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Background Significant genetic association has been found in patients with severe carotid artery stenosis (CAS). The present study wished to investigate if metabolites may also act as biomarkers for CAS. Methods Consecutive patients with at least one carotid artery stenosis > = 60% on cerebral angiography were prospectively recruited from May 2007 to January 2016. Normal controls were recruited from outpatient clinic who had no stroke and coronary artery disease (CAD) history, and the brain magnetic resonance or computed tomographic angiography showed bilateral CAS

The phenotypic characteristics of traditional serrated adenoma (TSA)-associated malignancies remain obscure. This study was a morphologic reappraisal of 27 colorectal carcinomas arising from TSA (TSA-CRCs) and 53 BRAF-mutated/microsatellite-stable colorectal carcinomas (BRAF-mut/MSS CRCs). Makinen's criteria for serrated adenocarcinoma were applied to assess the morphologic similarity of the 2 entities. Tumor budding, another histologic feature of serrated adenocarcinoma, was also evaluated. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a commonly mutated gene in the serrated pathway, was assessed with immunohistochemistry. Tumors with aberrant PTEN expression were subjected to molecular analysis using quantitative methylation assay, exon sequencing, and fluorescence in situ hybridization. Most cases (>90%) of TSA-CRCs and BRAF-mut/MSS CRCs exhibited a constellation of serrated morphology, including epithelial serrations, abundant eosinophilic cytoplasm, and discernible/vesicular nuclei. A majority (65%) of them qualified for the diagnosis of serrated adenocarcinoma. High-grade tumor budding was closely associated with serrated morphology and was a significant independent factor for poor patient survival in multivariate analysis (P=0.008). Aberrant PTEN expression was detected in nearly half of the cases of both entities (P=0.501). Among the 44 samples with aberrant PTEN expression, 8 harbored PTEN somatic mutations, which were characterized by random distribution without hotspot clustering, 12 had promoter hypermethylation, and 14 had deleted alleles. These findings support a unique model of colorectal carcinogenesis that is similar between TSA-CRCs and BRAF-mut/MSS CRCs. Both entities exhibited common histologic patterns and similar molecular alterations and may well constitute the TSA pathway.

BACKGROUND A comprehensive metabolomics-based approach to address the impact of specific gut microbiota on allergen sensitization for childhood rhinitis and asthma is still lacking. METHODS Eighty-five children with rhinitis (n = 27) and with asthma (n = 34) and healthy controls (n = 24) were enrolled. Fecal metabolomic analysis with 1 H-nuclear magnetic resonance (NMR) spectroscopy and microbiome composition analysis by bacterial 16S rRNA sequencing were performed. An integrative analysis of their associations with allergen-specific IgE levels for allergic rhinitis and asthma was also assessed. RESULTS Amino acid, β-alanine, and butanoate were the predominant metabolic pathways in the gut. Among them, amino acid metabolism was negatively correlated with the phylum Firmicutes, which was significantly reduced in children with rhinitis and asthma. Levels of histidine and butyrate metabolites were significantly reduced in children with rhinitis (P = 0.029) and asthma (P = 0.009), respectively. In children with asthma, a reduction in butyrate-producing bacteria, including Faecalibacterium and Roseburia spp., and an increase in Clostridium spp. were negatively correlated with fecal amino acids and butyrate, respectively (P

Fibrin formation in infectious parapneumonic effusion (IPE) characterizes complicated parapneumonic effusion and is important for providing guidelines for the management of IPEs that require aggressive interventions. We aim to identify metabolic mechanisms associated with bacterial invasion, inflammatory cytokines, and biochemical markers in cases of fibrinous infectious pleural effusions in children with pneumonia. Pleural fluid metabolites were determined by 1H nuclear magnetic resonance spectroscopy. Metabolites that contributed to the separation between fibrinous and nonfibrinous IPEs were identified using supervised partial least squares discriminant analysis ( Q2/ R2 = 0.84; Ppermutation < 0.01). IL-1β in the inflammatory cytokines and glucose in the biochemical markers were significantly correlated with 11 and 9 pleural fluid metabolites, respectively, and exhibited significant overlaps. Four metabolites, including glucose, lactic acid, 3-hydroxybutyric acid, and hypoxanthine, were significantly correlated with plasminogen activator inhibitor type 1 in the fibrinolytic system enzymes. Metabolic pathway analysis revealed that anaerobic bacterial fermentation with increased lactic acid and butyric acid via glucose consumption and adenosine triphosphate hydrolysis with increased hypoxanthine appeared to be associated with fibrinous IPE. Our results demonstrate that an increase in lactic acid anaerobic fermentation and hypoxanthine accumulation under hypoxic conditions are associated with fibrin formation in IPE, representing advanced pleural inflammatory progress in children with pneumonia.

Functional capacity is a crucial parameter correlated with outcomes. The currently used New York Heart Association functional classification (NYHA Fc) system has substantial limitations, leading to inaccurate classification. This study investigated whether amino acid-based assessment on metabolic status provides an objective way to assess functional capacity and prognosis in heart failure (HF) outpatients. Plasma concentrations of histidine, ornithine, and phenylalanine (HOP) were measured on 890 HF outpatients to assess metabolic status by calculating the HOP score. Cardiopulmonary exercise testing (CPET) was performed in 387 patients to measure metabolic equivalents (MET) in order to define the functional class based on MET (MET Fc). Patients were followed for composite events (death/HF-related rehospitalization) up to one year. We found only 47% concordance between the MET Fc and NYHA Fc. HOP scores worked better than NYHA Fc for discriminating patients with MET Fc II and III from those with MET Fc I, with the optimal cutoff value set at 8.8. HOP scores≥8.8 were associated with risk factors for composite events in different kinds of HF populations and were a powerful predictor of composite events in univariate analysis. In multivariable analysis, HOP scores≥8.8 remained a powerful event predictor, independent of other risk factors. Kaplan-Meier curves revealed that HOP scores of ≥8.8 stratified patients at higher risk of composite events in a variety of HF populations. In conclusion, amino acid-based assessment of metabolic status correlates with functional capacity in HF outpatients and provides prognostic value for a variety of HF populations.

Aging is a complex progression of biological processes and is the causal contributor to the development of diabetes mellitus (DM). DM is the most common degenerative disease and is the fifth leading cause of death in Taiwan, where the trend of DM mortality has been steadily increasing. Metabolomics, important branch of systems biology, has been mainly utilized to understand endogenous metabolites in biological systems and their dynamic changes as they relate to endogenous and exogenous factors. The purpose of this study was to elucidate the metabolomic profiles in elderly people and its relation to lipid disorder (LD). We collected 486 elderly individuals aged &ge, 65 years and performed untargeted and targeted metabolite analysis using nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography&mdash, mass spectrometry (LC/MS). Several metabolites, including branched-chain amino acids, alanine, glutamate and alpha-aminoadipic acid were elevated in LD compared to the control group. Based on multivariate analysis, four metabolites were selected in the best model to predict DM progression: phosphatidylcholine acyl-alkyl (PC ae) C34:3, PC ae C44:3, SM C24:1 and PCae C36:3. The combined area under the curve (AUC) of those metabolites (0.82) was better for DM classification than individual values. This study found that targeted metabolic signatures not only distinguish the LD within the control group but also differentiated DM from LD in elderly Taiwanese. These metabolites could indicate the nutritional status and act as potential metabolic biomarkers for the elderly in Taiwan.

Examination of changes in urinary metabolomic profiles after vegetable ingestion may lead to new methods of assessing plant food intake. To this regard, we developed a proof-of-principle methodology to identify urinary metabolomic signatures for spinach, celery, and onion. Three feeding studies were conducted. In the first study, healthy individuals were fed with spinach, celery, onion, and no vegetables in four separate experiments with pooled urinary samples for metabolite discovery. The same protocol was used to validate the finding at the individual level in the second study and when feeding all three vegetables simultaneously in the third study. An LC-MS-based metabolomics approach was adopted to search for indicative metabolites from urine samples collected during multiple time periods before and after the meal. Consequently, a total of 1, 9, and 3 nonoverlapping urinary metabolites were associated with the intake of spinach, celery, and onion, respectively. The PCA signature of these metabolites followed a similar "time cycle" pattern, which maximized at approximately 2-4 h after intake. In addition, the metabolite profiles for the same vegetable were consistent across samples, regardless of whether it was consumed individually or in combination. The developed methodology along with the identified urinary metabolomic signatures were potential tools for assessing plant food intake.

Liver transplantation has become the ultimate treatment for patients with end stage liver disease. However, early allograft dysfunction (EAD) has been associated with allograft loss or mortality after transplantation. We aim to utilize a metabolomic platform to identify novel biomarkers for more accurate correlation with EAD using blood samples collected from 51 recipients undergoing living donor liver transplantation (LDLT) by 1H-nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography coupled with mass spectrometry (LC-MS). Principal component analysis (PCA) and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) were used to search for a relationship between the metabolomic profiles and the presence of EAD.Cholesteryl esters (CEs), triacylglycerols (TGs), phosphatidylcholines (PCs) and lysophosphatidylcholine (lysoPC) were identified in association with EAD and a combination of cholesterol oleate, PC (16:0/16:0), and lysoPC (16:0) gave an optimal area under the curve (AUC) of 0.9487 and 0.7884 in the prediction of EAD and in-hospital mortality, respectively after LDLT. Such biomarkers may add as a potential clinical panel for the prediction of graft function and mortality after LDLT.

BACKGROUND Based on the breakthrough of genomics analysis, The Cancer Genome Atlas Research Group recently proposed an integrative genomic analysis, dividing gastric cancer (GC) into four subtypes, characterized by the chromosomal instability (CIN) status. However, the CIN status of GC is still vaguely characterized and lacking the valuable easy-to-use CIN markers to diagnosis in molecular and histological detection. AIM To explore the associations of CIN with downstream lipidomics profiles. METHODS We collected cancerous and noncancerous tissue samples from 18 patients with GC; the samples were divided into CIN and non-CIN types based on the system of The Cancer Genome Atlas Research Group and 409 sequenced oncogenes and tumor suppressor genes. We identified the lipidomics profiles of the GC samples and samples of their adjacent noncancerous tissues by using liquid chromatography–mass spectrometry. Furthermore, we selected leading metabolites based on variable importance in projection scores of > 1.0 and P < 0.05. RESULTS Twelve men and six women participated in this study; the participants had a median age of 67.5 years (range, 52–87 years) and were divided into CIN (n = 9) and non-CIN (n = 9) groups. The GC samples exhibited distinct profiles of lysophosphocholine, phosphocholine, phosphatidylethanolamine, phosphatidylinositol, phosphoserine, sphingomyelin, ceramide, and triglycerides compared with their adjacent noncancerous tissues. The glycerophospholipid levels (phosphocholine, phosphatidylethanolamine, and phosphatidylinositol) were 1.4- to 2.3-times higher in the CIN group compared with the non-CIN group (P < 0.05). Alterations in the glycerolipid and glycerophospholipid pathways indicated progression of GC toward CIN. CONCLUSION The lipidomics profiles of GC samples were distinct from those of their adjacent noncancerous tissues. CIN status of GC is primarily associated with downstream lipidomics in the glycerophospholipid pathway.

Non-alcoholic fatty liver disease (NAFLD) as a global health problem has clinical manifestations ranging from simple non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and cancer. The role of different types of fatty acids in driving the early progression of NAFL to NASH is not understood. Lipid overload causing lipotoxicity and inflammation has been considered as an essential pathogenic factor. To correlate the lipid profiles with cellular lipotoxicity, we utilized palmitic acid (C16:0)- and especially unprecedented palmitoleic acid (C16:1)-induced lipid overload HepG2 cell models coupled with lipidomic technology involving labeling with stable isotopes. C16:0 induced inflammation and cell death, whereas C16:1 induced significant lipid droplet accumulation. Moreover, inhibition of de novo sphingolipid synthesis by myriocin (Myr) aggravated C16:0 induced lipoapoptosis. Lipid profiles are different in C16:0 and C16:1-treated cells. Stable isotope-labeled lipidomics elucidates the roles of specific fatty acids that affect lipid metabolism and cause lipotoxicity or lipid droplet formation. It indicates that not only saturation or monounsaturation of fatty acids plays a role in hepatic lipotoxicity but also Myr inhibition exasperates lipoapoptosis through ceramide in-direct pathway. Using the techniques presented in this study, we can potentially investigate the mechanism of lipid metabolism and the heterogeneous development of NAFLD.

Background This study aimed to deconvolve the levels of infiltrating immune cells in non-small cell lung cancer (NSCLC) and to identify specific gene co-expression modules associated with prognosis of NSCLC. Materials and Methods CIBERSORT algorithm was employed to infer the relative abundance of 22 immune cell subtypes in 1751 NSCLC subjects. The patterns of immune infiltration were identified for NSCLC with different clinical and genomic features and were used to construct an immunoscore by LASSO regression associated with NSCLC survival. Weighted gene co-expression network analysis (WGCNA) was employed to identify specific modules related to immunoscore and NSCLC survival. An integrated prognostic model was constructed with immunoscore combined with the available clinical variables and the selected gene modules to predict the prognosis of NSCLC. Results We found distinct immune infiltration patterns for NSCLC with different genotype. EGFR-mutant NSCLC was characterized by enriched resting memory CD4+ T cell. An immunoscore was established based on the infiltration abundance of 17 selected immune cell subtypes. Patients with a low immunoscore had a prolonged survival and higher abundance of CD4+ T cell, resting dendritic cells and resting mast cells. The WGCNA analysis identified the gene modules significantly associated with immunoscore and the prognosis of NSCLC. The immunoscore was further incorporated with clinical parameters and selected gene modules to fit a predictive model which stratified patients into subgroups with significantly different survival. Conclusion The distinct immune profiles are associated with differential overall survival of NSCLC and the integrated model can robustly predict the prognosis of NSCLC.

Background The heart is a highly adaptive organ that demonstrates remarkable structural, functional, and metabolic remodeling in response to physiological and pathological stimuli. We hypothesize that the heart undergoes differential adaptations in high-fat and high-fructose diet, resulting in a distinct phenotype. Methods High-fat and high-fructose diet-induced obese and non-obese insulin resistance (IR) rat models were used to understand how the heart adapts to long-term (12-week) overnutrition. Results Rats fed the high-fat diet developed obese IR, whereas high-fructose diet developed non-obese IR. Obese IR rats developed fibrotic hypertrophy with impairment of preload-independent contractility. The sympathetic and renin–angiotensin–aldosterone (RAA) systems and myocardial adrenergic signaling were activated in obese IR rats. Non-obese IR rats developed apoptotic cardiomyopathy with severe systolic dysfunction. Myocardial calcium cycling regulatory proteins (CCRPs) were dysregulated in non-obese IR rats; specifically, troponin I protein expression was downregulated. Moreover, compared with the controls, lipidomics analysis revealed substantial differences in lipid metabolites in non-obese IR and obese IR rats. The overproduction of lysophosphatidylcholine (lysoPC) and fatty acids was observed in non-obese IR rat hearts. A strong correlation was observed between the myocardial lysoPC and plasma troponin I levels. Treatment of cardiomyocytes with lysoPC resulted in cell death in a dose- and time-dependent manner. The overproduction of myocardial lysoPCs was associated with circulating sPLA 2 levels. Conclusion Obese IR rats developed severe fibrotic hypertrophy with the activation of adrenergic signaling and sympathetic and RAA systems. The sPLA 2 –lysoPC may play a crucial role in the induction of apoptotic cardiomyopathy in high fructose-induced non-obese IR rats.

Huntington's disease (HD), caused by expanded CAG repeats encoding a polyglutamine tract in the huntingtin protein, presents with a predominant degeneration of neurons in the striatum and cortex. Although a few studies have identified substantial metabolite alterations in plasma, the picture of plasma metabolomics of HD has not been clearly depicted yet. Using a global metabolomics screening for plasma from 15 HD patients and 17 controls, HD patient group was separated from the control group by a panel of metabolites belonging to carnitine, amino acid and phosphatidylcholine species. The quantification of 184 related metabolites (including carnitine, amino acid and phosphatidylcholine species) in 29 HD patients, 9 presymptomatic HD carriers and 44 controls further showed one up-regulated (glycine) and 9 down-regulated metabolites (taurine, serotonin, valine, isoleucine, phosphatidylcholine acyl-alkyl C36:0 and C34:0 and lysophosphatidylcholine acyl C20:3). To understand the biosynthetic alterations of phosphatidylcholine in HD, we examined the expression levels and activities of a panel of key enzymes responsible for phosphatidylcholine metabolism. The results showed down-regulation of PCYT1A and increased activity of phospholipase A2 in HD leukocytes. These metabolic profiles strongly indicate that disturbed metabolism is involved in pathogenesis of HD and provide clue for the development of novel treatment strategies for HD.

Mononuclear complexes [Cd(HMPCA)2(H2O)4] (1) and [Co(H2MPCA)2(DMF)2(H2O)2]Cl2 (2), and 3D coordination polymer [Cd3Cl2(HMPCA)4(H2O)2]·2H2O (3) (H2MPCA = 3-methyl-1H-pyrazole-4-carboxylic acid) were synthesized and characterized by elemental analysis, IR spectra, thermogravimetric analysis, and X-ray single-crystal structure analysis. In 3, HMPCA− anions bridged trinuclear Cd(II) ions clusters to form an 8-connected 3D network with channels. The complexes all display green fluorescence in the solid state. As a bifunctional catalyst, complex 2 exhibited excellent catalytic activity for oxygen evolution reaction (OER), and certain catalytic activity for oxygen reduction reaction (ORR).

In the absence/presence of different N ancillary ligands, four copper(II)-pyrazolecarboxylate complexes, [Cu(HMPCA)2(ImH)2]·2H2O (1), [Cu2(MPCA)2(H2O)4] (2), [Cu2(MPCA)2(4,4′-bpy)(H2O)2]n·5nH2O (3) and [Cu3(MPCA)3(Phen)3]2·2EtOH·15H2O (4) (H2MPCA = 5-methyl-1H-pyrazole-3-carboxylic acid, ImH = imidazole, 4,4′-bpy = 4,4′-bipyridine and Phen = 1,10-phenanthroline) were obtained. All complexes have been structurally characterized. Compounds 2 and 3 containing the same bis(μ-pyrazolato)dicopper(II) planes range from dinuclear to 1D polymer. Trinuclear complex 4 contains the first reported cyclic-trinuclear copper(II)–pyrazolato structure without any μ3 ligand core. Magnetic susceptibility data show that complexes 2–4 exhibit antiferromagnetic couplings between the adjacent magnetic centers.

Glucose-6-phosphate dehydrogenase (G6PD)-deficient cells are highly susceptible to viral infection. This study examined the mechanism underlying this phenomenon by measuring the expression of antiviral genes—tumor necrosis factor alpha (TNF-α) and GTPase myxovirus resistance 1 (MX1)—in G6PD-knockdown cells upon human coronavirus 229E (HCoV-229E) and enterovirus 71 (EV71) infection. Molecular analysis revealed that the promoter activities of TNF-α and MX1 were downregulated in G6PD-knockdown cells, and that the IκB degradation and DNA binding activity of NF-κB were decreased. The HSCARG protein, a nicotinamide adenine dinucleotide phosphate (NADPH) sensor and negative regulator of NF-κB, was upregulated in G6PD-knockdown cells with decreased NADPH/NADP+ ratio. Treatment of G6PD-knockdown cells with siRNA against HSCARG enhanced the DNA binding activity of NF-κB and the expression of TNF-α and MX1, but suppressed the expression of viral genes, however, the overexpression of HSCARG inhibited the antiviral response. Exogenous G6PD or IDH1 expression inhibited the expression of HSCARG, resulting in increased expression of TNF-α and MX1 and reduced viral gene expression upon virus infection. Our findings suggest that the increased susceptibility of the G6PD-knockdown cells to viral infection was due to impaired NF-κB signaling and antiviral response mediated by HSCARG.

Nuclear and mitochondrial crosstalk plays an important role in regulating diverse cellular functions. It is contributed partly by non-canonical signaling in these two key subcellular compartments. Disruption of this signaling network has been shown to associate with oncogenic transformation. Our lab has long-term interests in studying the molecular mechanisms of cellular transformation by the oncogenic lymphocyte-specific protein tyrosine kinase (Lck). Previous reports from our lab show novel roles of Lck in both nucleus and mitochondrion of human and mouse T leukemic cell lines that exhibit metabolic reprogramming. However, it remains largely unclear how dysregulated nuclear and mitochondrial crosstalk leads to altered cellular metabolism in Lck-transformed leukemic cells. The purpose of our study is to combine transcriptomic, proteomic, and metabolomic approaches to establish a link between altered nuclear gene expression, mitochondrial activity, and metabolic shift in Lck-transformed leukemic cells. For human T cell leukemia, we compared Jurkat T cells with its Lck-deficient derivative Jcam cell line. For mouse T cell leukemia, we compared EL4 cells that express normal levels of Lck and LSTRA cells that overexpress active Lck kinase. For additional verification, Jcam cells were reconstituted with wild-type Lck and EL4 cells were transfected with constitutively-active Lck mutant kinase. Total RNAs were subjected to transcriptomic analysis to identify genes significantly upregulated or downregulated in Lck-transformed cells. Tyrosine-phosphorylated proteins were enriched from Lck-transformed cells and identified by LC-MS/MS. Hydrophilic metabolites were extracted from whole cells and subjected to targeted metabolomic analysis using LC-MS/MS. Pathway analysis of our transcriptomic data revealed significant changes of gene expression involved in several pathways, including cell adhesion and glycolysis pathways. We verified several glycolytic genes downregulated in Lck-transformed cells. These targets were further confirmed by reduced levels of corresponding metabolites. Proteomic analysis identified a set of novel target proteins potentially phosphorylated by Lck. Cyclin-dependent kinase 1 (CDK1) is of particular interest because its phosphorylation status correlates with its activity in regulating electron transport chain functions within mitochondrion. Our data suggest a link between tyrosine-phosphorylated CDK1 and reduced mitochondrial respiration. In conclusion, integrated transcriptomic, proteomic, and metabolomic analyses enabled us to identify novel target genes regulated, proteins phosphorylated, and metabolites altered in Lck-transformed leukemic cells. Collectively, our data demonstrate a unique pattern of metabolic reprogramming both similar and distinct from the well-known Warburg effect in cancer cells. Citation Format: Ching-Yu Chu, Szu-Yuan Chen, Fu-Yu Chueh, Mei-Ling Cheng, Chao-Lan Yu. Integrated transcriptomic, proteomic, and metabolomic analyses of human and mouse T cell leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2564.

Summary: Reprogramming of glucose metabolism is a key event in tumorigenesis and progression. Here, we show that active c-Src stimulates glycolysis by phosphorylating (Tyr194) and activating PFKFB3, a key enzyme that boosts glycolysis by producing fructose-2,6-bisphosphate and activating PFK1. Increased glycolysis intermediates replenish non-oxidative pentose phosphate pathway (PPP) and serine pathway for biosynthesis of cancer cells. PFKFB3 knockout (KO) cells and their counterpart reconstituted with PFKFB3-Y194F show comparably impaired abilities for proliferation, migration, and xenograft formation. Furthermore, PFKFB3-Y194F knockin mice show impaired glycolysis and, mating of these mice with APCmin/+ mice attenuates spontaneous colon cancer formation in APCmin/+ mice. In summary, we identify a specific mechanism by which c-Src mediates glucose metabolism to meet cancer cells’ requirements for maximal biosynthesis and proliferation. The PFKFB3-Tyr194 phosphorylation level highly correlates with c-Src activity in clinical tumor samples, indicating its potential as an evaluation for tumor prognosis. : Ma et al. identify a mechanism of c-Src in promoting tumorigenesis and progression by phosphorylating and activating PFKFB3, an indispensable activator of the rate-limiting enzyme PFK1. PFKFB3 activation further stimulates glycolysis that provides precursors for biosynthesis of proliferating tumor cells.

Enterovirus 71 (EV71) infection is an endemic disease in Southeast Asia and China. We have previously shown that EV71 virus causes functional changes in mitochondria. It is speculative whether EV71 virus alters the host cell metabolism to its own benefit. Using a metabolomics approach, we demonstrate that EV71-infected Vero cells had significant changes in metabolism. Glutathione and its related metabolites, and several amino acids, such as glutamate and aspartate, changed significantly with the infectious dose of virus. Other pathways, including glycolysis and tricarboxylic acid cycle, were also altered. A change in glutamine/glutamate metabolism is critical to the viral infection. The presence of glutamine in culture medium was associated with an increase in viral replication. Dimethyl &alpha, ketoglutarate treatment partially mimicked the effect of glutamine supplementation. In addition, the immunoblot analysis revealed that the expression of glutamate dehydrogenase (GDH) and trifunctional carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) increased during infection. Knockdown of expression of glutaminase (GLS), GDH and CAD drastically reduced the cytopathic effect (CPE) and viral replication. Furthermore, we found that CAD bound VP1 to promote the de novo pyrimidine synthesis. Our findings suggest that virus may induce metabolic reprogramming of host cells to promote its replication through interactions between viral and host cell proteins.

Metabolic disturbances represent functional perturbation in peripheral tissues and predict outcomes in patients with heart failure (HF). This study developed an amino acid-based metabolic panel and sought to see whether this panel could add diagnostic and prognostic value to currently used B-type natriuretic peptide (BNP) measurements. Mass spectrometry and ultra-performance liquid chromatography were performed on 1288 participants, including 129 normal controls and 712 patients at HF stages A to D in the initial cohort and 447 stage C patients in the validation cohort. Patients were followed up for composite events (death/HF-related rehospitalization). Histidine, ornithine, and phenylalanine were 3 metabolites found strongly significant to identify patients at stage C and were adopted to develop the HOP panel. Compared to BNP, HOP had better value in discriminating the patients at different stages, especially in elderly patients and those with atrial fibrillation, high body mass index, or kidney dysfunction. HOP was correlated with the distance of 6 min walking distance better than BNP. For prognosis, HOP predicted composite events in patients at stages C and D, independent of log (BNP), age, sex, left ventricular ejection fraction, New York Heart Association functional class, HF stage, diabetes mellitus, chronic kidney disease, hypertension, hemoglobin, and albumin. Higher BNP (≥750 pg/mL) along with higher HOP (≥14) robustly predicted lower event-free survival compared to all others [hazard ratio=3.15 (2.23–4.46), p<0.001]. The prognostic value of HOP was confirmed in the validation cohort. In conclusion, aiming for clinical applications, this study proved that the HOP panel provides diagnostic and prognostic value additive to BNP and traditional risk factors.

Background. High-fat diet (HFD) induces systemic insulin resistance leading to myocardial dysfunction. We aim to characterize the early adaptations of myocardial glucose utility to HFD-induced insulin resistance. Methods. Male Sprague–Dawley rats were assigned into two groups, fed a regular chow diet or HFD ad libitum for 10 weeks. We used in vivo imaging of cardiac magnetic resonance (CMR), 18F-FDG PET, and ex vivo nuclear magnetic resonance (NMR) metabolomic analysis for the carbon-13-labeled glucose ([U-13C]Glc) perfused myocardium. Results. As compared with controls, HFD rats had a higher ejection fraction and a smaller left ventricular end-systolic volume (P<0.05), with SUVmax of myocardium on 18F-FDG PET significantly increased in 4 weeks (P<0.005). The [U-13C]Glc probed the increased glucose uptake being metabolized into pyruvate and acetyl-CoA, undergoing oxidative phosphorylation via the tricarboxylic acid (TCA) cycle, and then synthesized into glutamic acid and glutamine, associated with overexpressed LC3B (P<0.05). Conclusions. HFD-induced IR associated with increased glucose utility undergoing oxidative phosphorylation via the TCA cycle in the myocardium is supported by overexpression of glucose transporter, acetyl-CoA synthase. Noninvasive imaging biomarker has potentials in detecting the metabolic perturbations prior to the decline of the left ventricular function.

Dietary leucine supplementation has been explored for the therapeutic intervention of obesity and obesity-induced metabolic dysfunctions. In this study, we aim to examine the effects of dietary leucine supplementation in db/db mice. Mice were treated with or without leucine (1.5% w/v) in drinking water for 12 weeks. The leucine supplement was found to reduce insulin resistance and hepatic steatosis in db/db mice. Using Nuclear Magnetic Resonance (NMR)-based lipidomics, we found that the reduction of hepatic triglyceride synthesis was correlated with attenuated development of fatty liver. In addition, diabetic nephropathy (DN) was also ameliorated by leucine. Using liquid chromatography&ndash, time-of-flight mass spectrometry (LC-TOF MS)-based urine metabolomics analysis, we found that the disturbance of the tricarboxylic acid (TCA) cycle was reversed by leucine. The beneficial effects of leucine were probably due to AMP-activated protein kinase (AMPK) activation in the liver and kidneys of db/db mice. Thus, dietary leucine supplementation may potentially be a nutritional intervention to attenuate hepatic steatosis and early DN in type II diabetes.

Oxidative stress is commonly involved in the pathogenesis of various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Therefore, lipophilic antioxidants, such as vitamin A, carotinoids, vitamin E, coenzyme Q10, docosahexaenoic acid and eicosapentaenoic acid, have received increasing attention as therapeutic and preventive intervention for neurodegenerative diseases. Although difficulties exist with clinical studies due to the nature of the long-standing progression of neurodegenerative diseases, findings in cell and animal models, as well as biomarker studies have implied a relationship between lipophilic antioxidants and neurodegeneration. By reviewing current findings and their implication in neurodegenerative diseases, we conclude that although none of these lipophilic antioxidants have yet provided clear-cut clinical evidence toward beneficial effects in neurodegenerative diseases, they could demonstrate neuroprotection in cellular and/or animal studies. Results from future multidisciplinary studies with optimization of factors including drug dosage, delivery route and chemical structure may provide us with novel treatments for neurodegenerative diseases using lipophilic antioxidants.

In heart failure (HF), metabolic disturbances represent functional perturbations in peripheral tissues and also predict patient outcomes. This study developed a simplified essential amino acid-based profile and tested whether it could improve prognostication. Plasma essential amino acids and lipidomics were measured on 1084 participants. The initial cohort included 94 normal controls and 599 patients hospitalized due to acute/decompensated HF. The validation cohort included 391 HF patients. Patients were followed for composite events (death/HF related re-hospitalization) and were categorized into three groups: high risk type 1 (leucine ≥145 μM and phenylalanine ≥ 88.9 μM), high risk type 2 (leucine

PURPOSE To examine the outcome of laser peripheral iridotomy (LPI) for primary angle closure and determine predictors of future lens extraction (LE). METHODS A retrospective chart review of 218 eyes from 128 consecutive patients undergoing LPI between 2010 and 2012 at a university hospital. Baseline factors including age, peak intraocular pressure (IOP) before LPI, diagnosis (primary angle closure suspect, primary angle closure, primary angle closure glaucoma), and acute or non-acute presentation were recorded. Patients were followed for 3.7±1.6 years. Kaplan-Meier curves were constructed to examine survival times to LE and Cox proportional hazard regression was used to identify factors associated with LE. RESULTS In total, 91 of 218 eyes (41.7%) initially treated with LPI had LE during follow-up. For eyes with non-acute presentation, 12%, 25%, and 32% had LE at 1, 2, and 3 years, respectively. For eyes with acute presentation, 27%, 42%, and 50% had LE at 1, 2, and 3 years. In univariable analysis, older age, higher IOP, worse visual field, and primary angle closure glaucoma diagnosis were associated with LE, with older age and higher IOP remaining significant in multivariable analysis. There was a 1.09-fold increased odds of LE for each year older at baseline and each 1 mm Hg higher IOP was associated with a 1.08-fold increased odds of LE. CONCLUSIONS A large proportion of patients with angle closure treated with LPI went on to require LE. Patients with features associated with higher odds of LE might be considered for LE as a primary procedure.

Amino acid-derived metabolites, including protein-bound uremic toxins, may have prognostic value for patients with heart failure (HF). The aim of this study was to investigate whether p-cresyl sulfate (PCS), indoxyl sulfate (IS), and arginine metabolites provided prognostic values in addition to the traditional biomarker, B-type natriuretic peptide (BNP), in patients with HF. Chromatography mass spectrometry was performed to measure tyrosine, tryptophan, arginine, PCS, IS, and asymmetric (ADMA) and symmetric dimethylarginine (SDMA) in the plasma from 51 normal controls and 136 HF patients. Compared to the normal controls, PCS levels significantly increased in HF patients (p = 0.003). During the follow-up (2.3 ± 1.1 years), 35 (25.7 %) patients experienced a composite event of death or HF-related re-hospitalization. In univariable analysis, PCS, estimated glomerular filtration rate (eGFR), BNP, DMA/arginine ratio, and ADMA/arginine ratio were associated with a higher rate of composite events. In the multivariable analysis, PCS was the only independent predictor of composite events [hazard ratio (HR) 1.06 (per 10 μM), 95 % confidence interval (CI) 1.01–1.11, p = 0.02]. Kaplan–Meier curves showed that a PCS level of ≥50 μM was significantly associated with a higher composite event rate than those with a PCS level of

Background Identification of novel biomarkers is needed to improve the diagnosis and prognosis of heart failure (HF). Metabolic disturbance is remarkable in patients with HF. Objectives This study sought to assess the diagnostic and prognostic values of metabolomics in HF. Methods Mass spectrometry–based profiling of plasma metabolites was performed in 515 participants; the discovery phase study enrolled 51 normal control subjects and 183 HF patients, and the validation study enrolled 63 control subjects and 218 patients with stage C HF. Another independent group of 32 patients with stage C HF who recovered to New York Heart Association functional class I at 6 and 12 months was profiled as the “recovery” group. Results A panel of metabolites, including histidine, phenylalanine, spermidine, and phosphatidylcholine C34:4, has a diagnostic value similar to B-type natriuretic peptide (BNP). In the recovery group, the values of this panel significantly improved at 6 and 12 months. To evaluate the prognostic values, events were defined as the combined endpoints of death or HF-related re-hospitalization. A metabolite panel, which consisted of the asymmetric methylarginine/arginine ratio, butyrylcarnitine, spermidine, and the total amount of essential amino acids, provided significant prognostic values (p Conclusions Metabolomics demonstrate powerful diagnostic value in estimating HF-related metabolic disturbance. The profile of metabolites provides better prognostic value versus conventional biomarkers.

Hydrothermal reactions of trivalent lanthanide salts with a rigid ligand 3,4-pyrazoledicarboxylic acid (H3pdc) yielded a series of lanthanide compounds, namely, [Ln(H2pdc)3(H2O)4]·xH2O (Ln = Ce(1), Pr(2), Nd(3) and Sm(4)). In the presence of oxalate as ancillary ligand, 2D coordination polymers {[Ln(μ2-Hpdc)(μ2-C2O4)1/2(H2O)2]·H2O}n (Ln = Ce(5), Pr(6), Nd(7) and Sm(8)) are formed. Structure analyses reveal that compounds 1–4 are isostructural, featuring mononuclear structures. Whereas 5–8 are also isostructural and exhibit (3,4)-connected 2D layer structures with (4.52)(4.53.7.8) topology. Magnetic susceptibility data show that compounds 6 and 7 exhibit antiferromagnetic couplings between the adjacent magnetic centers.

Aims: Glucose 6-phosphate dehydrogenase (G6PD) is essential for maintenance of nicotinamide dinucleotide hydrogen phosphate (NADPH) levels and redox homeostasis. A number of drugs, such as antimalarial drugs, act to induce reactive oxygen species and hemolytic crisis in G6PD-deficient patients. We used diamide (DIA) to mimic drug-induced oxidative stress and studied how these drugs affect cellular metabolism using a metabolomic approach. Results: There are a few differences in metabolome between red blood cells (RBCs) from normal and G6PD-deficient individuals. DIA causes modest changes in normal RBC metabolism. In contrast, there are significant changes in various biochemical pathways, namely glutathione (GSH) metabolism, purine metabolism, and glycolysis, in G6PD-deficient cells. GSH depletion is concomitant with a shift in energy metabolism. Adenosine monophosphate (AMP) and adenosine diphosphate (ADP) accumulation activates AMP protein kinase (AMPK) and increases entry of glucose into glycolysis. However, inhibition of pyruvate kinase (PK) reduces the efficacy of energy production. Metabolic changes and protein oxidation occurs to a greater extent in G6PD-deficient RBCs than in normal cells, leading to severe irreversible loss of deformability of the former. Innovation and Conclusion: Normal and G6PD-deficient RBCs differ in their responses to oxidants. Normal cells have adequate NADPH regeneration for maintenance of GSH pool. In contrast, G6PD-deficient cells are unable to regenerate enough NADPH under a stressful situation, and switch to biosynthetic pathway for GSH supply. Rapid GSH exhaustion causes energy crisis and futile AMPK activation. Our findings suggest that drug-induced oxidative stress differentially affects metabolism and metabolite signaling in normal and G6PD-deficient cells. It also provides an insight into the pathophysiology of acute hemolytic anemia in G6PD-deficient patients. Antioxid. Redox Signal. 22, 744–759.

The surface of a clay teapot tends to be coated with a waterproof film after constant use for tea preparation. The waterproof films of two kinds of teapots ( zisha and zhuni ) used for preparing oolong tea and old oolong tea were extracted and subjected to gas chromatography–mass spectrometry analysis. The results showed that comparable constituents were detected in these films; they were primarily fatty acids and linear hydrocarbons that were particularly rich in palmitic acid and stearic acid. To explore the source of these two abundant fatty acids, the fatty acid compositions of fresh tea leaves, granules, infusion, and vapor of infusion were analyzed by gas chromatography. Fresh tea leaves were rich in palmitic acid (C-16:0), unsaturated linolenic acid (C-18:3), linoleic acid (C-18:2), and oleic acid (C-18:1), which were presumably from the phospholipid membrane. During the process of manufacturing oolong tea, the three unsaturated fatty acids may be substantially degraded or oxidized to stearic acid (C-18:0), which was enriched with palmitic acid in the tea granules and in the infusion. The vapor of the tea infusion is primarily composed of palmitic acid and stearic acid. Thus, the coated films of teapots mostly originated from the lipophilic compounds of the tea infusions.

Annexin A10 (ANXA10) is a member of the ANX family that is normally expressed in gastric mucosa. ANXA10 was recently observed to be upregulated in sessile serrated adenoma, a precursor to microsatellite-unstable colorectal cancer. We investigated the use of ANXA10 in diagnosing colorectal carcinoma. In an immunohistochemical analysis, the intensity and quantity of ANXA10, MUC5AC, MUC6 and CDX2 in 123 colorectal carcinomas were graded. We determined the molecular status of BRAF and KRAS mutations, as well as the microsatellite instability status and the CpG island methylator phenotype in all colorectal carcinomas, and subcategorized into four molecular subgroups according to the molecular derangements. Nuclear ANXA10 staining was present in 36 colorectal carcinomas, exhibiting a strong significant association with the BRAF mutation status (P

Two coordination polymers, namely, {[Cd(cdpc)(hmt)(H2O)]·H2O}n (1), and [Mn(Hcdpc)2(4, 4′-bpy)(H2O)]n (2), were constructed by synergistic assembly through the mixed-ligand synthetic strategy (H2cdpc = 1-carboxymethyl-3, 5-dimethyl-1H-pyrazole-4-carboxylic acid, hmt = hexamethylenetetramine, and 4, 4′-bpy = 4, 4′-dipyridine). Their structures were determined by single-crystal X-ray diffraction analyses and further characterized by elemental analyses, IR spectra, powder X-ray diffraction (PXRD), and thermogravimetric (TG) analyses. Single X-ray diffraction analysis reveals that complex 1 is a 2D 4-connected sql sheet, and complex 2 is an interesting 1D loop chain. The two complexes are further expanded to 3D supramolecular structure through non-covalent bonds. Besides, luminescent properties of two complexes in the solid state and magnetic property of 2 were also investigated.

Lipids play an important role in the pathogenesis of cardiovascular disease. Changes in lipids of erythrocytes are indicative of the outcome of pathophysiological processes. In the present study, we assessed whether the lipid profiles of erythrocytes from heart failure (HF) patients are informative of their disease risk. The lipidomes of erythrocytes from 10 control subjects and 29 patients at different HF stages were analyzed using liquid chromatography time-of-flight mass spectrometry. The lipid composition of erythrocytes obtained from HF patients was significantly different from that of normal controls. The levels of phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), and sphingomyelins decreased in HF erythrocytes as compared with those of control subjects; however, the levels of lysoPCs, lysoPEs, and ceramides increased in HF erythrocytes. Notably, the oxidized cholesterol 7-ketocholesterol (7KCh) accumulated to higher level in HF erythrocytes than in plasma from the same patients. We further validated our findings with a cohort of 115 subjects of control subjects (n=28) and patients (n=87). Mechanistically, 7KCh promoted reactive oxygen species (ROS) formation in cardiomyocytes; and induced their death, probably through an ATF4-dependent pathway. Our findings suggest that erythrocytic 7KCh can be a risk factor for HF, and is probably implicated in its pathophysiology. Keywords: Heart failure, Lipidomics, 7-ketocholesterol, Oxidative stress

Background How hepatitis C virus (HCV)–associated lipid metabolic alterations recover after sustained virological response (SVR) remains elusive. Objective The aforementioned recovery pattern was investigated. Methods In a prospective cohort study of 438 chronic hepatitis C (CHC) patients with SVR after anti-HCV therapy, 164 sex- and age-matched genotype I (G1) and G2 patients underwent paired-serum liquid chromatography-tandem mass spectrometry analyses before and 24 weeks after therapy. Subjects without CHC served as controls (n = 100). Results CHC patients had lower baseline lipid levels than controls. Among CHC patients, pre-therapy total cholesterol levels were positively associated with HCV RNA levels; G1 patients had higher pre-therapy HCV RNA levels than G2 patients. Repeated measures analysis of variance of CHC patients showed that lathosterol, lanosterol, total hydroxysphingomyelin, and total phosphatidylcholines levels, and total dicarboxyacylcarnitine/total acylcarnitine (indicators of ω-oxidation) and pre-β-lipoprotein ratios elevated 24 weeks after therapy compared with the levels before therapy. Levels of total lysophosphatidylcholines and α- and β-lipoprotein ratios decreased. Subgroup analyses showed elevated 7-dehydrocholesterol and lanosterol levels, particularly in G2 and male patients, who had broader spectra of altered phosphatidylcholines and acylcarnitines than G1 and female patients, respectively. Compared with controls, CHC patients had higher post-therapy levels of total lysophosphatidylcholines and hydroxysphingomyelins and ratios of total dicarboxyacylcarnitines/total acylcarnitines but lower cholesterol levels. Conclusions At 24 weeks after therapy, accelerated cholesterol biosynthesis, hepatic lipid export, ω-oxidation, and decreased systemic inflammation were noted in CHC patients with SVR, with greater efficiency in G2 and male patients. Regardless, HCV-associated lipid metabolic alterations required >24 weeks for restoration or were incompletely reversible after SVR.

No effective drug is currently available for treatment of enterovirus 71 (EV71) infection. Schizonepeta tenuifolia Briq. (ST) has been used as a herbal constituent of traditional Chinese medicine. We studied whether the aqueous extract of Schizonepeta tenuifolia Briq (STE) has antiviral activity. STE inhibited replication of EV71, as evident by its ability to diminish plaque formation and cytopathic effect induced by EV71, and to inhibit the synthesis of viral RNA and protein. Moreover, daily single-dose STE treatment significantly improved the survival of EV71-infected mice, and ameliorated the symptoms. Mechanistically, STE exerts multiple effects on enteroviral infection. Treatment with STE reduced viral attachment and entry; the cleavage of eukaryotic translation initiation factor 4 G (eIF4G) by EV71 protease, 2Apro; virus-induced reactive oxygen species (ROS) formation; and relocation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) from the nucleus to the cytoplasm. It was accompanied by a decline in EV71-associated hyperphosphorylation of p38 kinase and EPS15. It is plausible that STE may inhibit ROS-induced p38 kinase activation, and subsequent hnRNP A1 relocation and EPS15-mediated membrane trafficking in infected cells. These findings suggest that STE possesses anti-EV71 activities, and may serve as health food or candidate antiviral drug for protection against EV71.

Guillain-Barre Syndrome (GBS) is an inflammatory disease of the peripheral nervous system. Given that plasma metabolic profiles in GBS patients have never been explored, plasma samples of 38 GBS patients, 22 multiple sclerosis (MS) patients, and 40 healthy controls were analyzed by using untargeted and targeted metabolomics analysis. The untargeted analysis showed that levels of a set of plasma lipid metabolites were significantly decreased in GBS patients compared to the controls. Furthermore, the targeted analysis demonstrated that levels of 41 metabolites in GBS patients were significantly changed compared to either the controls or MS patients. A further metabolic analysis showed that 12 of 41 metabolites were significantly lower in classical GBS patients compared to Miller-Fisher syndrome. Among them, each of PCae C34:0, PCae C42:2, PCae C42:3, and SM C24:0 was inversely correlated with Hughes functional grading scale of GBS patients at both nadir and discharge. Receiver operating characteristic curve analysis of combination of three metabolites (PCaa C42:2, PCae C36:0 and SM C24:0) showed a good discrimination between the GBS and the controls (area under curve = 0.86). This study has demonstrated disruption of lipid metabolites in GBS may be potential biomarkers to indicate disease severity and prognosis of GBS.

Background Guillain-Barre syndrome (GBS) is an acute inflammatory polyneuropathy resulting in demyelination in peripheral nervous system. Myelin enriched in lipids is easily oxidized by reactive oxygen species during inflammation. Oxidative stress and lipophilic anti-oxidative capacities in GBS patients have not been fully explored. To evaluate the redox status of GBS patients, we measured malondialdehyde (MDA), myeloperoxidase (MPO), lipophilic antioxidants, and tocopherols concentrations in plasma from GBS patients and age-matched healthy controls. Results Concentrations of γ-tocopherol and δ-tocopherol decreased significantly, and α-carotene significantly increased in GBS patients compared to healthy controls. However, no significant changes in MDA and MPO concentrations were detected. In GBS patients, the γ-tocopherol concentration correlated positively with concentrations of δ-tocopherol, α-tocopherol, lutein, Q10, and γ-CEHC, respectively. Similarly, the δ-tocopherol concentration correlated positively with γ-tocopherol, α-tocopherol, lutein, Q10, δ-CEHC, and γ-CEHC concentrations, respectively. The receiver operating characteristics curve analysis showed that γ-tocopherol may serve as a good predictor for GBS. Conclusions Diminished lipophilic antioxidant defense, mainly γ-tocopherol and δ-tocopherol, in GBS patients accounting for their lowered resistance to reactive oxygen species is probably associated with pathogenesis of GBS, and potentially useful for the development of therapeutic strategies.

Summary Background Trichilemmoma is a benign follicular epithelial tumour exhibiting outer root sheath differentiation. It is associated with Cowden syndrome and naevus sebaceus (NS), but the pathogenesis of sporadic tumours is poorly understood. Recently, NS was found to be caused by postzygotic HRAS or KRAS mutations. Objectives We sought to determine whether NS-related and NS-unrelated trichilemmomas harbour RAS mutations. Methods Formalin-fixed and paraffin-embedded blocks of 12 NS-related and 15 NS-unrelated trichilemmomas from 26 individuals were retrieved and analysed to determine the presence of mutations in exons 1 and 2 of the HRAS, KRAS and NRAS genes by polymerase chain reaction and direct sequencing. Mutational hotspots of the FGFR3 and PIK3CA genes were also analysed for NS-unrelated cases. Results Among the 27 cases, mutually exclusive HRAS c.37G>C and c.182A>G mutations were observed in 17 and three tumours, respectively. Of the 12 NS-related tumours, 11 (92%) harboured the HRAS c.37G>C substitution. Of the 15 sporadic tumours, nine (60%) harboured HRAS mutations, including six c.37G>C and three c.182A>G. An HRAS c.182A>G mutation was observed only in sporadic tumours. No mutations were observed in the other genes that were tested. Conclusions The high frequency of HRAS activating mutations, including the c.182A>G substitution, which was rather rare in NS, suggests that most trichilemmomas are authentic neoplasms.

4-Chloro-2,6-bis[(3,5-dimethyl-1 H-pyrazol-1-yl)methyl]phenol has been synthesised and characterised, including by single-crystal X-ray diffraction. The benzene ring system is planar and makes dihedral angles of 88.90°(0.14) and 59.84°(0.11) with two pyrazole rings, respectively, and the two pyrazole rings are arranged trans to each other with the dihedral angles 87.22°(0.15). The luminescent property of the title compound was investigated. The molecular structure of the title compound has been optimised by density functional theory with B3LYP/6-31G (d, p) level, the optimised geometer parameters and vibrational frequencies are consistent with the experiment data.

Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 and dentatorubropallidoluysian atrophy, as well as Huntington disease, are a group of neurodegenerative disorders caused by a CAG triplet-repeat expansion encoding a long polyglutamine (polyQ) tract in the respective mutant proteins. The cytoplasmic and nuclear aggregate formation, a pathological hallmark of polyQ diseases, is probably the initial process triggering the subsequent pathological events. Compromised oxidative stress defense capacity and mitochondrial dysfunction have emerged as contributing factors to the pathogenesis of polyQ diseases. The roots of licorice ( Glycyrrhiza species) have long been used as an herbal medicine. In this study, we demonstrate the aggregate-inhibitory effect of Glycyrrhiza inflata herb extract and its constituents licochalcone A and ammonium glycyrrhizinate (AMGZ) in both 293 and SH-SY5Y ATXN3/Q 75 cells, SCA3 cell models. The reporter assay showed that G. inflata herb extract, licochalcone A, and AMGZ could enhance the promoter activity of peroxisome proliferator-activated receptor γ, coactivator 1α (PPARGC1A), a known regulator of mitochondrial biogenesis and antioxidative response genes. G. inflata extract, licochalcone A, and AMGZ upregulated PPARGC1A expression and its downstream target genes, SOD2 and CYCS, in the 293 ATXN3/Q 75 cell model. The expression of nuclear factor erythroid 2-related factor 2 (NFE2L2), the principal transcription factor that binds to antioxidant-responsive elements (AREs) to promote ARE-dependent gene expression when the cells respond to oxidative stress, and its downstream genes, HMOX1, NQO1, GCLC, and GSTP1, was also increased by G. inflata herb extract, licochalcone A, and AMGZ. Knockdown of PPARGC1A increased aggregates in ATXN3/Q 75 cells and also attenuated the aggregate-inhibiting effect of the tested compounds. G. inflata extract and its constituents significantly elevated GSH/GSSG ratio and reduced reactive oxidative species in ATXN3/Q 75 cells. The study results suggest that the tested agents activate PPARGC1A activity and NFE2L2–ARE signaling to increase mitochondrial biogenesis, decrease oxidative stress, and reduce aggregate formation in SCA3 cellular models.

A new ligand 1-carboxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid (H2L1) and its isomer 1-carboxymethyl-3-methyl-1H-pyrazole-4-carboxylic acid (H2L2) have been synthesized and characterized by IR and 1H NMR. Three complexes of these ligands, [M(HL1)2(H2O)2] (1: M = Zn; 2: M = Cu) and [Cd(HL2)2(H2O)2] (3) were synthesized by the reactions of H2L1 or H2L2 with the corresponding M(NO3)2·6H2O. The complexes were characterized by physico-chemical and spectroscopic methods, single-crystal X-ray diffraction, and thermogravimetric analysis. Complexes 1 and 2 are isostructural, while complex 3 crystallizes in the triclinic system. The M(II) atom in each of the complexes has a distorted octahedral geometry involving two oxygen and two nitrogen atoms from two anionic (HL1)− or (HL2)− ligands and two oxygen atoms from water ligands. Adjacent monomeric components are connected by hydrogen bonds to form a 3D supramolecular network. The free ligands and complexes 1 and 3 show dual-emissive luminescence in the solid state at room temperature. The luminescence intensity of solid complex 1 is weakened in the presence of NH3. Two new isomers, H2L1 and H2L2, and three complexes, [Zn(HL1)2(H2O)2], [Cu(HL1)2(H2O)2], and [Cd(HL2)2(H2O)2] have been synthesized, which display dual-emissive luminescence in the solid state.

Glucose-6-phosphate dehydrogenase (G6PD) is critical to the maintenance of NADPH pool and redox homeostasis. Conventionally, G6PD deficiency has been associated with hemolytic disorders. Most biochemical variants were identified and characterized at molecular level. Recently, a number of studies have shone light on the roles of G6PD in aspects of physiology other than erythrocytic pathophysiology. G6PD deficiency alters the redox homeostasis, and affects dysfunctional cell growth and signaling, anomalous embryonic development, and altered susceptibility to infection. The present article gives a brief review of basic science and clinical findings about G6PD, and covers the latest development in the field. Moreover, how G6PD status alters the susceptibility of the affected individuals to certain degenerative diseases is also discussed.

When the railway pass through the desert and highlands, it is often corroded and buried by the sand. So it is necessary to spread out nylon material sand-fixation net along with the railway for windbreak and sand-fixation. The using of the refractory nylon net is restricted because it is difficult to be degraded. Nowadays, much attention has been paid to the desertification. To mitigate the effects of desertification, it is imperative to research for a new type of sand-fixation material. Here, we deal fiber-linen with advanced surface treatment technology to make a new kind of material which can be degraded. It is not only environmental-friendly and advanced but also very cheap, Whats more, it has the excellent abilities of ageing resistance, water resistance, and UV resistance.

Autophagy and endoplasmic reticulum (ER) stress response is important for cancer cells to maintain malignancy and resistance to therapy. trans-Resveratrol (RSV), a non-flavonoid agent, has been shown to induce apoptosis in human nasopharyngeal carcinoma (NPC) cells. In this study, the involvements of tumor-specific ER stress and autophagy in the RSV-mediated apoptosis were investigated. In addition to traditional autophagosomes, the images of transmission electron microscopy (TEM) indicated that RSV markedly induced larger, crescent-shaped vacuoles with single-layered membranes whose the expanded cisternae contains multi-lamellar membrane structures. Prolonged exposure to RSV induced a massive accumulation of ER expansion. Using an EGFP-LC3B transfection and confocal laser microscopy approach, we found RSV-induced EGFP-LC3 puncta co-localized with ER-tracker red dye, implicating the involvement of LC3II in ER expansion. The proapoptotic effect of RSV was enhanced after suppression of autophagy by ATG7 siRNA or blocking the autophagic flux by bafilomycin A1, but that was not changed after targeted silence of IRE1 or CHOP by siRNA. Using caspase inhibitors, we demonstrated the upregulation of caspase-12 (casp12) and the activation of casp4 were associated with the proapoptotic induction of RSV through the caspase-9/caspase-3 pathway. Intriguingly, siRNA knockdown of casp12, but not caspase-4, decreased the susceptibility of the NPC cells to RSV-mediated apoptosis. Further, we showed that RSV dose-dependently increased the ceramide accumulation as assessed by LC-MS/MS system. Using serine palmitoyltransferase (SPT, a key enzyme of de novo ceramide biosynthesis) inhibitors (L-cycloserine and myriocin), we found the increased ceramide accumulation was strongly correlated with the proapoptotic potential of RSV. This study revealed the ER expansion and upregulation of ER casp12 together may indicate profound biological effects of RSV and contributed to NPC cell death. Targeting the different status of ER stress may provide a possible strategy for cancer treatments.

In response to infection, neutrophils employ various strategies to defend against the invading microbes. One of such defense mechanisms is the formation of neutrophil extracellular traps (NETs). Recent studies suggest that reactive oxygen species is a signal critical to NET formation. This prompts us to examine whether neutrophils from individuals with glucose-6-phosphate dehydrogenase (G6PD) Taiwan-Hakka variant, which are prone to oxidative stress generation, have altered ability to form NET. We adopted an image-based method to study the NET formation potential in neutrophils from G6PD-deficient patients. Neutrophils from either normal or G6PD-deficient individuals underwent NETosis in response to phorbol 12-myristate 13-acetate (PMA). The extent of NETosis in the former did not significantly differ from that of the latter. Diphenyleneiodonium sulfate (DPI) and 3-methyladenine (MA) inhibited PMA-stimulated NET formation in these cells, suggesting the involvement of NADPH oxidase and autophagy in the process. Glucose oxidase (GO) and xanthine oxidase/xanthine (XO/X) could induce a similar extent of NET formation in normal and G6PD-deficient neutrophils. GO- or XO-induced NETosis was not inhibitable by MA, implying that reactive oxygen species (ROS) can act as an independent signal for activation of NETosis. Mechanistically, enhanced superoxide production in neutrophils was associated with increases in levels of NAD(+) and NADP(+), as well as activation of NAD(+) kinase. Taken together, these findings suggest that G6PD-deficient neutrophils are as equally efficient as normal cells in NET formation, and their deficiency in G6PD-associated NADPH regeneration capacity is largely compensated for by nicotinamide nucleotide biosynthesis.

Glucose-6-phosphate dehydrogenase (G6PD) is pivotal to reduced nicotinamide adenine dinucleotide phosphate (NADPH) production and cellular redox balance. Cells with G6PD deficiency are susceptible to oxidant-induced death at high oxidative stress. However, it remains unclear what precise biological processes are affected by G6PD deficiency due to altered cellular redox homeostasis, particularly at low oxidative stress. To further explore the biological role of G6PD, we generated G6PD-knockdown cell clones using lung cancer line A549. We identified proteins differentially expressed in the knockdown clones without the addition of exogenous oxidant by means of isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with multidimensional liquid chromatography–mass spectrometry (LC–MS/MS). We validated a panel of proteins that showed altered expression in G6PD-knockdown clones and were involved in metabolism of xenobiotic and glutathione (GSH) as well as energy metabolism. To determine ...

Bamboo paper sludge is a kind of industrial solid wastes and it is difficult to deal with it. In this study, the spectrum of bamboo paper sludge and the relationship between sludge with two different adhesives were investigated. Besides, the contents of C, H, O, N, S were measured by elemental analysis instrument of Vario Ⅲ. The results showed that: bamboo paper sludge FTIR spectrum was composed of five regions; kaolin and benzene derivatives were contained in sludge. UF was covered the surface of sludge forming a thick glue line and spectra was covered. But, the phenomenon did not appear in PF. The content of C, H, O, N, S in bamboo paper sludge was 35.68%, 6.4%, 18.48%, 3.27%, 1.21% respectively.