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This study aimed to characterize the lipidomic responses to community-acquired pneumonia (CAP) and provide new insight into the underlying mechanisms of pathogenesis and potential avenues for diagnostic and therapeutic treatments. This study was performed from January 2017 to October 2018. Lipidomic profiles were generated using ultra high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) platform. Spearman's rank correlation test and multiple linear regression analysis were applied to explore the correlation between changes in the relative abundance of lipids and clinical parameters. Kaplan–Meier methods were used to build 30-day survival curves. From the UHPLC-MS/MS results, a total of 509 and 195 lipid species were detected in the positive and negative ionization mode respectively. Positive ionization covered six lipid classes (glycerol-phospholipids, glycerolipids, sphingolipids, sterol-lipids, prenol-lipids, and fatty acid), whilst negative ionization covered three (glycerol-phospholipids, sphingolipids, fatty acid). Four lipids were selected as targets: PC (16:0_18:1), PC (18:2_20:4), PC (36:4), and PC (38:6). The relative increase of the areas under the curves for all four lipids were superior to the pneumonia severity index and CURB-65 (confusion, urea, respiratory rate, blood pressure, and age ≥65 years old) for discriminating severe CAP from CAP. Decreasing relative levels of PC (18:2_20:4), PC (38:6), and PC (36:4) were negatively related to fraction of inspiration O2; Changes in the relative abundance of PC (16:0_18:1) and PC (18:2_20:4) had significantly linear relationship with procalcitonin. Patients with an elevated level of PC (16:0_18:1) had significantly longer duration of hospital stays. As the relative abundance of PC (18:2_20:4), PC (36:4), and PC (38:6) decreased, the length of hospitalization days and 30-day mortality rate increased significantly (all log-rank p<0.05). Therefore, using the UHPLC-MS/MS platform's serum lipidomic approach can help reveal changes in lipid abundance during CAP and establish lipid profiles related to disease severity. [ABSTRACT FROM AUTHOR]

The intramuscular fat (IMF) content and fatty acid composition are important meat quality traits that are mostly affected by the cattle breed. Muscle, adipose tissue and liver are important organs involved in the development of intramuscular adipose tissue. Thus, we hypothesized that there were marked differences in the adipogenesis and lipid metabolism of these tissues between Wagyu-cross and Holstein steers during the finishing phases. To test this hypothesis, we analyzed the expression levels of adipogenesis- and lipid metabolism-related genes in longissimus muscle (LM), subcutaneous fat (SCF) and liver from Wagyu-cross and Holstein steers at 26 months of age. The IMF content and fatty acid profile of LM were determined. Wagyu-cross steers had a higher IMF content and MUFA percentages in the LM than Holstein steers (P<0.05). The relative expression of FGF2, COL1A1, SREBP1c, SCD1, GRP78 and LEP was greater in the LM of Wagyu-cross steers than in Holstein steers (P<0.05). In contrast, Holstein steer SCF had higher (P<0.05) mRNA expression levels of FABP4 and ADIPOQ than Wagyu-cross steers. In the liver, the expression of SREBP1c and GRP78 in Wagyu-cross steers was significantly higher than that in Holstein steers (P<0.05). The results demonstrate that both intramuscular adipogenesis and fibrogenesis are enhanced in Wagyu-cross steers compared with Holstein steers during the finishing phase and that IMF deposition is positively correlated with the maturity of SCF and hepatic lipid accumulation in Wagyu-cross steers. [ABSTRACT FROM AUTHOR]

Background: Gangliosides are a class of sphingolipids that are present in the cell membranes of vertebrates. Gangliosides influence a broad range of cellular processes through effects on signal transduction, being found abundantly in the brain, and having a role in neurodevelopment. Objective: We aimed to assess the effects of maternal daily consumption of ganglioside-enriched milk vs non-enriched milk and a non-supplemented group of pregnant women on maternal ganglioside levels and pregnancy outcomes. Design: Double-blind parallel randomized controlled trial. Methods: 1,500 women aged 20–40 years were recruited in Chongqing (China) between 11 and 14 weeks of a singleton pregnancy, and randomized into three groups: Control–received standard powdered milk formulation (≥4 mg gangliosides/day); Complex milk lipid-enhanced (CML-E) group–same formulation enriched with complex milk lipids (≥8 mg gangliosides/day) from milk fat globule membrane; Reference–received no milk. Serum ganglioside levels were measured in a randomly selected subsample of 250 women per group. Results: CML-E milk was associated with marginally greater total gangliosides levels in maternal serum compared to Control (13.02 vs 12.69 μg/ml; p = 0.034) but not to Reference group. CML-E milk did not affect cord blood ganglioside levels. Among the 1500 women, CML-E milk consumption was associated with a lower rate of gestational diabetes mellitus than control milk [relative risk 0.80 (95% CI 0.64, 0.99)], but which was not different to the Reference group. CML-E milk supplementation had no other effects on maternal or newborn health. Conclusions: Maternal supplementation with milk fat globule membrane, as a source of gangliosides, was not associated with any adverse health outcomes, and did not increase serum gangliosides compared with the non-supplemented reference group. Trial registration: Chinese Clinical Trial Register (ChiCTR-IOR-16007700). Clinical trial registration: ChiCTR-IOR-16007700; www.chictr.org.cn/showprojen.aspx?proj=12972. [ABSTRACT FROM AUTHOR]

Flip-flop of lipids of the lipid bilayer (LBL) constituting the plasma membrane (PM) plays a crucial role in a myriad of events ranging from cellular signaling and regulation of cell shapes to cell homeostasis, membrane asymmetry, phagocytosis, and cell apoptosis. While extensive research has been conducted to probe the lipid flip flop of planar lipid bilayers (LBLs), less is known regarding lipid flip-flop for highly curved, nanoscopic LBL systems despite the vast importance of membrane curvature in defining the morphology of cells and organelles and in maintaining a variety of cellular functions, enabling trafficking, and recruiting and localizing shape-responsive proteins. In this paper, we conduct molecular dynamics (MD) simulations to study the energetics, structure, and configuration of a lipid molecule undergoing flip-flop and desorption in a highly curved LBL, represented as a nanoparticle-supported lipid bilayer (NPSLBL) system. We compare our findings against those of a planar substrate supported lipid bilayer (PSSLBL). Our MD simulation results reveal that despite the vast differences in the curvature and other curvature-dictated properties (e.g., lipid packing fraction, difference in the number of lipids between inner and outer leaflets, etc.) between the NPSLBL and the PSSLBL, the energetics of lipid flip-flop and lipid desorption as well as the configuration of the lipid molecule undergoing lipid flip-flop are very similar for the NPSLBL and the PSSLBL. In other words, our results establish that the curvature of the LBL plays an insignificant role in lipid flip-flop and desorption. [ABSTRACT FROM AUTHOR]

Background: HIV patients are at increased cardiovascular risk while available European cardiovascular recommendations are ambiguous. Methods: Retrospective analysis of 389 HIV-patients was conducted. Cardiovascular risk was determined by D:A:D, Framingham and SCORE scales. Patients were divided into risk groups as recommended by EACS 2019, PTN AIDS 2019 and ESC/EAS 2019 Guidelines and hypolipemic treatment was evaluated. Results: In total, 389 HIV-positive patients took part in the study, most of whom were men (n = 312, 80.4%), mean age 41.69±10years. Mean lipid levels among all HIV patients: Tch:177.2±36mg/dl, HDL:48.9±18mg/dl, LDL:103.8±31mg/dl, TG:143.3±81mg/dl, AIP:0.45±0.3, non-HDL:129.2±36 mg/dl. Most of the participants (n = 360, 92.5%) were assigned to the high cardiovascular risk group according to ESC/EAS and PTN AIDS guidelines. The achievement of therapeutic LDLs according to ESC/EAS was 10.3% for those at very high cardiovascular risk (8.7% on lipid lowering treatment vs. 16.7% without hypolipemic drugs) and 12.0% (5.8% treated vs. 13.6% untreated) at high cardiovascular risk; according to PTN AIDS,17.2% achievement was noted by the very high-risk group (13% treated vs. 33.3% untreated), and 45.9% for the high-risk group (37.7% treated vs. 48.0% untreated); according to EACS Guidelines, 2.5% achievement in secondary prevention (3.8% treatedvs. 0% untreated) and 24.7% in primary prevention (22.2% treated vs. 26.1% untreated). Mean doses of statins were 8.75mg±6mg (Rosuvastatin) and 22.35±19mg (Atorvastatin). Conclusions: The achievement of therapeutic LDLs by all recommendations is unsatisfactory, and generally worse in patients on lipid lowering therapy. Hypolipemic treatment of our HIV patients is based on low doses of statins, even in secondary prevention. [ABSTRACT FROM AUTHOR]

MORN (Membrane Occupation and Recognition Nexus) repeat proteins have a wide taxonomic distribution, being found in both prokaryotes and eukaryotes. Despite this ubiquity, they remain poorly characterised at both a structural and a functional level compared to other common repeats. In functional terms, they are often assumed to be lipid-binding modules that mediate membrane targeting. We addressed this putative activity by focusing on a protein composed solely of MORN repeats—Trypanosoma brucei MORN1. Surprisingly, no evidence for binding to membranes or lipid vesicles by TbMORN1 could be obtained either in vivo or in vitro. Conversely, TbMORN1 did interact with individual phospholipids. High- and low-resolution structures of the MORN1 protein from Trypanosoma brucei and homologous proteins from the parasites Toxoplasma gondii and Plasmodium falciparum were obtained using a combination of macromolecular crystallography, small-angle X-ray scattering, and electron microscopy. This enabled a first structure-based definition of the MORN repeat itself. Furthermore, all three structures dimerised via their C-termini in an antiparallel configuration. The dimers could form extended or V-shaped quaternary structures depending on the presence of specific interface residues. This work provides a new perspective on MORN repeats, showing that they are protein-protein interaction modules capable of mediating both dimerisation and oligomerisation. [ABSTRACT FROM AUTHOR]

Plant-derived terpenoids are extensively used in perfume, food, cosmetic and pharmaceutical industries, and several attempts are being made to produce terpenes in heterologous hosts. Native hosts have evolved to accumulate large quantities of terpenes in specialized cells. However, heterologous cells lack the capacity needed to produce and store high amounts of non-native terpenes, leading to reduced growth and loss of volatile terpenes by evaporation. Here, we describe how to direct the sesquiterpene patchoulol production into cytoplasmic lipid droplets (LDs) in Physcomitrium patens (syn. Physcomitrella patens), by attaching patchoulol synthase (PTS) to proteins linked to plant LD biogenesis. Three different LD-proteins: Oleosin (PpOLE1), Lipid Droplet Associated Protein (AtLDAP1) and Seipin (PpSeipin325) were tested as anchors. Ectopic expression of PTS increased the number and size of LDs, implying an unknown mechanism between heterologous terpene production and LD biogenesis. The expression of PTS physically linked to Seipin increased the LD size and the retention of patchoulol in the cell. Overall, the expression of PTS was lower in the anchored mutants than in the control, but when normalized to the expression the production of patchoulol was higher in the seipin-linked mutants. [ABSTRACT FROM AUTHOR]

The activity of antimicrobial peptides (AMPs) has significant bacterial species bias, the mechanisms of which are not fully understood. We employed single-molecule tracking to measure the affinity of three different AMPs to hybrid supported bilayers composed of lipid A extracted from four different Gram negative bacteria and observed a strong empirical anticorrelation between the affinity of a particular AMP to a given lipid A layer and the activity of that AMP towards the bacterium from which that lipid A was extracted. This suggested that the species bias of AMP activity is directly related to AMP interactions with bacterial outer membranes, despite the fact that the mechanism of antimicrobial activity occurs at the inner membrane. The trend also suggested that the interactions between AMPs and the outer membrane lipid A (even in the absence of other components, such as lipopolysaccharides) capture effects that are relevant to the minimum inhibitory concentration. [ABSTRACT FROM AUTHOR]

Antigen cross presentation, whereby exogenous antigens are presented by MHC class I molecules to CD8+ T cells, is essential for generating adaptive immunity to pathogens and tumor cells. Following endocytosis, it is widely understood that protein antigens must be transferred from endosomes to the cytosol where they are subject to ubiquitination and proteasome degradation prior to being translocated into the endoplasmic reticulum (ER), or possibly endosomes, via the TAP1/TAP2 complex. Revealing how antigens egress from endocytic organelles (endosome-to-cytosol transfer, ECT), however, has proved vexing. Here, we used two independent screens to identify the hydrogen peroxide-transporting channel aquaporin-3 (AQP3) as a regulator of ECT. AQP3 overexpression increased ECT, whereas AQP3 knockout or knockdown decreased ECT. Mechanistically, AQP3 appears to be important for hydrogen peroxide entry into the endosomal lumen where it affects lipid peroxidation and subsequent antigen release. AQP3-mediated regulation of ECT was functionally significant, as AQP3 modulation had a direct impact on the efficiency of antigen cross presentation in vitro. Finally, AQP3-/- mice exhibited a reduced ability to mount an anti-viral response and cross present exogenous extended peptide. Together, these results indicate that the AQP3-mediated transport of hydrogen peroxide can regulate endosomal lipid peroxidation and suggest that compromised membrane integrity and coordinated release of endosomal cargo is a likely mechanism for ECT. [ABSTRACT FROM AUTHOR]

SR-BI binds various lipoproteins, including HDL, LDL as well as VLDL, and mediates selective cholesteryl ester (CE) uptake. HDL derived CE accumulates in cellular lipid droplets (LDs), which also store triacylglycerol (TAG). We hypothesized that SR-BI could significantly facilitate LD formation, in part, by directly transporting LDL derived neutral lipids (NL) such as CE and TAG into LDs without lipolysis and de novo lipid synthesis. SR-BI overexpression greatly increased LDL uptake and LD formation in stably transfected HeLa cells (SR-BI-HeLa). LDs isolated from SR-BI-HeLa contained 4- and 7-times more CE and TAG, respectively, than mock-transfected HeLa (Mock-HeLa). In contrast, LDL receptor overexpression in HeLa (LDLr-HeLa) greatly increased LDL uptake, degradation with moderate 1.5- and 2-fold increases of CE and TAG, respectively. Utilizing CE and TAG analogs, BODIPY-TAG (BP-TAG) and BODIPY-CE (BP-CE), for tracking LDL NL, we found that after initial binding of LDL to SR-BI-HeLa, apoB remained at the cell surface, while BP-CE and BP-TAG were sorted and simultaneously transported together to LDs. Both lipids demonstrated limited internalization to lysosomes or endoplasmic reticulum in SR-BI-HeLa. In LDLr-HeLa, NLs demonstrated clear lysosomal sequestration without their sorting to LDs. An inhibition of TAG and CE de novo synthesis by 90–95% only reduced TAG and CE LD content by 45–50%, and had little effect on BP-CE and BP-TAG transport to LDs in SR-BI HeLa. Furthermore, intravenous infusion of 1–2 mg of LDL increased liver LDs in normal (WT) but not in SR-BI KO mice. Mice transgenic for human SR-BI demonstrated higher liver LD accumulation than WT mice. Finally, Electro Spray Infusion Mass Spectrometry (ESI-MS) using deuterated d-CE found that LDs accumulated up to 40% of unmodified d-CE LDL. We conclude that SR-BI mediates LDL-induced LD formation in vitro and in vivo. In addition to cytosolic NL hydrolysis and de novo lipid synthesis, this process includes selective sorting and transport of LDL NL to LDs with limited lysosomal NL sequestration and the transport of LDL CE, and TAG directly to LDs independently of de novo synthesis. [ABSTRACT FROM AUTHOR]

The oral lipid tolerance test (OLTT) has been known to assess intestinal fat metabolism and whole-body lipid metabolism, but rodent models for OLTT are not yet established. Differences in OLTT methodology preclude the generation of definitive results, which may cause some confusion about the anti-hypertriglyceridemia effects of the test materials. To standardize and generate more appropriate methodology for the OLTT, we examined the effects of mice strain, dietary lipid sources, fasting period, and gender on lipid-induced hypertriglyceridemia in mice. First, lipid-induced hypertriglyceridemia was more strongly observed in male ddY mice than in C57BL/6N or ICR mice. Second, the administration of olive and soybean oils remarkably represented lipid-induced hypertriglyceridemia. Third, fasting period before the OLTT largely affected the plasma triglyceride elevation. Fasting for 12 h, but less than 48 h, provoked lipid-induced hypertriglyceridemia. Fourth, we explored the suppressive effects of epigallocatechin gallate (EGCG), a green tea polyphenol, on lipid-induced hypertriglyceridemia. The administration of 100 mg/kg of EGCG suppressed lipid-induced hypertriglyceridemia and intestinal lipase activity. Fifth, EGCG-induced suppressive effects were observed after lipid-induced hypertriglyceridemia was observed in male mice, but not in female mice. Lastly, lipid-induced hypertriglyceridemia could be more effectively induced in mice fed a high-fat diet for 1 week before the OLTT. These findings indicate that male ddY mice after 12 h fasting displayed marked lipid-induced hypertriglyceridemia in response to soybean oil. Hence, the defined experiment condition may be a more appropriate OLTT model for evaluating lipid-induced hypertriglyceridemia. [ABSTRACT FROM AUTHOR]

Ever decreasing efficiency of antibiotic treatment due to growing antibiotic resistance of pathogenic bacteria is a critical issue in clinical practice. The two generally accepted major approaches to this problem are the search for new antibiotics and the development of antibiotic adjuvants to enhance the antimicrobial activity of known compounds. It was therefore the aim of the present study to test whether alkylresorcinols, a class of phenolic lipids, can be used as adjuvants to potentiate the effect of various classes of antibiotics. Alkylresorcinols were combined with 12 clinically used antibiotics. Growth-inhibiting activity against a broad range of pro- and eukaryotic microorganisms was determined. Test organisms did comprise 10 bacterial and 2 fungal collection strains, including E. coli and S. aureus, and clinical isolates of K. pneumoniae. The highest adjuvant activity was observed in the case of 4-hexylresorcinol (4-HR), a natural compound found in plants with antimicrobial activity. 50% of the minimal inhibitory concentration (MIC) of 4-HR caused an up to 50-fold decrease in the MIC of antibiotics of various classes. Application of 4-HR as an adjuvant revealed its efficiency against germination of bacterial dormant forms (spores) and prevented formation of antibiotic-tolerant persister cells. Using an in vivo mouse model of K. pneumoniae-induced sepsis, we could demonstrate that the combination of 4-HR and polymyxin was highly effective. 75% of animals were free of infection after treatment as compared to none of the animals receiving the antibiotic alone. We conclude that alkylresorcinols such as 4-HR can be used as an adjuvant to increase the efficiency of several known antibiotics. We suggest that by this approach the risk for development of genetically determined antibiotic resistance can be minimized due to the multimodal mode of action of 4-HR. [ABSTRACT FROM AUTHOR]

Potentilla longifolia is a kind of Chaoyao medicine, which is a branch of traditional Chinese medicine. The plant is often referred to as ganyancao or ganyearmcao, which means that it has a significant therapeutic effect on liver inflammation. In previous experiments, we found that a water extract of ganyearmcao inhibited lipid accumulation. In the present study, we isolated one new (ganyearmcaoone A, 1) and eight known compounds (2–9) from a water extract of the dried roots of ganyearmcao; all of the compounds were isolated for the first time from this medicinal plant. We elucidated the chemical structures of these compounds using comprehensive analyses of HR-ESI-MS and 1D, 2D NMR. We evaluated the inhibitory effects of the nine compounds on lipid accumulation in 3T3-L1 cells; we did so using photographic and quantitative assessments of the lipid content with oil red O staining and by measuring triglyceride levels. Compared with the control, compounds 6 and 9 significantly inhibited differentiation of 3T3-L1 cells and lipid accumulation. Compound 1 showed potential inhibitory effects on lipid accumulation. Molecular docking results indicated that compounds 6 and 9 may efficiently bind to AMPK and its downstream kinase (SCD1), thereby inhibiting lipid accumulation. Our results demonstrate that ganyearmcao and its components may play an important role in treating diseases related to lipid accumulation in the future. [ABSTRACT FROM AUTHOR]

Background: A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR).Methods and Findings: Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study.Conclusions: We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk. [ABSTRACT FROM AUTHOR]

Aims: Inflammation plays a pivotal role in atherothrombosis. Colchicine is an anti-inflammatory drug that may attenuate this process. Cardiovascular protective effects of anti-inflammatory drugs, however, seem to be limited to patients with a biochemical response. We therefore investigated whether short-term exposure to colchicine reduced inflammatory markers and whether additional laboratory changes occur in patients with chronic coronary artery disease. Methods & results: In 138 consecutive patients with chronic coronary artery disease and a high sensitivity C-reactive Protein (hs-CRP) ≥ 2 mg/L, inflammatory markers, lipids, haematologic parameters and renal function were measured at baseline and after 30 days exposure to colchicine 0.5mg once daily. Hs-CRP decreased from baseline 4.40 mg/L (interquartile range [IQR] 2.83–6.99 mg/L) to 2.33 mg/L (IQR 1.41–4.17, median of the differences -1.66 mg/L, 95% confidence interval [CI] -2.17 – -1.22 mg/L, p-value <0.01), corresponding to a median change from baseline of -40%. Interleukin-6 decreased from 2.51 ng/L (IQR 1.59–4.32 ng/L) to 2.22 ng/L (median of the differences -0.36 ng/L, 95%CI -0.70 – -0.01 ng/L, p-value 0.04), corresponding to a median change from baseline of -16%. No clinically relevant changes in lipid fractions were observed. Both leukocyte and thrombocyte count decreased (median change from baseline -7% and -4% respectively). Estimated glomerular filtration rate decreased with a mean change from baseline of -2%. Conclusion: In patients with chronic coronary artery disease and elevated hs-CRP, one-month exposure to colchicine 0.5 mg once daily was associated with a reduction of inflammatory markers. A small effect was seen on white blood cell count and platelet count, as well as a small decrease in estimated glomerular filtration rate. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of HIV infection and combined antiretroviral therapy (c-ART) on various proatherogenic biomarkers and lipids and to investigate their relationship with subclinical atherosclerosis in a cohort of treatment-naive HIV-infected patients. Methods: We performed a prospective, comparative, multicenter study of 2 groups of treatment-naive HIV-infected patients (group A, CD4>500 cells/μL, not starting c-ART; and group B, CD4<500 cells/μL, starting c-ART at baseline) and a healthy control group. Laboratory analyses and carotid ultrasound were performed at baseline and at months 12 and 24. The parameters measured were low-density lipoprotein (LDL) particle phenotype, lipoprotein-associated phospholipase A2 (Lp-PLA2), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), sCD14, sCD163, monocyte chemoattractant protein-1(MCP-1), and asymmetric dimethylarginine (ADMA). A linear mixed model based on patient clusters was used to assess differences in biomarkers between the study groups and over time. Results: The study population comprised 62 HIV-infected patients (group A, n = 31; group B, n = 31) and 22 controls. Age was 37 (30–43) years, and 81% were men. At baseline, the HIV-infected patients had a worse LDL particle phenotype and higher plasma concentration of sCD14, sCD163, hs-CRP, and LDL-Lp-PLA2 than the controls. At month 12, there was an increase in total cholesterol (p = 0.002), HDL-c (p = 0.003), and Apo A-I (p = 0.049) and a decrease in sCD14 (p = <0.001) and sCD163 (p<0.001), although only in group B. LDL particle size increased in group B at month 24 (p = 0.038). No changes were observed in group A or in the healthy controls. Common carotid intima-media thickness increased in HIV-infected patients at month 24 (Group A p = 0.053; group B p = 0.048). Plasma levels of sCD14, sCD163, and hs-CRP correlated with lipid values. Conclusions: In treatment-naive HIV-infected patients, initiation of c-ART was associated with an improvement in LDL particle phenotype and inflammatory/immune biomarkers, reaching values similar to those of the controls. HIV infection was associated with progression of carotid intima-media thickness. [ABSTRACT FROM AUTHOR]

Background: Chronic childhood malnutrition, or stunting, remains a persistent barrier to achieve optimal cognitive development, child growth and ability to reach full potential. Almost half of children under-five years of age are stunted in the province of Sindh, Pakistan. Objective: The primary objective of this study was to test the hypothesis that the provision of lipid-based nutrient supplement—medium-quantity (LNS-MQ) known as Wawamum will result in a 10% reduction in risk of being stunted at the age of 24 months in the intervention group compared with the control group. Design: A cluster randomized controlled trial was conducted in Thatta and Sujawal districts of Sindh province, Pakistan. A total of 870 (419 in intervention; 451 in control) children between 6–18 months old were enrolled in the study. The unit of randomization was union council and considered as a cluster. A total of 12 clusters, 6 in each study group were randomly assigned to intervention and control group. All children received standard government health services, while children in the intervention group also received 50 grams/day of Wawamum. Results: Children who received Wawamum were found to have a significantly reduced risk of stunting (RR = 0.91, 95% CI; 0.88–0.94, p<0.001) and wasting (RR = 0.78, 95% CI; 0.67–0.92, p = 0.004) as compared to children who received the standard government health services. There was no evidence of a reduction in the risk of underweight (RR = 0.94, 95% CI; 0.85–1.04, p = 0.235) in the intervention group compared to the control group. Statistically significant reduction in anaemia in the intervention group was also found as compared to the control group (RR = 0.97, 95% CI; 0.94–0.99, p = 0.042). The subgroup analysis by age, showed intervention effect is significant in reduction of risk of stunting in younger children of aged 6–12 month (RR = 0.83, 95% CI; 0.81–0.86, p = <0.001) and their older peers aged 13–18 month- (RR = 0.90, 95% CI; 0.83–0.97, p = 0.008). The mean compliance of Wawamum was 60% among children. Conclusions: The study confirmed that the provision of Wawamum to children 6–23 months of age is effective in reducing the risk of stunting, wasting and anaemia. This approach should be scaled up among the most food insecure areas/households with a high prevalence of stunting to achieve positive outcomes for nutrition and health. This study was registered at clinicaltrials.gov as NCT02422953. Clinical Trial Registration Number: NCT02422953 [ABSTRACT FROM AUTHOR]

Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology. Author summary: Cardiovascular disease affects about a third of the world's population and is mediated by the buildup of lipids (primarily derived from plasma lipoproteins) in the wall of blood vessels. An essential protein required for the synthesis of the lipoproteins, from insects to humans, is microsomal triglyceride transfer protein (MTP). This protein transfers lipids, including triglycerides and phospholipids, to apolipoprotein B (APOB) for the assembly of ApoB-containing lipoproteins. Here we report a mutation in MTP that blocks the transfer of triglycerides but not phospholipids. Modeling based on the recent crystal structure of the MTP complex suggests the G865V mutation may block access to the region of the protein that binds triglyceride. In zebrafish, the residual phospholipid transfer activity of the mutant protein is sufficient to support secretion of small ApoB-containing lipoproteins and prevent a number of serious health conditions observed in humans harboring null MTP mutations (e.g., intestinal fat malabsorption, growth retardation). These results suggest that selective inhibitors of MTP that can mimic this mutation may be a feasible therapeutic approach to treat dyslipidemias in humans. [ABSTRACT FROM AUTHOR]

Marmoset wasting syndrome (MWS) is clinically characterized by progressive weight loss. Although morbidity and mortality of MWS are relatively high in captive marmosets, its causes remain unknown. Lipid mediators are bioactive metabolites which are produced from polyunsaturated fatty acids, such as arachidonic acid (AA) and eicosapentaenoic acid. These lipid metabolites regulate a wide range of inflammatory responses and they are excreted into the urine. As urinary lipid profiles reflect systemic inflammatory conditions, we comprehensively measured the levels of 141 types of lipid metabolites in the urines obtained from healthy common marmoset (Callithrix jacchus) (N = 7) or marmosets with MWS (N = 7). We found that 41 types of metabolites were detected in all urine samples of both groups. Among them, AA-derived metabolites accounted for 63% (26/41 types) of all detected metabolites. Notably, the levels of AA-derived prostaglandin (PG) E2, PGF2α, thromboxane (TX) B2 and F2-isoprostanes significantly increased in the urine samples of marmosets with MWS. In this study, we found some urinary lipid metabolites which may be involved in the development of MWS. Although the cause of MWS remains unclear, our findings may provide some insight into understanding the mechanisms of development of MWS. [ABSTRACT FROM AUTHOR]

Lipid droplets are essential cellular organelles for storage of fatty acids and triglycerides. The hepatitis C virus (HCV) translocates several of its proteins onto their surface and uses them for production of infectious progeny. We recently reported that the lipid droplet-associated α/β hydrolase domain-containing protein 5 (ABHD5/CGI-58) participates in HCV assembly by mobilizing lipid droplet-associated lipids. However, ABHD5 itself has no lipase activity and it remained unclear how ABHD5 mediates lipolysis critical for HCV assembly. Here, we identify adipose triglyceride lipase (ATGL) as ABHD5 effector and new host factor involved in the hepatic lipid droplet degradation as well as in HCV and lipoprotein morphogenesis. Modulation of ATGL protein expression and lipase activity controlled lipid droplet lipolysis and virus production. ABHD4 is a paralog of ABHD5 unable to activate ATGL or support HCV assembly and lipid droplet lipolysis. Grafting ABHD5 residues critical for activation of ATGL onto ABHD4 restored the interaction between lipase and co-lipase and bestowed the pro-viral and lipolytic functions onto the engineered protein. Congruently, mutation of the predicted ABHD5 protein interface to ATGL ablated ABHD5 functions in lipid droplet lipolysis and HCV assembly. Interestingly, minor alleles of ABHD5 and ATGL associated with neutral lipid storage diseases in human, are also impaired in lipid droplet lipolysis and their pro-viral functions. Collectively, these results show that ABHD5 cooperates with ATGL to mobilize triglycerides for HCV infectious virus production. Moreover, viral manipulation of lipid droplet homeostasis via the ABHD5-ATGL axis, akin to natural genetic variation in these proteins, emerges as a possible mechanism by which chronic HCV infection causes liver steatosis. Author summary: The multifaceted role of lipid droplets and their position as the main metabolic hub in the cell makes them a coveted target for intracellular pathogens, be there parasites, bacteria or viruses. Lipid droplets are the main energy reservoir of the cell, and this is often the function hijacked by the pathogens. With its low density, its apolipoprotein coat and its neutral lipid core, the HCV particle resembles host-circulating lipoproteins. Here we report that HCV hijacks the lipid droplet-associated adipose triglyceride lipase (ATGL) for its morphogenesis. Given that ABHD5 and to some extent ATGL also participate in lipoprotein secretion, our results indicate that lipid droplets might serve as a source for the lipids of the atypical HCV lipo-viro-particle. They also imply that viral hijacking of the ABHD5-ATGL host machinery might disturb lipid droplet homeostasis thus contributing to HCV-dependent liver steatosis. [ABSTRACT FROM AUTHOR]

Sediments from stratified marine environments often show an enhanced preservation of organic matter (OM) which is attributed to the limitation, or absence, of oxygen in the bottom waters and surface sediments. Yet there is still a limited knowledge about the changes that the associated biomarker signals undergo in the different parts of a stratified environment, and as to which extent the situation in the productive upper parts of the water column is eventually reflected in the sedimentary record. To better understand these processes we studied particulate matter samples from the stratified, partly anoxic Eastern Gotland Basin (EGB, Central Baltic Sea) during a strong cyanobacterial bloom in August 2016. Endmember samples representing the main biomass producers within the phytoplankton (cyanobacteria) and mesozooplankton (copepods) were obtained from different levels of the water column. Major extractable lipids (fatty acids, n-alcohols, sterols, and selected hydrocarbons) were analysed from the same materials and compared to samples cored from the underlying surface sediments (0–12 cm). Given the annually recurring phenomenon of cyanobacterial blooms we anticipated to find a considerable lipid footprint of the major primary producers in the sedimentary record of the EGB. Unexpectedly, however, lipids in the surface sediments largely derived from the storage lipids (mainly wax esters) of the copepod Pseudocalanus spp. which thrived in deeper, more saline and oxygen-depleted waters. Carbon number and unsaturation patterns suggest that the component n-alcohols of these wax esters are transformed into the corresponding n-fatty acids prior to further degradation in the sediment. In the EGB deposits, most of the plankton-derived lipids studied appear to be degraded on a time scale of decades. In terms of relative abundances, long-chain n-alkyl lipids and C29 sterols from terrestrial plant sources instead become predominant in the deeper sediment layers. Likewise, higher stanol/sterol ratios of C27-sterols vs. C29-sterols indicate a more intense biodegradation of planktonic OM as compared to terrestrial OM. Our observations indicate that primary produced particulate OM is heavily modified by mesozooplankton grazing. This overprint adds on the influence of heterotrophic microorganisms and, in the sediment, preferential preservation of terrestrial biomarkers. Taken together, these factors result in a major decoupling of the biomarker signals between the productive upper mixed layer and the oxygen-depleted bottom waters and sediments of the EGB. [ABSTRACT FROM AUTHOR]

Increased cytoplasmic lipid droplets (LDs) and elevated AKT/mTOR signaling are characteristics of clear cell renal cell carcinoma (ccRCC). Lysophosphatidic acid (LPA), a potent lipid mitogen generated via autotaxin (elevated in ccRCC), can modulate tumor progression but its role in altering chemotherapeutic sensitivity to mTOR inhibitors is unclear and thus is the focus of the studies presented herein. Using malignant (A-498, 769-P and 786-O) and normal immortalized kidney (HK-2) cell lines, we investigated their cellular responsiveness to Temsirolimus (TEMS, mTOR inhibitor) in the absence or presence of LPA by monitoring alterations in AKT/mTOR pathway mediators (via western blotting), LDs (using LipidTOX and real-time PCR to assess transcript changes in modulators of LD biogenesis/turnover), mitochondrial networks (via immunofluorescence staining for TOM20 and TOM70), as well as cellular viability. We identified that TEMS reduced cellular viability in all renal cell lines, with increased sensitivity in the presence of an autophagy inhibitor. TEMS also altered activation of AKT/mTOR pathway mediators, abundance of LDs, and fragmentation of mitochondrial networks. We observed that these effects were antagonized by LPA. In HK-2 cells, LPA markedly increased LD size and abundance, coinciding with phospho-MAPK and phospho-S6 activation, increased diacylglycerol O-acetyltransferase 2 (DGAT2) mRNA (which produces triacylglycerides), and survival. Inhibiting MAPK partially antagonized LPA-induced LD changes. Collectively, we have identified that LPA can reverse the effects of TEMS by increasing LDs in a MAPK-dependent manner; these results suggest that LPA may contribute to the pathogenesis and chemotherapeutic resistance of ccRCC. [ABSTRACT FROM AUTHOR]

Global trade and climate change are re-shaping the distribution map of pandemic pathogens. One major emerging concern is Xylella fastidiosa, a tropical bacterium recently introduced into Europe from America. In last decades, X. fastidiosa was detected in several European countries. X. fastidiosa is an insect vector-transmitted bacterial plant pathogen associated with severe diseases in a wide range of hosts. X. fastidiosa through a tight coordination of the adherent biofilm and the planktonic states, invades the host systemically. The planktonic phase is correlated to low cell density and vessel colonization. Increase in cell density triggers a quorum sensing system based on mixture of cis 2-enoic fatty acids—diffusible signalling factors (DSF) that promote stickiness and biofilm. The lipidome profile of Olea europaea L. (cv. Ogliarola salentina) samples, collected in groves located in infected zones and uninfected zones was performed. The untargeted analysis of the lipid profiles of Olive Quick Decline Syndrome (OQDS) positive (+) and negative (-) plants showed a clustering of OQDS+ plants apart from OQDS-. The targeted lipids profile of plants OQDS+ and OQDS- identified a shortlist of 10 lipids that increase their amount in OQDS+ and X. fastidiosa positive olive trees. These lipid entities, provided to X. fastidiosa subsp. pauca pure culture, impact on the dual phase, e.g. planktonic ↔ biofilm. This study provides novel insights on OQDS lipid hallmarks and on molecules that might modulate biofilm phase in X. fastidiosa subsp. pauca. [ABSTRACT FROM AUTHOR]

Lipids represent an important source of nutrition for infecting mycobacteria, accumulating within the necrotic core of granulomas and present in foamy macrophages associated with mycobacterial infection. In order to better understand the timing, process and importance of lipid accumulation, we developed methods for direct in vivo visualization and quantification of this process using the zebrafish-M. marinum larval model of infection. We find that neutral lipids accumulate cell-autonomously in mycobacterium-infected macrophages in vivo during early infection, with detectable levels of accumulation by two days post-infection. Treatment with ezetimibe, an FDA-approved drug, resulted in decreased levels of free cholesterol and neutral lipids, and a reduction of bacterial growth in vivo. The effect of ezetimibe in reducing bacterial growth was dependent on the mce4 operon, a key bacterial determinant of lipid utilization. Thus, in vivo, lipid accumulation can occur cell-autonomously at early timepoints of mycobacterial infection, and limitation of this process results in decreased bacterial burden. [ABSTRACT FROM AUTHOR]

Human skin, not previously frozen, was studied by small-angle X-ray diffraction. The samples were folded so that a 6μm X-ray beam passed through the top layer of skin, stratum corneum. Diffraction patterns recorded with this method consisted of peaks at about q = 0.5, 1.0 and 1.4 nm-1 in the direction perpendicular to the skin surface more clearly than in previous studies. These peaks are interpreted to arise from lipids between corneocytes. A simple unit of a linear electron density profile with three minima was used to account for the observed intensity profiles. Combinations of calculated diffraction from models with one, two and three units accounted for the major part of the observed diffraction pattern, showing the diversity in the structure of the intercellular lipids. [ABSTRACT FROM AUTHOR]

Background: In the primary analysis of a 12-month double-blind randomized active placebo-controlled trial, treatment of children with cystic fibrosis (CF) and pancreatic insufficiency (PI) with a readily absorbable structured lipid (Encala™, Envara Health, Wayne, PA) was safe, well-tolerated and improved dietary fat absorption (stool coefficient of fat absorption [CFA]), growth, and plasma fatty acids (FA). Objective: To determine if the Encala™ treatment effect varied by severity of baseline fat malabsorption. Methods: Subjects (n = 66, 10.5±3.0 yrs, 39% female) with baseline CFA who completed a three-month treatment with Encala™ or a calorie and macronutrient-matched placebo were included in this subgroup analysis. Subjects were categorized by median baseline CFA: low CFA (<88%) and high CFA (≥88%). At baseline and 3-month evaluations, CFA (72-hour stool, weighed food record) and height (HAZ), weight (WAZ) and BMI (BMIZ) Z-scores were calculated. Fasting plasma fatty acid (FA) concentrations were also measured. Results: Subjects in the low CFA subgroup had significantly improved CFA (+7.5±7.2%, mean 86.3±6.7, p = 0.002), and reduced stool fat loss (-5.7±7.2 g/24 hours) following three months of EncalaTM treatment. These subjects also had increased plasma linoleic acid (+20%), α-linolenic acid (+56%), and total FA (+20%) (p≤0.005 for all) concentrations and improvements in HAZ (0.06±0.08), WAZ (0.17±0.16), and BMIZ (0.20±0.25) (p≤0.002 for all). CFA and FA were unchanged with placebo in the low CFA group, with some WAZ increases (0.14±0.24, p = 0.02). High CFA subjects (both placebo and Encala™ groups) had improvements in WAZ and some FA. Conclusions: Subjects with CF, PI and more severe fat malabsorption experienced greater improvements in CFA, FA and growth after three months of Encala™ treatment. Encala™ was safe, well-tolerated and efficacious in patients with CF and PI with residual fat malabsorption and improved dietary energy absorption, weight gain and FA status in this at-risk group. [ABSTRACT FROM AUTHOR]

Lipid droplets (LD) are affected in multiple human disorders. These highly dynamic organelles are involved in many cellular roles. While their intracellular dispersion is crucial to ensure their function and other organelles-contact, underlying mechanisms are still unclear. Here we show that Spastin, one of the major proteins involved in Hereditary Spastic Paraplegia (HSP), controls LD dispersion. Spastin depletion in zebrafish affects metabolic properties and organelle dynamics. These functions are ensured by a conserved complex set of splice variants. M1 isoforms determine LD dispersion in the cell by orchestrating endoplasmic reticulum (ER) shape along microtubules (MTs). To further impact LD fate, Spastin modulates transcripts levels and subcellular location of other HSP key players, notably Seipin and REEP1. In pathological conditions, mutations in human Spastin M1 disrupt this mechanism and impacts LD network. Spastin depletion influences not only other key proteins but also modulates specific neutral lipids and phospholipids, revealing an impact on membrane and organelle components. Altogether our results show that Spastin and its partners converge in a common machinery that coordinates LD dispersion and ER shape along MTs. Any alteration of this system results in HSP clinical features and impacts lipids profile, thus opening new avenues for novel biomarkers of HSP. Author summary: Hereditary spastic paraplegia is a group of inherited diseases characterized by spasticity and gait disorder. Spastin mutations represent the most common cause of hereditary spastic paraplegia. While Spastin was initially defined as a microtubule severing protein, alternative isoforms impact organelles. In the present work, we identify how Spastin combines the specificity of different splice variants to coordinate endoplasmic reticulum shape and lipid droplet dispersion. When mutated, Spastin impairs this synchronization between organelle dynamics, and affects other proteins involved in hereditary spastic paraplegia, notably REEP1 and Seipin. The coordination of lipid droplet dispersion and reticulum shaping under the control of Spastin is a unique trafficking model, affected in the different forms of hereditary spastic paraplegia. The impact of Spastin on this machinery results in the alteration of the lipid profile, particularly phospholipids and neutral lipids in muscle and brain. These potential biomarkers open new therapeutic avenues in hereditary spastic paraplegia. [ABSTRACT FROM AUTHOR]

The activation process of G protein-coupled receptors (GPCRs) has been extensively studied, both experimentally and computationally. In particular, Molecular Dynamics (MD) simulations have proven useful in exploring GPCR conformational space. The typical behaviour of class A GPCRs, when subjected to unbiased MD simulations from their crystallized inactive state, is to fluctuate between inactive and intermediate(s) conformations, even with bound agonist. Fully active conformation(s) are rarely stabilized unless a G protein is also bound. Despite several crystal structures of the adenosine A2a receptor (A2aR) having been resolved in complex with co-crystallized agonists and Gs protein, its agonist-mediated activation process is still not completely understood. In order to thoroughly examine the conformational landscape of A2aR activation, we performed unbiased microsecond-length MD simulations in quadruplicate, starting from the inactive conformation either in apo or with bound agonists: endogenous adenosine or synthetic NECA, embedded in two homogeneous phospholipid membranes: 1,2-dioleoyl-sn-glycerol-3-phosphoglycerol (DOPG) or 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC). In DOPC with bound adenosine or NECA, we observe transition to an intermediate receptor conformation consistent with the known adenosine-bound crystal state. In apo state in DOPG, two different intermediate conformations are obtained. One is similar to that observed with bound adenosine in DOPC, while the other is closer to the active state but not yet fully active. Exclusively, in DOPG with bound adenosine or NECA, we reproducibly identify receptor conformations with fully active features, which are able to dock Gs protein. These different receptor conformations can be attributed to the action/absence of agonist and phospholipid-mediated allosteric effects on the intracellular side of the receptor. Author summary: Unbiased microsecond-length MD simulations of the adenosine A2a receptor (A2aR) were performed in quadruplicate, starting from the inactive conformation either in apo or with bound agonists: adenosine or NECA, each of them embedded in two different homogeneous phospholipid membranes. Different intermediate or active receptor conformations were found depending on the presence/absence of bound agonist and type of lipid environment. Exclusively, in DOPG with bound agonist, we reproducibly identify receptor conformations with fully active features, which are able to dock Gs protein. These different receptor conformations can be attributed to the action/absence of agonist and phospholipid-mediated allosteric effects on the intracellular side of the receptor. Dynamic structural data are key for the understanding of agonist-mediated GPCR activation simulated in realistic membrane environments. [ABSTRACT FROM AUTHOR]

The association of lipid parameters with cardiovascular outcomes and the impact of kidney function on this association have not been thoroughly evaluated in chronic kidney disease (CKD) patients with diabetes. We reviewed the National Health Insurance Database of Korea, containing the data of 10,505,818 subjects who received routine check-ups in 2009. We analyzed the association of lipid profile parameters with major adverse cardiovascular events (MACEs) risk and all-cause mortality in a nationally representative cohort of 51,757 lipid-lowering medication-naïve patients who had CKD and diabetes. Advanced CKD patients with eGFR <30 mL/min/1.73 m2 (n = 10,775) had lower serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) but higher non-HDL-c levels and triglyceride (TG) to HDL-c ratios. There was a positive linear association between serum LDL-c and MACE risk in both early and advanced CKD patients (P <0.001 for trend), except for the category of LDL-c 30–49 mg/dL in extremely low LDL-c subgroup analyses. A U-shaped relationship was observed between serum LDL-c and all-cause mortality (the 4th and 8th octile groups; lowest hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.87–1.05 and highest HR 1.14, 95% CI 1.04–1.26, respectively). A similar pattern remained in both early and advanced CKD patients. The TG/HDL-c ratio categories showed a positive linear association for MACE risk in early CKD (P <0.001 for trend), but this correlation disappeared in advanced CKD patients. There was no correlation between the serum TG/HDL-c ratio and all-cause mortality in the study patients. The LDL-c level predicted the risk for MACEs and all-cause mortality in both early and advanced CKD patients with diabetes, although the patterns of the association differed from each other. However, the TG/HDL-c ratio categories could not predict the risk for either MACEs or all-cause mortality in advanced CKD patients with diabetes, except that the TG/HDL-c ratio predicted MACE risk in early CKD patients with diabetes. [ABSTRACT FROM AUTHOR]

L-Ara4N modification of the 4'-phosphate of native lipid A is characteristic of colistin-resistant E. coli strains carrying chromosomal mutations; this modification often co-occurs with PEtN modification of the 1-phosphate of the lipid A structure. For colistin-susceptible strains, only one major peak at I m/z i 1,796.2, corresponding to native lipid A, was detected, whereas for colistin-resistant strains, an additional peak at I m/z i 1,919.2 was present; the latter arises from the addition of a PEtN moiety to the 1-phosphate group of lipid A (Fig 1, left column, bottom panel). I coli i strains; colistin-susceptible strains had a PRR of zero, whereas colistin-resistant strains had a positive PRR. [Extracted from the article]

This study examined the effects of a 6-week Nordic Walking (NW) training, at the intensity corresponding to the dominance of lipid metabolism, on the levels of selected physiological indices, the haemodynamic indices of the cardiovascular system and physical fitness in sedentary women older than 55 years of age. In addition, the physiological response of the female body to the walking effort on treadmill with poles (NW) and without poles (W) was compared and the influence of training on this response was determined. A single group study with a pre-test/post-test study design was conducted. Eighteen women performed NW controlled intensity training 3 times a week for 6 weeks. Body composition, resting blood pressure (BP), heart rate (HR), maximum oxygen uptake (VO2max) as well as circulatory and respiratory indices in two graded walking efforts on mechanical treadmill NW and W were measured before and after training period. The intensity of workouts, which considered the dominance of lipid metabolism, was determined individually, based on the dynamics of changes in the level of physiological indices during the graded intensity NW. After the course of training, body mass, fat mass, resting BP and HR decreased significantly (p < 0.05). HR and respiratory exchange ratio recorded during NW and W at 1.75 m.s-1 walking speed decreased, while the oxygen pulse increased (p < 0.05). VO2max increased significantly (p < 0.05). Before and after the training period HR, oxygen uptake per minute, and energy expenditure during NW were significantly higher than in W (p < 0.05). The study showed that 6-week NW training at the intensity corresponding to the dominance of lipid metabolism can provide improvement in body composition, cardiovascular function and physical performance in previously sedentary women. NW compared to the regular walk with the same speed revealed higher energy expenditure. [ABSTRACT FROM AUTHOR]

Background: Circulating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD.Methods and Findings: We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39-73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10-8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10-8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation-higher trait; 95% CI: 1.49-1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25-1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56-1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31-2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57-1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02-1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation-higher HDL cholesterol (OR 0.80; 95% CI: 0.75-0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77-0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components.Conclusions: These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the relationship between lipid layer thickness (LLT), incomplete blinking rate and tear film stability in patients with different myopia degrees after small-incision lenticule extraction (SMILE) and to determine whether there is a difference in the prevalence of dry eye disease (DED) after SMILE among patients with different myopia degrees. Methods: Fifty patients (100 eyes) were enrolled in this study; they were divided into 3 groups according to the degree of spherical refraction: a low-myopia group (LMG; spherical refraction ≤-3.00 D, 20 eyes), a moderate-myopia group (MMG; -3.00 D < spherical refraction <-6.00 D, 40 eyes), and a high-myopia group (HMG; spherical refraction ≧-6.00 D, 40 eyes). Testing indicators included the ocular surface disease index (OSDI), fluorescein tear film breakup time (FBUT), corneal fluorescence staining (CFS), the Schirmer test (SI), lipid layer thickness (LLT), blink rate (BR) per 20 seconds, incomplete blinking rate, noninvasive keratograph assessment of first and average tear film breakup time (NIKBUTf, NIKBUTav), and tear meniscus height (TMH). Each indicator was evaluated preoperatively and postoperatively at 1 w, 1 mo and 3 mo. Results: The mean age was 29.12±5.95 years. There were no significant differences among the three groups (p>0.05), except preoperative age (p = 0.006). There were significant differences in the FBUT among the three groups at postoperative 1 w and 1 mo (p<0.05). There were significant differences in the incomplete blinking rate and FBUT between the LMG and the HMG at postoperative 1 mo (p<0.05). The number of first tear film breakup points located beyond the 6 mm diameter of the cornea was higher in the HMG than in the other groups. The prevalence of DED in the LMG, the MMG, the HMG was 15%, 8% and 23%, respectively, at 1 w postoperative and 30%, 45% and 53%, respectively, at postoperative 1 mo. The change in LLT was significantly correlated with the changes in FBUT (r = 0.408, p<0.001) and incomplete blinking rate (r = -0.266, p = 0.007). The change in OSDI was negatively correlated with the change in SI (r = -0.502, p = 0.000). Conclusions: The changes in LLT and incomplete blinking rate decreased the stability of the tear film. The changes in LLT, FBUT and incomplete blinking rate differed postoperatively with different myopia degrees. The prevalence of DED was higher in the HMG than in the other two groups. [ABSTRACT FROM AUTHOR]

Circadian (daily) regulation of metabolic pathways implies that food may be metabolized differentially over the daily cycle. To test that hypothesis, we monitored the metabolism of older subjects in a whole-room respiratory chamber over two separate 56-h sessions in a random crossover design. In one session, one of the 3 daily meals was presented as breakfast, whereas in the other session, a nutritionally equivalent meal was presented as a late-evening snack. The duration of the overnight fast was the same for both sessions. Whereas the two sessions did not differ in overall energy expenditure, the respiratory exchange ratio (RER) was different during sleep between the two sessions. Unexpectedly, this difference in RER due to daily meal timing was not due to daily differences in physical activity, sleep disruption, or core body temperature (CBT). Rather, we found that the daily timing of nutrient availability coupled with daily/circadian control of metabolism drives a switch in substrate preference such that the late-evening Snack Session resulted in significantly lower lipid oxidation (LO) compared to the Breakfast Session. Therefore, the timing of meals during the day/night cycle affects how ingested food is oxidized or stored in humans, with important implications for optimal eating habits. [ABSTRACT FROM AUTHOR]

Smoke exposure is known to decrease total pulmonary surfactant and alter its composition, but the role of surfactant in chronic obstructive pulmonary disease (COPD) remains unknown. We aimed to analyze the compositional changes in the surfactant lipidome in COPD and identify specific lipids associated with pulmonary function decline. Bronchoalveolar lavage (BAL) fluid was obtained from 12 former smokers with COPD and 5 non-smoking, non-asthmatic healthy control volunteers. Lipids were extracted and analyzed by liquid chromatography and mass spectrometry. Pulmonary function data were obtained by spirometry, and correlations of lung function with lipid species were determined. Wild-type C57BL/6 mice were exposed to 6 months of second-hand smoke in a full-body chamber. Surfactant lipids were decreased by 60% in subjects with COPD. All phospholipid classes were dramatically decreased, including ether phospholipids, which have not been studied in pulmonary surfactant. Availability of phospholipid, cholesterol, and sphingomyelin in BAL strongly correlated with pulmonary function and this was attributable to specific lipid species of phosphatidylcholine with surface tension reducing properties, and of phosphatidylglycerol with antimicrobial roles, as well as to other less studied lipid species. Mice exposed to smoke for six months recapitulated surfactant lipidomic changes observed in human subjects with COPD. In summary, we show that the surfactant lipidome is substantially altered in subjects with COPD, and decreased availability of phospholipids correlated with decreased pulmonary function. Further investigation of surfactant alterations in COPD would improve our understanding of its physiopathology and reveal new potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Atomic Force Microscopy was utilized to study the morphology of Gag, ΨRNA, and their binding complexes with lipids in a solution environment with 0.1Å vertical and 1nm lateral resolution. TARpolyA RNA was used as a RNA control. The lipid used was phospha-tidylinositol-(4,5)-bisphosphate (PI(4,5)P2). The morphology of specific complexes Gag-ΨRNA, Gag-TARpolyA RNA, Gag-PI(4,5)P2 and PI(4,5)P2-ΨRNA-Gag were studied. They were imaged on either positively or negatively charged mica substrates depending on the net charges carried. Gag and its complexes consist of monomers, dimers and tetramers, which was confirmed by gel electrophoresis. The addition of specific ΨRNA to Gag is found to increase Gag multimerization. Non-specific TARpolyA RNA was found not to lead to an increase in Gag multimerization. The addition PI(4,5)P2 to Gag increases Gag multimerization, but to a lesser extent than ΨRNA. When both ΨRNA and PI(4,5)P2 are present Gag undergoes comformational changes and an even higher degree of multimerization. [ABSTRACT FROM AUTHOR]

Background: Dyslipidemia and abnormal glycemic traits are leading causes of morbidity and mortality. Although the association between the two traits is well established, there still exists a gap in the evidence for the direction of causality. Objective: This study aimed to examine the direction of the causal relationship between lipids and glycemic traits in an Indian population using bidirectional Mendelian randomization (BMR). Methods: The BMR analysis was conducted on 4900 individuals (2450 sib-pairs) from the Indian Migration Study. Instrument variables were generated for each lipid and glycemic trait (fasting insulin, fasting glucose, HOMA-IR, HOMA-β, LDL-cholesterol, HDL-cholesterol, total cholesterol and triglycerides) to examine the causal relationship by applying two-stage least squares (2SLS) regression in both directions. Results: Lipid and glycemic traits were found to be associated observationally, however, results from 2SLS showed that only triglycerides, defined by weighted genetic risk score (wGRS) of 3 SNPs (rs662799 at APOAV, rs780094 at GCKR and rs4420638 at APOE/C1/C4), were observed to be causally effecting 1.15% variation in HOMA-IR (SE = 0.22, P = 0.010), 1.53% in HOMA- β (SE = 0.21, P = 0.001) and 1.18% in fasting insulin (SE = 0.23, P = 0.009). No evidence for a causal effect was observed in the reverse direction or between any other lipid and glycemic traits. Conclusion: The study findings suggest that triglycerides may causally impact various glycemic traits. However, the findings need to be replicated in larger studies. [ABSTRACT FROM AUTHOR]

Pseudozyma antarctica is a nonpathogenic phyllosphere yeast known as an excellent producer of industrial lipases and mannosylerythritol lipids (MELs), which are multi-functional glycolipids. The fungus produces a much higher amount of MELs from vegetable oil than from glucose, whereas its close relative, Ustilago maydis UM521, produces a lower amount of MELs from vegetable oil. In the present study, we used previous gene expression profiles measured by DNA microarray analyses after culturing on two carbon sources, glucose and soybean oil, to further characterize MEL biosynthesis in P. antarctica T-34. A total of 264 genes were found with induction ratios and expression intensities under oily conditions with similar tendencies to those of MEL cluster genes. Of these, 93 were categorized as metabolic genes using the Eukaryotic Orthologous Groups classification. Within this metabolic category, amino acids, carbohydrates, inorganic ions, and secondary metabolite metabolism, as well as energy production and conversion, but not lipid metabolism, were enriched. Furthermore, genes involved in central metabolic pathways, such as glycolysis and the tricarboxylic acid cycle, were highly induced in P. antarctica T-34 under oily conditions, whereas they were suppressed in U. maydis UM521. These results suggest that the central metabolism of P. antarctica T-34 under oily conditions contributes to its excellent oil utilization and extracellular glycolipid production. [ABSTRACT FROM AUTHOR]

Low parity women are at increased risk of cardiovascular mortality. Unfavourable lipid profiles have been found in one-child mothers years before they conceive. However, it remains unclear whether unfavourable lipid profiles are evident in these women also after their first birth. The aim was to estimate post-pregnancy lipid levels in one-child mothers compared to mothers with two or more children and to assess these lipid's associations with number of children. We used data on 32 618 parous women (4 490 one-child mothers and 28 128 women with ≥2 children) examined after first childbirth as part of Cohort of Norway (1994–2003) with linked data on reproduction and number of children from the Medical Birth Registry of Norway (1967–2008). Odds ratios (ORs) with 95% confidence intervals (CIs) for one lifetime pregnancy (vs. ≥2 pregnancies) by lipid quintiles were obtained by logistic regression and adjusted for age at examination, year of first birth, body mass index, oral contraceptive use, smoking and educational level. Compared to women with the lowest quintiles, ORs for one lifetime pregnancy for the highest quintiles of LDL and total cholesterol were 1.30 (95%CI: 1.14–1.45) and 1.43 (95%CI: 1.27–1.61), respectively. Sensitivity analysis (women <40 years) showed no appreciable change in our results. In stratified analyses, estimates were slightly stronger in overweight/obese, physically inactive and women with self-perceived bad health. Mean lipid levels measured after childbirth in women with one child were significantly higher compared to mothers with two or more children and were associated with higher probability of having only one child. These findings corroborate an association between serum lipid levels and one lifetime pregnancy (as a feature of subfecundity), emphasizing that these particular women may be a specific predetermined risk group for cardiovascular related disease and death. [ABSTRACT FROM AUTHOR]

Reconstructed human adipose tissues represent novel tools available to perform in vitro pharmaco-toxicological studies. We used adipose-derived human stromal/stem cells to reconstruct, using tissue engineering techniques, such an adipose tridimensional model. To determine to what extent the in vitro model is representative of its native counterpart, adipogenic differentiation, triglycerides accumulation and phospholipids profiles were analysed. Ingenuity Pathway Analysis software revealed pathways enriched with differentially-expressed genes between native and reconstructed human adipose tissues. Interestingly, genes related to fatty acid metabolism were downregulated in vitro, which could be explained in part by the insufficient amount of essential fatty acids provided by the fetal calf serum used for the culture. Indeed, the lipid profile of the reconstructed human adipose tissues indicated a particular lack of linoleic acid, which could interfere with physiological cell processes such as membrane trafficking, signaling and inflammatory responses. Supplementation in the culture medium was able to influence the lipid profile of the reconstructed human adipose tissues. This study demonstrates the possibility to directly modulate the phospholipid profile of reconstructed human adipose tissues. This reinforces its use as a relevant physiological or pathological model for further pharmacological and metabolic studies of human adipose tissue functions. [ABSTRACT FROM AUTHOR]

Background: Preterm birth has previously been linked with cardiovascular disease (CVD) in adulthood. However, associations with lipid disorders (e.g., high cholesterol or triglycerides), which are major risk factors for CVD, have seldom been examined and are conflicting. Clinicians will increasingly encounter adult survivors of preterm birth and will need to understand the long-term health sequelae. We conducted the first large population-based study to determine whether preterm birth is associated with an increased risk of lipid disorders.Methods and Findings: A retrospective national cohort study was conducted of all 2,235,012 persons born as singletons in Sweden during 1973 to 1995 (48.6% women), who were followed up for lipid disorders identified from nationwide inpatient, outpatient, and pharmacy data through 2016 (maximum age 44 years). Cox regression was used to adjust for other perinatal and maternal factors, and co-sibling analyses assessed the potential influence of unmeasured shared familial (genetic and/or environmental) factors. A total of 25,050 (1.1%) persons were identified with lipid disorders in 30.3 million person-years of follow-up. Each additional 5 weeks of gestation were associated with a 14% reduction in risk of lipid disorders (adjusted hazard ratio [HR], 0.86; 95% CI, 0.83-0.89; P < 0.001). Relative to full-term birth (gestational age 39-41 weeks), the adjusted HR associated with preterm birth (<37 weeks) was 1.23 (95% CI, 1.16-1.29; P < 0.001), and further stratified was 2.00 (1.41-2.85; P < 0.001) for extremely preterm (22-27 weeks), 1.33 (1.19-1.49; P < 0.001) for very preterm (28-33 weeks), and 1.19 (1.12-1.26; P < 0.001) for late preterm (34-36 weeks). These findings were similar in men and women (e.g., preterm versus full-term, men: HR, 1.22; 95% CI, 1.14-1.31; P < 0.001; women: HR, 1.23; 1.12-1.32; P < 0.001). Co-sibling analyses suggested that they were substantially though not completely explained by shared genetic or environmental factors in families. The main study limitation was the unavailability of laboratory data to assess specific types or severity of lipid disorders.Conclusions: In this large national cohort, preterm birth was associated with an increased risk of lipid disorders in early- to midadulthood. Persons born prematurely may need early preventive evaluation and long-term monitoring for lipid disorders to reduce their future cardiovascular risks. [ABSTRACT FROM AUTHOR]

Tenofovir alafenamide (TAF) has similar efficacy compared to tenofovir disoproxil fumarate (TDF), but a less favorable effect on lipids. Aim of this retrospective multicentre study was to evaluate the impact on lipids of switching from rilpivirine (RPV)/ emtricitabine (FTC)/TDF to RPV/FTC/TAF in a cohort of HIV-1 infected patients. Total cholesterol (TC), high density lipoproteins (HDL) and low density lipoproteins (LDL) were compared at the moment of the switch and at the first following evaluation, by using paired t-test. Overall, 573 patients were considered, 99% with HIV-RNA <50 copies/ml, with mean age of 49.7 (±0.4) years and median 13.4 (6.9–22.5) years of HIV infection. In the study population with available data (431/573, 75%), mean TC changed from 173 ±1.7 to 188 ±1.8 mg/dl; mean HDL from 46 ±0.7 to 51± 0.7 mg/dl; mean LDL from 111 ±1.5 to 120 ±1.8 mg/dl (p<0.0001 for all). Neither LDL/HDL nor TC/HDL ratio changed significantly, with LDL/HDL from 2.6 ±0.5 to 2.5 ±0.5 (p = 0.12) and TC/HDL from 4.0 ±0.6 to 3.9 ±0.6 (p = 0.11). In patients with baseline diagnosis of hypercholesterolemia (TC>200 mg/dl, N = 87), there was no significant change in TC (224 ±2.2 to 228 ±3.4 mg/dl, p = 0.286) or LDL (150±2.5 to 151±3.2 mg/dl, p = 0.751), while HDL increased from 51 ±1.6 to 55 ±1.7 mg/dl (p<0.0001) and both LDL/HDL and TC/HDL ratio decreased significantly, from 3.2±0.1 to 3.0 ±0.1 (p = 0.025) and from 4.7±0.1 to 4.4 ±0.1 (p = 0.004). In this real life study, a slight increase in lipids was found after switching from RPV/FTC/TDF to RPV/FTC/TAF, but these results were not confirmed in people with hypercholesterolemia, in which lipids did not change and LDL/HDL and TC/HDL ratio decreased. [ABSTRACT FROM AUTHOR]

Expression of the Alzheimer's disease associated polypeptide Aβ42 and the human polypeptide hormon islet amyloid polypeptide (hIAPP) and the prohormone precursor (hproIAPP) in neurons of Drosophila melanogaster leads to the formation of protein aggregates in the fat body tissue surrounding the brain. We determined the structure of these membrane-encircled protein aggregates using transmission electron microscopy (TEM) and observed the dissolution of protein aggregates after starvation. Electron tomography (ET) as an extension of transmission electron microscopy revealed that these aggregates were comprised of granular subunits having a diameter of 20 nm aligned into highly ordered structures in all three dimensions. The three dimensional (3D) lattice of hIAPP granules were constructed of two unit cells, a body centered tetragonal (BCT) and a triclinic unit cell. A 5-fold twinned structure was observed consisting of the cyclic twinning of the BCT and triclinic unit cells. The interaction between the two nearest hIAPP granules in both unit cells is not only governed by the van der Waals forces and the dipole-dipole interaction but potentially also by filament-like structures that can connect the nearest neighbors. Hence, our 3D structural analysis provides novel insight into the aggregation process of hIAPP in the fat body tissue of Drosophila melanogaster. [ABSTRACT FROM AUTHOR]

Grafting has been widely applied to melon (Cucumis melo L.) production to alleviate obstacles of continuous cropping and control soil-borne diseases. However, grafting often leads to a decline of fruit quality. For example, sometimes bitter fruits are produced on grafted plants. However, the underlying physiological mechanism still remains unclear. This study investigated the effects of different rootstocks on the taste of fruits of the Balengcui, an oriental melon cultivar, during summer production. The results showed that all grafted plants with Cucurbita maxima Duch. rootstocks produced bitter fruits, while non-grafted plants and plants grafted onto muskmelon rootstocks produced no bitter fruits. Liquid chromatography–mass spectrometry and metabonomic analysis were performed to investigate the mechanism underlying the occurrence of bitter fruits. Metabolite comparisons of fruits from plants grafted onto Ribenxuesong rootstocks both with non-grafted plants and plants grafted onto muskmelon rootstocks showed that 17 metabolites including phospholipids, cucurbitacins and flavonoids, exhibited changes. The three Cucurbitacins, Cucurbitacin O, Cucurbitacin C, and Cucurbitacin S, increased dramatically. The 10 phospholipids PS(18:1(9Z)/18:2(9Z,12Z)), PS(P-18:0/15:0), PA(18:1(11Z)/18:1(11Z)), PE(16:0/18:0), PS(O-16:0/17:2(9Z,12Z)), PI(16:0/18:2(9Z,12Z)), PA(15:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)), PS(P-16:0/17:2(9Z,12Z)), PS(22:0/22:1(11Z)), and PA(17:1(9Z)/0:0)) were significantly decreased, while two PA (16:0/18:2 (9Z, 12Z) and 16:0/18:1 (11Z)), two flavonoids (pelargonidin 3-(6''-malonylglucoside)-5-glucoside and malvidin 3-rutinoside) significantly increased in fruits of plants grafted onto Cucurbita maxima Duch. rootstocks. These metabolites were involved in the glycerophospholipid metabolic pathway, the mevalonate pathway, and the phenylpropanoid pathway. In summary, these results showed that the bitter fruits of grafted Balengcui were caused by Cucurbita maxima Duch. rootstocks. Phospholipids, cucurbitacins, and flavonoids were the key contributors for the occurrence of bitter fruits in Balengcui melon after grafting onto Cucurbita maxima Duch. rootstocks. [ABSTRACT FROM AUTHOR]

Conjugated linoleic acid was detected in rabbit caecotrophs, due to the presence of microbial lipid activity in rabbit cecum. However, the effect of CLA as a functional food in growing rabbit is not well established. Therefore, this study was conducted to determine the effect of CLA on production, meat quality, and its nutrigenomic effect on edible parts of rabbit carcass including skeletal muscle, liver, and adipose tissue. Therefore, seventy five weaned V-Line male rabbits, 30 days old, were randomly allocated into three dietary treatments receiving either basal control diet, diet supplemented with 0.5% (CLAL), or 1% CLA (CLAH). Total experimental period (63 d) was segmented into 7 days adaptation and 56 days experimental period. Dietary supplementation of CLA did not alter growth performance, however, the fat percentage of longissimus lumborum muscle was decreased, with an increase in protein and polyunsaturated fatty acids (PUFA) percentage. Saturated fatty acids (SFA) and mono unsaturated fatty acids (MUFA) were not increased in CLA treated groups. There was tissue specific sensing of CLA, since subcutaneous adipose tissue gene expression of PPARA was downregulated, however, CPT1A tended to be upregulated in liver of CLAL group only (P = 0.09). In skeletal muscle, FASN and PPARG were upregulated in CLAH group only (P ≤0.01). Marked cytoplasmic vacuolation was noticed in liver of CLAH group without altering hepatocyte structure. Adipocyte size was decreased in CLA fed groups, in a dose dependent manner (P <0.01). Cell proliferation determined by PCNA was lower (P <0.01) in adipose tissue of CLA groups. Our data indicate that dietary supplementation of CLA (c9,t11-CLA and t10,c12- CLA) at a dose of 0.5% in growing rabbit diet produce rabbit meat rich in PUFA and lower fat % without altering growth performance and hepatocyte structure. [ABSTRACT FROM AUTHOR]

We recently introduced a MαCD-based method to efficiently replace virtually the entire population of plasma membrane outer leaflet phospholipids and sphingolipids of cultured mammalian cells with exogenous lipids (Li et al, (2016) Proc. Natl. Acad. Sci USA 113:14025–14030). Here, we show if the lipid-to- MαCD ratio is too high or low, cells can round up and develop membrane leakiness. We found that this cell damage can be reversed/prevented if cells are allowed to recover from the exchange step by incubation in complete growth medium. After exchange and transfer to complete growth medium cell growth was similar to that of untreated cells. In some cases, cell damage was also prevented by carrying out exchange at close to room temperature (rather than at 37°C). Exchange with lipids that do (sphingomyelin) or do not (unsaturated phosphatidylcholine) support a high level of membrane order in lipid vesicles had the analogous effect on plasma membrane order, confirming exogenous lipid localization in the plasma membrane. Importantly, changes in lipid composition and plasma membrane properties after exchange and recovery persisted for several hours. Thus, it should be possible to use lipid exchange to investigate the effect of plasma membrane lipid composition upon several aspects of membrane structure and function. [ABSTRACT FROM AUTHOR]

Introduction: Propofol causes a profound inhibition of fatty acid oxidation and reduces spare electron transfer chain capacity in a range of human and rodent cells and tissues–a feature that might be related to the pathogenesis of Propofol Infusion Syndrome. We aimed to explore the mechanism of propofol-induced alteration of bioenergetic pathways by describing its kinetic characteristics. Methods: We obtained samples of skeletal and cardiac muscle from Wistar rat (n = 3) and human subjects: vastus lateralis from hip surgery patients (n = 11) and myocardium from brain-dead organ donors (n = 10). We assessed mitochondrial functional indices using standard SUIT protocol and high resolution respirometry in fresh tissue homogenates with or without short-term exposure to a range of propofol concentration (2.5–100 μg/ml). After finding concentrations of propofol causing partial inhibition of a particular pathways, we used that concentration to construct kinetic curves by plotting oxygen flux against substrate concentration during its stepwise titration in the presence or absence of propofol. By spectrophotometry we also measured the influence of the same propofol concentrations on the activity of isolated respiratory complexes. Results: We found that human muscle and cardiac tissues are more sensitive to propofol-mediated inhibition of bioenergetic pathways than rat’s tissue. In human homogenates, palmitoyl carnitine-driven respiration was inhibited at much lower concentrations of propofol than that required for a reduction of electron transfer chain capacity, suggesting FAO inhibition mechanism different from downstream limitation or carnitine-palmitoyl transferase-1 inhibition. Inhibition of Complex I was characterised by more marked reduction of Vmax, in keeping with non-competitive nature of the inhibition and the pattern was similar to the inhibition of Complex II or electron transfer chain capacity. There was neither inhibition of Complex IV nor increased leak through inner mitochondrial membrane with up to 100 μg/ml of propofol. If measured in isolation by spectrophotometry, propofol 10 μg/ml did not affect the activity of any respiratory complexes. Conclusion: In human skeletal and heart muscle homogenates, propofol in concentrations that are achieved in propofol-anaesthetized patients, causes a direct inhibition of fatty acid oxidation, in addition to inhibiting flux of electrons through inner mitochondrial membrane. The inhibition is more marked in human as compared to rodent tissues. [ABSTRACT FROM AUTHOR]

Background: Physical exercise has been shown to be effective in relation to fatigue, aerobic fitness, and lower body strength in men with prostate cancer. However, research into the clinically relevant effects of interventions conducted in heterogeneous patient populations and in real-life clinical practice settings is warranted.Methods and Findings: We conducted a pragmatic, multicentre, parallel randomised controlled trial in 5 Danish urological departments. Recruitment began in May 2015, the first participant was randomised in June 2015, and the last participant was included in February 2017. In total, 214 men with prostate cancer were randomly assigned to either 6 months of free-of-charge football training twice weekly at a local club (football group [FG]) (n = 109) or usual care (usual care group [UG]) (n = 105), including brief information on physical activity recommendations at randomisation. Participants were on average 68.4 (SD 6.2) years old, 157 (73%) were retired, 87 (41%) were on castration-based treatment, 19 (9%) had received chemotherapy, and 41 (19%) had skeletal metastases at baseline. In this 1-year follow-up study, we evaluated the effects of community-based football training on the following outcomes: primary outcome, quality of life; secondary outcomes: continuation of football after 6 months, hip and lumbar spine bone mineral density (BMD), mental health score, fat and lean body mass, and safety outcomes, i.e., fractures, falls, and hospital admissions. Intention to treat (ITT) and per protocol (PP) analyses were conducted. No statistically significant between-group difference was observed in change in prostate-cancer-specific quality of life (ITT: 1.9 points [95% CI -1.9 to 5.8], p = 0.325; PP: 3.6 points [95% CI -0.9 to 8.2], p = 0.119). A statistically significant between-group difference was observed in change in total hip BMD, in favour of FG (0.007 g/cm2 [95% CI 0.004 to 0.013], p = 0.037). No differences were observed in change in lumbar spine BMD or lean body mass. Among patients allocated to football, 59% chose to continue playing football after the end of the 6-month intervention period. At 1-year follow-up in the PP population, FG participants had more improvement on the Mental Component Summary (2.9 [95% CI 0.0 to 5.7], p = 0.048 points higher) than UG participants, as well as a greater loss of fat mass (-0.9 kg [95% CI -1.7 to -0.1], p = 0.029). There were no differences between groups in relation to fractures or falls. Hospital admissions were more frequent in UG compared to FG (33 versus 20; the odds ratio based on PP analysis was 0.34 for FG compared to UG). There were 3 deaths in FG and 4 in UG. Main limitations of the study were the physically active control group and assessment of physical activity by means of self-report.Conclusions: In this trial, participants allocated to football appeared to have improved hip BMD and fewer hospital admissions. Men who played football more than once a week for 1 year lost fat mass and reported improved mental health. Community-based football proved to be acceptable, even when club membership was not subsidised.Trial Registration: ClinicalTrials.gov NCT02430792. [ABSTRACT FROM AUTHOR]

Objective: Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model. Method: Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues. Results: In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice. Conclusions: Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation. [ABSTRACT FROM AUTHOR]

Background and objectives: The construction of whole-body magnetic resonance (MR) imaging atlases allows to perform statistical analysis with applications in anomaly detection, longitudinal, and correlation studies. Atlas-based methods require a common coordinate system to which all the subjects are mapped through image registration. Optimisation of the reference space is an important aspect that affects the subsequent analysis of the registered data, and having a reference space that is neutral with respect to local tissue volume is valuable in correlation studies. The purpose of this work is to generate a reference space for whole-body imaging that has zero voxel-wise average volume change when mapped to a cohort. Methods: This work proposes an approach to register multiple whole-body images to a common template using volume changes to generate a synthetic reference space, starting with an initial reference and refining it by warping it with a deformation that brings the voxel-wise average volume change associated to the mappings of all the images in the cohort to zero. Results: Experiments on fat/water separated whole-body MR images show how the method effectively generates a reference space neutral with respect to volume changes, without reducing the quality of the registration nor introducing artefacts in the anatomy, while providing better alignment when compared to an implicit reference groupwise approach. Conclusions: The proposed method allows to quickly generate a reference space neutral with respect to local volume changes, that retains the registration quality of a sharp template, and that can be used for statistical analysis of voxel-wise correlations in large datasets of whole-body image data. [ABSTRACT FROM AUTHOR]