Naturally Derived Luminescent Material in Engineered Silk and Its Application as a Fluorescent Dye with a Large Stokes Shift and Sensing Capability.

Silkworms have provided valuable byproducts (spanning from high-quality textiles to health supplements) to humans for millennia. Despite their importance in sericultural economy and biotechnology, manifold possibilities inherent in the myriad natural or artificially generated silk varieties have been underestimated. In this paper, we report that the Yeonnokjam silk strain, which shows light-green color, contains quercetin fluorochrome (QueF) in sericin, and QueF can be used as a fluorescence dye with a large Stokes shift and high sensitivity to environmental temperature and pH, thus functioning as an environmental sensing material. A Stokes shift exceeding 180 nm, a quantum efficiency of 1.28%, and a rapid fluorescence decay of 0.67 ns are obtained, which are influenced by solvent polarities. Moreover, QueF can be used as a UV blocker as well, and its low cytotoxicity and biocompatibility further suggest promising prospects for diverse application in cosmetics and medical materials in the future.

Regulation of hepatic lipogenesis by asymmetric arginine methylation.

BACKGROUND AND AIMS: Hepatic lipogenesis is elevated in nutrient abundant conditions to convert the excess carbohydrate into triacylglycerol (TAG). Fatty acyl moiety of TAG is eventually transported into adipose tissues by very low density lipoprotein, leading to the accumulation of TAG as a preferred storage form of excess energy. Disruption of the balance between TAG clearance and synthesis leads to the accumulation of lipids in the liver, leading to the progression of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis. Protein arginine methyltransferase (PRMT) 6 has been linked to the various metabolic processes including hepatic gluconeogenesis, muscle atrophy and lipodystrophy in mouse models. However, the role of PRMT6 in the control of hepatic lipogenesis has not been elucidated to date. METHODS: We assessed the interaction between PRMT6 and LXR alpha by using co-immunoprecipitation assay. The specific arginine residue of LXR alpha that is methylated by PRMT6 was assessed by LC-MS/MS assay and the functional consequences of LXR alpha methylation was explored by mSREBP-1c luciferase assay. The effect of PRMT6 on hepatic lipogenesis was assessed by adenovirus-mediated ectopic expression of PRMT6 or knockdown of PRMT6 via shRNA in hepatocytes. Finally, the role of PRMT6 in hepatic lipid metabolism in vivo was explored by either ectopic expression of LXR alpha mutant that is defective in PRMT6-mediated arginine methylation or knockdown of PRMT6 in liver. RESULTS: We found that promoter activity of sterol regulatory element binding protein (SREBP) 1c is robustly activated by PRMT6. Interestingly, we demonstrated that PRMT6 binds to LXR alpha, a transcription factor for SREBP-1c, via its LXXLL motif, leading to the asymmetric dimethylation of an arginine residue and activation of this protein. Indeed, ectopic expression of PRMT6 in hepatocytes led to the enhanced expression of LXR alpha target genes in the lipogenic pathway. Conversely, genetic or pharmacological inhibition of PRMT6 diminished expression of lipogenic genes and the lipid accumulation in primary hepatocytes. Mechanistically, we found that asymmetric dimethylation of LXR alpha led to the dissociation of small heterodimer partner (SHP), a transcriptional co-inhibitor of this factor, resulting in the activation of LXR alpha-mediated transcriptional process. Finally, we showed that disruption of asymmetric dimethylation of LXR alpha in the liver led to the diminished expression of genes in the lipogenesis, resulting in the reduced hepatic lipid accumulation in high fat diet-fed mice in vivo. CONCLUSIONS: We showed that PRMT6 modulates LXR alpha activity by conferring asymmetric dimethylation of arginine 253, thus blocking SHP-mediated inhibition and promoting hepatic lipid accumulation. These results suggest that PRMT6 is critical in the control of lipid homeostasis by regulation of LXR alpha-mediated lipogenesis in the liver.

The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism.

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

Type 2 Diabetes Self-Management Interventions Among Asian Americans in the United States: A Scoping Review.

Introduction: Type 2 diabetes (T2D) is one of the leading causes of death among Asian Americans. Despite being a culturally diverse racial group with differences in history, language, religion, and values, Asian Americans are often viewed as a monolith. With the high prevalence rate of T2D, a careful examination of self-management interventions across Asian Americans is needed to develop effective and culturally sensitive interventions. Objective: To describe existing literature by examining study characteristics, different intervention components, and outcome measures of various T2D interventions among Asian Americans. Methods: Using Arksey and O'Malley's framework to ground this review, six online databases were used to identify studies. Results: A total of 18 publications were included. Thirteen studies were published after 2013, with 44% and 22% of these studies focused on Chinese Americans and Korean Americans. We found a lack of geographic diversity in the location of the studies. Majority of the participants were females. Most of the interventions were implemented in person. Licensed health care providers were the most common interventionists, with a number of studies using community health workers. Outcome measures focused on three key areas: physiological, psychosocial and behavioral, and program-related outcomes. Many of the studies measured changes in HbA1C, self-efficacy, distress, depression, and quality of life. Overall, we saw improvements in physiological measures in most of the studies. For example, majority of the studies showed a decline in the participants' HbA1C. Most studies showed an increase or improvement in healthy behaviors. Studies that measured efficacy, knowledge, attitude, motivation, quality of life, or general health showed improvement from baseline. All the studies that measured distress or depression showed a reduction of symptoms postintervention. Conclusion: Overall, we found that culturally tailored interventions that focus on specific Asian American subpopulations saw an improvement in physiological, psychosocial, or behavioral measures. There were several gaps in the existing T2D self-management programs or interventions among Asian Americans studied in the United States. Based on our analysis, we recommend when designing or implementing self-management interventions among Asian Americans, considerations should be made for targeted recruitment for understudied Asian American subgroups, gender, and location.

NMR-based metabolomic analysis of human plasma to examine the effect of exposure to persistent organic pollutants.

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 1H nuclear magnetic resonance (NMR) and statistical analyses. The concentrations of PCBs and OCPs in each sample were measured. Correlation analysis and a covariate-adjusted general linear model (GLM) were used to investigate the association of the concentration of POPs with circulating metabolites in human blood samples. We found that four categories of Σ6PCBs and Σ5OCPs based on rank were significantly correlated with 4 and 5 metabolites, respectively, after adjusting for confounding factors, including age, sex, body mass index (BMI), smoking status, alcohol intake, physical activity, triglycerides, and total cholesterol. According to the GLM analyses, 3 metabolites, namely, creatinine, acetate, and formate, among the 4 correlated metabolites were associated with four categories of rank-based Σ6PCBs. On the other hand, the quartiles of the rank-based Σ5OCPs were not associated with any circulating metabolites among the 5 correlated metabolites. Our findings indicate that the metabolites related to short-chain fatty acids and creatine can be useful risk indicators for estimating the effect of PCB exposure.

Lipidomic profiling analysis of human plasma from subjects with hypercholesterolemia to evaluate the intake of yellow yeast rice fermented by Aspergillus terreus DSMK01.

Yellow yeast rice (YYR) is a Korean functional food fermented with Aspergillus terreus and contains monacolin K, a cholesterol-lowering ingredient. However, the effects of YYR on lipid metabolism alterations have not been reported until now. In this study, we performed a mass spectrometry-based lipidomic analysis of plasma samples from subjects (31 from the YYR group and 27 from the placebo group) with LDL-C higher than 130 mg dL-1 to investigate the effects of the intake of YYR. Lipidomic profiling showed that the levels of sphingomyelin (SM) were significantly decreased in the YYR intake group compared with the placebo group. The SM level in the YYR intake group showed a significant association with the ApoB/ApoA1 ratio (p = 0.004, r = 0.503), an indicator of the effect of lipid-lowering therapy. This study suggests that global lipidomic profiling could be used to identify changes in lipid metabolism induced by YYR intake and provide information that these lipid changes are associated with improved hypercholesterolemia.

BCAT1 promotes osteoclast maturation by regulating branched-chain amino acid metabolism.

Branched-chain aminotransferase 1 (BCAT1) transfers the amine group on branched-chain amino acids (BCAAs) to alpha-ketoglutarate. This generates glutamate along with alpha-keto acids that are eventually oxidized to provide the cell with energy. BCAT1 thus plays a critical role in sustaining BCAA concentrations and availability as an energy source. Osteoclasts have high metabolic needs during differentiation. When we assessed the levels of amino acids in bone marrow macrophages (BMMs) that were undergoing receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation, we found that the BCAA levels steadily increase during this process. In vitro analyses then showed that all three BCAAs but especially valine were needed for osteoclast maturation. Moreover, selective inhibition of BCAT1 with gabapentin significantly reduced osteoclast maturation. Expression of enzymatically dead BCAT1 also abrogated osteoclast maturation. Importantly, gabapentin inhibited lipopolysaccharide (LPS)-induced bone loss of calvaria in mice. These findings suggest that BCAT1 could serve as a therapeutic target that dampens osteoclast formation.

MAX-Phase Films Overcome Scaling Limitations to the Resistivity of Metal Thin Films.

Metal thin films have been widely used as conductors in semiconductor devices for several decades. However, the resistivity of metal thin films such as Cu and TiN increases substantially (>1000%) as they become thinner (<10 nm) when using high-density integration to improve device performance. In this study, the resistivities of MAX-phase V2AlC films grown on sapphire substrates exhibited a significantly weaker dependence on the film thickness than conventional metal films that resulted in a resistivity increase of only 30%, as the V2AlC film thickness decreased from approximately 45 to 5 nm. The resistivity was almost identical for film thicknesses of 10-50 nm. The small change in the resistivity of V2AlC films with decreasing film thickness originated from the highly ordered crystalline quality and a small electron mean free path (11-13.6 nm). Thus, MAX-phase thin films have great potential for advanced metal technology applications to overcome the current scaling limitations of semiconductor devices.

Association between circulating bile acid alterations and nonalcoholic steatohepatitis independent of obesity and diabetes mellitus.

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.

Comparable Plasma Lipid Changes in Patients with High-Grade Cervical Intraepithelial Neoplasia and Patients with Cervical Cancer.

Cervical cancer is the fourth most prevalent cancer among women worldwide and usually develops from cervical intraepithelial neoplasia (CIN). In the present study, we compared alterations in lipids associated with high-grade CIN and cervical cancer with those associated with a normal status and low-grade CIN by performing global lipid profiling on plasma (66 healthy controls and 55 patients with CIN1, 44 with CIN2/3, and 60 with cervical cancer) using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry. We identified 246 lipids and found 31 lipids with similar alterations in both high-grade CIN and cervical cancer. Among these 31 lipids, four lipid classes (phosphatidylcholine, phosphatidylethanolamine, diglyceride, and free fatty acids) were identified as the major lipid classes with significant differences in the patients with CIN2/3 and cervical cancer compared to the healthy controls and the patients with CIN1. Lipid metabolites belonging to the same classes were positively correlated with each other. High-grade CIN and cervical cancer induce comparable changes in lipid levels, which are closely related to the development of cervical tumors. These results suggest that lipid profiling is a useful method for monitoring progression to cervical cancer.

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer.

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.

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.

Metabolic changes in urine and serum during progression of diabetic kidney disease in a mouse model.

Diabetic kidney disease (DKD) involves various pathogenic processes during progression to end stage renal disease, and activated metabolic pathways might be changing based on major pathophysiologic mechanisms as DKD progresses. In this study, nuclear magnetic resonance spectroscopy (NMR)-based metabolic profiling was performed in db/db mice to suggest potential biomarkers for early detection and its progression. We compared concentrations of serum and urinary metabolites between db/m and db/db mice at 8 or 20 weeks of age and investigated whether changes between 8 and 20 weeks in each group were significant. The metabolic profiles demonstrated significantly increased urine levels of glucose and tricarboxylic acid cycle intermediates at both 8 and 20 weeks of age in db/db mice. These intermediates also exhibited strong positive associations with urinary albumin excretion, suggesting that they may be potential biomarkers for early diagnosis. On the contrary, branched chain amino acid and homocysteine-methionine metabolism were activated early in the disease, whereas ketone and fatty acid metabolism were significantly changed in the late phase of the disease. We demonstrated phase-specific alterations in metabolites during progression of DKD. This study provides insights into perturbed mechanisms during evolution of the disease and identifies potential novel biomarkers for DKD.