from caecum, liver and serum. Human stool samples (healthy control [n = 22] and NAFLD patients [n = 23]) were collected to investigate clinical reproducibility for microbiota-derived metabolites signature and metabolomics biomarker. RESULTS: L. lactis and P. pentosaceus supplementation effectively normalized weight ratio, NAFLD activity score, biochemical markers, cytokines and gut-tight junction. While faecal microbiota varied according to the different treatments, key metabolic features including short chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites were analogously restored by both probiotic supplementations. The protective effects of indole compounds were validated with in vitro and in vivo models, including anti-inflammatory effects. The metabolomic signatures were replicated in NAFLD patients, accompanied by the comparable levels of Firmicutes/Bacteroidetes ratio, which was significantly higher (4.3) compared with control (0.6). Besides, the consequent biomarker panel with six stool metabolites (indole, BAs, and SCFAs) showed 0.922 (area under the curve) in the diagnosis of NAFLD. CONCLUSIONS: NAFLD progression was robustly associated with metabolic dys-regulations in the SCFAs, bile acid and indole compounds, and NAFLD can be accurately diagnosed using the metabolites. L. lactis and P. pentosaceus ameliorate NAFLD progression by modulating gut metagenomic and metabolic environment, particularly tryptophan pathway, of the gut-liver axis.

Annona muricata leaf extract attenuates hepatic lipogenesis and adipogenesis.

Annona muricata (graviola) is a medicinal plant that can be used to alleviate chronic human diseases by providing antioxidants and inducing immunomodulation. In this study, we found that treatment of AML12 hepatocytes with steam (SGE) and ethanol (EGE) extracts of graviola leaf downregulated the expression of fatty acid (FA) oxidation genes, including ACOX1, CPT1, and PPARα, with no change in the expression of FA synthesis genes. However, whereas EGE inhibited the differentiation and lipid accumulation of 3T3-L1 adipocytes and downregulated FA synthesis genes, no similar changes were observed in response to treatment with SGE. In an in vivo experiment using mice fed a high-fat diet (HFD), body weight was reduced in response to treatment with EGE, which also dose-dependently alleviated liver hepatocyte ballooning induced by the consumption of a HFD. However, genes involved in FA oxidation and the secretion of very low density lipoprotein (VLDL) were downregulated. We also found that the size of adipocytes was reduced in response to EGE treatment, and that there was a downregulated expression of genes involved in adipogenesis and FA synthesis. Furthermore, we detected increases in the levels of cholesterol in the plasma, whereas ALT activity was reduced. Collectively, these results indicates that EGE inhibits lipid influx into the liver and adipogenesis in adipose tissues. These bioactive properties of EGE indicate its potential as a natural ingredient that can be used to prevent obesity.

Bioactive Sphingolipids as Major Regulators of Coronary Artery Disease.

Atherosclerosis is the deposition of plaque in the main arteries. It is an inflammatory condition involving the accumulation of macrophages and various lipids (low-density lipoprotein [LDL] cholesterol, ceramide, S1P). Moreover, endothelial cells, macrophages, leukocytes, and smooth muscle cells are the major players in the atherogenic process. Sphingolipids are now emerging as important regulators in various pathophysiological processes, including the atherogenic process. Various sphingolipids exist, such as the ceramides, ceramide-1-phosphate, sphingosine, sphinganine, sphingosine-1-phosphate (S1P), sphingomyelin, and hundreds of glycosphingolipids. Among these, ceramides, glycosphingolipids, and S1P play important roles in the atherogenic processes. The atherosclerotic plaque consists of higher amounts of ceramide, glycosphingolipids, and sphingomyelin. The inhibition of the de novo ceramide biosynthesis reduces the development of atherosclerosis. S1P regulates atherogenesis via binding to the S1P receptor (S1PR). Among the five S1PRs (S1PR1-5), S1PR1 and S1PR3 mainly exert anti-atherosclerotic properties. This review mainly focuses on the effects of ceramide and S1P via the S1PR in the development of atherosclerosis. Moreover, it discusses the recent findings and potential therapeutic implications in atherosclerosis.

Probiotics ameliorate chronic low-grade inflammation and fat accumulation with gut microbiota composition change in diet-induced obese mice models.

Recent reports suggest that obesity is caused by dysbiosis of gut microbiota and that it could be prevented or treated through improvement in the composition and diversity of gut microbiota. In this study, high-fat diet (HFD)-induced obese mice were orally administered with Lactobacillus plantarum K50 (K50) isolated from kimchi and Lactobacillus rhamnosus GG (LGG) as a positive control for 12 weeks. Body weight and weights of epididymal, mesenteric, and subcutaneous adipose tissues and the liver were significantly reduced in K50-treated HFD-fed mice compared with HFD-fed mice. The serum triglyceride level was decreased and high-density lipoprotein cholesterol level was increased in K50-treated HFD-fed mice. The gut microbiota analysis showed that the L. plantarum K50 treatment reduced the Firmicutes/Bacteroidetes ratio and improved the gut microbiota composition. In addition, the level of total short-chain fatty acids (SCFAs) in K50-treated HFD-fed mice was higher than that in HFD-fed mice. A remarkable reduction in the fat content of adipose tissue and liver was also observed in K50-treated HFD-fed mice, accompanied by improvements in gene expression related to lipid metabolism, adipogenesis, and SCFA receptors. K50-treated mice had downregulated expression levels of genes and proteins such as TNFα and IL-1ß. Our findings confirm that L. plantarum K50 could be a good candidate for ameliorating fat accumulation and low-grade inflammation in metabolic tissues through gut microbiota improvement.

KEY POINTS: • Lactobacillus plantarum and L. rhamnosus GG were fed to HFD-induced obese mice.• L. plantarum K50 had dramatic ameliorating effects on obesity and related diseases.• These effects may be associated with the restoration of gut microbiota dysbiosis.

Clinical outcomes of endovascular treatment for ruptured thoracic aortic disease.

BACKGROUND/AIMS: Untreated rupture of the thoracic aorta is associated with a high mortality rate. We aimed to review the clinical results of endovascular treatment for ruptured thoracic aortic disease. METHODS: We retrospectively reviewed data on 37 patients (mean age, 67.0 ± 15.18 years) treated for ruptured thoracic aortic disease from January 2005 to May 2016. The median follow-up duration was 308 days (interquartile range, 61 to 1,036.5). The primary end-point of the study was the composite of death, secondary intervention, endoleak, and major stroke/paraplegia after endovascular treatment. RESULTS: The etiologies of ruptured thoracic aortic disease were aortic dissection (n = 11, 29.7%), intramural hematoma (n = 7, 18.9%), thoracic aortic aneurysm (n = 14, 37.8%), and traumatic aortic transection (n = 5, 13.5%). Three patients died within 24 hours of thoracic endovascular aortic repair, and one showed type I endoleak. The technical success rate was 89.2% (33/37). The in-hospital mortality rate was 13.5% (5/37); no deaths occurred during follow-up. The composite outcome rate during follow-up was 37.8% (14/37), comprising death (n = 5, 13.5%), secondary intervention (n = 5, 13.5%), endoleak (n = 5, 13.5%), and major stroke/paraplegia (n = 3, 8.1%). Left subclavian artery revascularization and proximal landing zone were not associated with the composite outcome. Low mean arterial pressure (MAP; ≤ 60 mmHg, [hazard ratio, 13.018; 95% confidence interval, 2.435 to 69.583, p = 0.003]) was the most significant predictor and high transfusion requirement in the first 24 hours was associated with event-free survival (log rank p = 0.018). CONCLUSION: Endovascular treatment achieves high technical success rates and acceptable clinical outcome. High transfusion volume and low MAP were associated with poor clinical outcomes.

Lactobacillus attenuates progression of nonalcoholic fatty liver disease by lowering cholesterol and steatosis.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is closely related to gut-microbiome. There is a paucity of research on which strains of gut microbiota affect the progression of NAFLD. This study explored the NAFLD-associated microbiome in humans and the role of Lactobacillus in the progression of NAFLD in mice. METHODS: The gut microbiome was analyzed via next-generation sequencing in healthy people (n=37) and NAFLD patients with elevated liver enzymes (n=57). Six-week-old male C57BL/6J mice were separated into six groups (n=10 per group; normal, Western, and four Western diet + strains [109 colony-forming units/g for 8 weeks; L. acidophilus, L. fermentum, L. paracasei, and L. plantarum]). Liver/body weight ratio, liver pathology, serum analysis, and metagenomics in the mice were examined. RESULTS: Compared to healthy subjects (1.6±4.3), NAFLD patients showed an elevated Firmicutes/Bacteroidetes ratio (25.0±29.0) and a reduced composition of Akkermansia and L. murinus (P<0.05). In the animal experiment, L. acidophilus group was associated with a significant reduction in liver/body weight ratio (5.5±0.4) compared to the Western group (6.2±0.6) (P<0.05). L. acidophilus (41.0±8.6), L. fermentum (44.3±12.6), and L. plantarum (39.0±7.6) groups showed decreased cholesterol levels compared to the Western group (85.7±8.6) (P<0.05). In comparison of steatosis, L. acidophilus (1.9±0.6), L. plantarum (2.4±0.7), and L. paracasei (2.0±0.9) groups showed significant improvement of steatosis compared to the Western group (2.6±0.5) (P<0.05). CONCLUSION: Ingestion of Lactobacillus, such as L. acidophilus, L. fermentum, and L. plantarum, ameliorates the progression of nonalcoholic steatosis by lowering cholesterol. The use of Lactobacillus can be considered as a useful strategy for the treatment of NAFLD.

Lactobacillus lactis CKDB001 ameliorate progression of nonalcoholic fatty liver disease through of gut microbiome: addendum.

According to our recent study (N.Y. LEE et al. Gut Microbes 2020; 11:882-99.)1, we reported that Lactobacillus and Pediococcus ameliorate progression of nonalcoholic fatty liver disease through modulation of the gut microbiome. According on the analysis method (Previous: 16s rRNA sequencing and Recent: whole gene sequencing), the probiotics named Lactobacillus bulgaricus that we used in the experiment was identified as Lactobacillus delbrueckii subsp. bulgaricus through 16s rRNA sequencing analysis. Recently, we performed a clearer analysis with whole gene sequencing to proceed with the clinical trial, it was identified as Lactobacillus delbrueckii subsp. lactis by whole gene sequencing. Therefore, we inform that the subspecies have been changed to lactis through WGS. Read L. bulgaricus in the previous paper as L. lactis. In this addendum, the results of the change to L. lactis are summarized, and descriptions have been added to Materials & methods and Discussion.

Histopathologic response after hydrophilic polyethylene glycol-coating stent and hydrophobic octadecylthiol-coating stent implantations in porcine coronary restenosis model.

Device-related problems of drug-eluting stents, including stent thrombosis related to antiproliferative drugs and polymers, can cause adverse events such as inflammation and neointimal hyperplasia. Stent surface modification, wherein the drug and polymer are not required, may overcome these problems. We developed hydrophilic polyethylene glycol (PEG)-coating and hydrophobic octadecylthiol (ODT)-coating stents without a drug and polymer and evaluated their histopathologic response in a porcine coronary restenosis model. PEG-coating stents (n = 12), bare-metal stents (BMS) (n = 12), and ODT-coating stents (n = 10) were implanted with oversizing in 34 porcine coronary arteries. Four weeks later, the histopathologic response, arterial injury, inflammation, and fibrin scores were analyzed. A p value < 0.05 was considered statistically significant. There were significant differences in the internal elastic lamina area, lumen area, neointimal area, percent area of stenosis, arterial injury score, inflammation score, and fibrin score among the groups. Compared to the BMS or ODT-coating stent group, the PEG-coating stent group had significantly increased internal elastic lamina and lumen area (all p < 0.001) and decreased neointimal area and percent area of stenosis (BMS: p = 0.03 and p < 0.001, respectively; ODT-coating: p = 0.013 and p < 0.001, respectively). Similarly, the PEG-coating group showed significantly lower inflammation and fibrin scores than the BMS or ODT-coating groups (BMS: p = 0.013 and p = 0.007, respectively; ODT-coating: p = 0.014 and p = 0.008, respectively). In conclusion, hydrophilic PEG-coating stent implantation was associated with lower inflammatory response, decreased fibrin deposition, and reduced neointimal hyperplasia than BMS or hydrophobic ODT-coating stent implantation in the porcine coronary restenosis model.

Circulating lipidomic alterations in obese and non-obese subjects with non-alcoholic fatty liver disease.

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 < 0.001) but not in obese NAFLD. Additionally, SM levels were significantly associated with systemic and adipose tissue insulin resistance (SM d38:0; P = 0.002 and <0.001, respectively). Five potential lipid metabolites for non-obese subjects and seven potential lipids for obese subjects were selected to predict NAFLD and NASH. These lipid combinations showed good diagnostic performance for non-obese (area under the curve [AUC] for NAFLD/NASH = 0.916/0.813) and obese (AUC for NAFLD/NASH = 0.967/0.812) subjects. Moreover, distinctly altered patterns of diacylglycerol (DAG), triacylglycerol (TAG) and SM levels were confirmed in the validation set depending on the histological severity of NAFLD. CONCLUSION: Non-obese and obese NAFLD subjects exhibit unique circulating lipidomic signatures, including DAGs, TAGs and SMs. These lipid combinations may be useful biomarkers for non-obese and obese NAFLD patients.

Near-infrared-emitting nanoparticles activate collagen synthesis via TGFß signaling.

Research efforts towards developing near-infrared (NIR) therapeutics to activate the proliferation of human keratinocytes and collagen synthesis in the skin microenvironment have been minimal, and the subject has not been fully explored. Herein, we describe the novel synthesis Ag2S nanoparticles (NPs) by using a sonochemical method and reveal the effects of NIR irradiation on the enhancement of the production of collagen through NIR-emitting Ag2S NPs. We also synthesized Li-doped Ag2S NPs that exhibited significantly increased emission intensity because of their enhanced absorption ability in the UV-NIR region. Both Ag2S and Li-doped Ag2S NPs activated the proliferation of HaCaT (human keratinocyte) and HDF (human dermal fibroblast) cells with no effect on cell morphology. While Ag2S NPs upregulated TIMP1 by only twofold in HaCaT cells and TGF-ß1 by only fourfold in HDF cells, Li-doped Ag2S NPs upregulated TGF-ß1 by tenfold, TIMP1 by 26-fold, and COL1A1 by 18-fold in HaCaT cells and upregulated TGF-ß1 by fivefold and COL1A1 by fourfold in HDF cells. Furthermore, Ag2S NPs activated TGF-ß1 signaling by increasing the phosphorylation of Smad2 and Smad3. The degree of activation was notably higher in cells treated with Li-doped Ag2S NPs, mainly caused by the higher PL intensity from Li-doped Ag2S NPs. Ag2S NPs NIR activates cell proliferation and collagen synthesis in skin keratinocytes and HDF cells, which can be applied to clinical light therapy and the development of anti-wrinkle agents for cosmetics.

Hepatic Expression of the Serine Palmitoyltransferase Subunit Sptlc2 Reduces Lipid Droplets in the Liver by Activating VLDL Secretion.

OBJECTIVE: Ceramide is a signaling molecule that contributes to insulin resistance and hepatosteatosis. In the present study, we activated de novo ceramide synthesis by inducing the hepatic expression of Sptlc2 to investigate the role of ceramide in glucose and lipid metabolism. METHODS: We first constructed an adenovirus containing Sptlc2 (AdSptlc2), which encodes a major catalytic subunit of serine palmitoyltransferase (SPT). We then infected hepatocytes and mice fed a regular diet with AdSptlc2 to activate de novo ceramide biosynthesis. The liver-specific effects of ceramide biosynthesis on glucose and lipid metabolism were investigated by measuring changes in insulin signaling, lipid droplet formation, and very low-density lipoprotein (VLDL) secretion. RESULTS: In HepG2 hepatocytes, adenoviral Sptlc2 expression inhibited insulin signaling and increased ceramide levels via activation of c-Jun N-terminal kinase and serine phosphorylation of insulin receptor substrate 1. In contrast, in mice, AdSptlc2 infection decreased plasma glucose levels by downregulating gluconeogenic genes and increased plasma triglyceride levels by increasing VLDL secretion. In mice infected with AdSptlc2, glucose intolerance and insulin sensitivity improved, while pyruvate utilization via gluconeogenesis decreased. CONCLUSION: Hepatic ceramide was found to modulate hepatosteatosis and the insulin response via increased VLDL secretion and inhibition of gluconeogenesis in vivo. Although inhibition of the insulin response was observed in vitro, the compensatory mechanism of relieving ceramide-induced stress and reducing ceramide levels resulted in improvements of glucose and lipid metabolic profiles in vivo. This discrepancy between in vitro and in vivo regulation mechanisms suggests that ceramide plays a role in non-alcoholic fatty liver disease and insulin resistance.

Ceramide and Sphingosine 1-Phosphate in Liver Diseases.

The liver is an important organ in the regulation of glucose and lipid metabolism. It is responsible for systemic energy homeostasis. When energy need exceeds the storage capacity in the liver, fatty acids are shunted into nonoxidative sphingolipid biosynthesis, which increases the level of cellular ceramides. Accumulation of ceramides alters substrate utilization from glucose to lipids, activates triglyceride storage, and results in the development of both insulin resistance and hepatosteatosis, increasing the likelihood of major metabolic diseases. Another sphingolipid metabolite, sphingosine 1-phosphate (S1P) is a bioactive signaling molecule that acts via S1P-specific G protein coupled receptors. It regulates many cellular and physiological events. Since an increase in plasma S1P is associated with obesity, it seems reasonable that recent studies have provided evidence that S1P is linked to lipid pathophysiology, including hepatosteatosis and fibrosis. Herein, we review recent findings on ceramides and S1P in obesity-mediated liver diseases and the therapeutic potential of these sphingolipid metabolites.