Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney.

The functional and structural changes in the proximal tubule play an important role in the occurrence and development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead to changes in the state of tubular epithelial cells (TECs), and among all the disturbances in metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production of mitochondrial reactive oxygen species (mtROS), is considered one of the primary factors causing diabetic tubular injury. Most studies have discussed how altered metabolic flux drives mitochondrial oxidative stress during DKD. In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs. Using SS31, a tetrapeptide that protects the mitochondrial cristae structure, we demonstrated that mitochondrial oxidative damage contributes to TEC injury and lipid peroxidation caused by lipid accumulation. Mitochondria protected using SS31 significantly reversed the decreased expression of key enzymes and regulators of fatty acid oxidation (FAO), but had no obvious effect on major glucose metabolic rate-limiting enzymes. Mitochondrial oxidative stress facilitated renal Sphingosine-1-phosphate (S1P) deposition and SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity, and the decreased Spns2 expression. These data suggest a role of mitochondrial oxidative damage in unbalanced lipid metabolism, including lipid droplet (LD) formulation, lipid peroxidation, and impaired FAO and sphingolipid homeostasis in DKD. An in vitro study demonstrated that high glucose drove elevated expression of cytosolic phospholipase A2 (cPLA2), which, in turn, was responsible for the altered lipid metabolism, including LD generation and S1P accumulation, in HK-2 cells. A mitochondria-targeted antioxidant inhibited the activation of cPLA2f isoforms. Taken together, these findings identify mechanistic links between mitochondrial oxidative metabolism and reprogrammed lipid metabolism in diabetic TECs, and provide further evidence for the nephroprotective effects of SS31 via influencing metabolic pathways.

Role of Na/K-ATPase α1 caveolin-binding motif in adipogenesis.

Deficiencies in mice and in humans have brought to the fore the importance of the caveolar network in key aspects of adipocyte biology. The conserved N-terminal caveolin-binding motif (CBM) of the ubiquitous Na/K-ATPase (NKA) α1 isoform, which allows NKA/caveolin-1 (Cav1) interaction, influences NKA signaling and caveolar distribution. It has been shown to be critical for animal development and ontogenesis, as well as lineage-specific differentiation of human induced pluripotent stem cells (hiPSCs). However, its role in postnatal adipogenesis has not been fully examined. Using a genetic approach to alter CBM in hiPSC-derived adipocytes (iAdi-mCBM) and in mice (mCBM), we investigated the regulatory function of NKA CBM signaling in adipogenesis. Seahorse XF cell metabolism analyses revealed impaired glycolysis and decreased ATP synthesis-coupled respiration in iAdi-mCBM. These metabolic dysfunctions were accompanied by evidence of extensive remodeling of the extracellular matrix (ECM), including increased collagen staining, overexpression of ECM marker genes, and heightened TGF-ß signaling uncovered by RNAseq analysis. Rescue of mCBM by lentiviral delivery of WT NKA α1 or treatment of mCBM hiPSCs with the TGF-ß inhibitor SB431542 normalized ECM, suggesting that NKA CBM signaling integrity is required for adequate control of TGF-ß signaling and ECM stiffness during adipogenesis. The physiological impact was revealed in mCBM male mice with reduced fat mass accompanied by histological and transcriptional evidence of elevated adipose fibrosis and decreased adipocyte size. Based on these findings, we propose that the genetic alteration of the NKA/Cav1 regulatory path uncovered in human iAdi leads to lipodystrophy in mice.NEW & NOTEWORTHY A Na/K-ATPase α1 caveolin-binding motif regulates adipogenesis. Mutation of this binding motif in the mouse leads to reduced fat with increased extracellular matrix production and inflammation. RNA-seq analysis and pharmacological interventions in human iPSC-derived adipocytes revealed that TGF-ß signal, rather than Na/K-ATPase-mediated ion transport, is a key mediator of NKA regulation of adipogenesis.

Na/K-ATPase signaling tonically inhibits sodium reabsorption in the renal proximal tubule.

Through its classic ATP-dependent ion-pumping function, basolateral Na/K-ATPase (NKA) generates the Na+ gradient that drives apical Na+ reabsorption in the renal proximal tubule (RPT), primarily through the Na+ /H+ exchanger (NHE3). Accordingly, activation of NKA-mediated ion transport decreases natriuresis through activation of basolateral (NKA) and apical (NHE3) Na+ reabsorption. In contrast, activation of the more recently discovered NKA signaling function triggers cellular redistribution of RPT NKA and NHE3 and decreases Na+ reabsorption. We used gene targeting to test the respective contributions of NKA signaling and ion pumping to the overall regulation of RPT Na+ reabsorption. Knockdown of RPT NKA in cells and mice increased membrane NHE3 and Na+ /HCO3 - cotransporter (NBCe1A). Urine output and absolute Na+ excretion decreased by 65%, driven by increased RPT Na+ reabsorption (as indicated by decreased lithium clearance and unchanged glomerular filtration rate), and accompanied by elevated blood pressure. This hyper reabsorptive phenotype was rescued upon crossing with RPT NHE3-/- mice, confirming the importance of NKA/NHE3 coupling. Hence, NKA signaling exerts a tonic inhibition on Na+ reabsorption by regulating key apical and basolateral Na+ transporters. This action, lifted upon NKA genetic suppression, tonically counteracts NKA's ATP-driven function of basolateral Na+ reabsorption. Strikingly, NKA signaling is not only physiologically relevant but it also appears to be functionally dominant over NKA ion pumping in the control of RPT reabsorption.

Mechanistic study of highly effective phosphate removal from aqueous solutions over a new lanthanum carbonate fabricated carbon nanotube film.

The effective purification of phosphate-containing wastewater is considered as increasingly important. In this study, a highly effective LC-CNT film was developed for efficient phosphate removal. Kinetic results showed that the adsorbent exhibited an improved mass transfer efficiency and a fast adsorption rate during adsorption (reaching 80% and 100% equilibrium adsorption capacity within 175 and 270 min, respectively). Kinetic model analysis suggested that the adsorption was a combined chemical physical process. Isotherm study revealed that the LC-CNT film showed a superior adsorption capacity (178.6 mg/g, estimated from the Langmuir model) with multiple adsorption mechanisms. pH study suggested that surface complexation and ligand exchange played important roles during adsorption, and the adsorbent worked well within the pH range of 3-7 with little La leakage. The ionic strength and competing anions showed little influence on the adsorbent effectiveness except for the carbonate and sulfate ions. The characterization and mechanism study revealed that the phosphate adsorption of the LC-CNT film was controlled by inner-sphere complexation, outer-sphere complexation and surface precipitation. The LC-CNT film also showed excellent regenerability and stability in cycling runs, further demonstrating its potential in industrial applications.

Adsorptive decontamination of antibiotics from livestock wastewater by using alkaline-modified biochar.

Efficient abatement of antibiotics from livestock wastewater is in urgent demand, but still challenging. In this study, alkaline-modified biochar with larger surface area (130.520 m2 g-1) and pore volume (0.128 cm3 g-1) was fabricated and explored for the adsorption of different types of antibiotics from livestock wastewater. Batch adsorption experiments demonstrated that the adsorption process was mainly determined by chemisorption and was heterogeneous, which could be moderately affected by the variations of solution pH (3-10). Furthermore, the computational analysis based on density functional theory (DFT) indicated that the -OH groups on biochar surface could serve as the dominant active sites for antibiotics adsorption due to the strongest adsorption energies between antibiotics and -OH groups. In addition, the antibiotics removal was also evaluated in multi-pollutants system, where biochar performed synergistic adsorption towards Zn2+/Cu2+ and antibiotics. Overall, these findings not only deepen our understandings on the adsorption mechanism between biochar and antibiotics, but also promote the application of biochar in the remediation of livestock wastewater.

A Prognostic Model of Head and Neck Cancer Based on Amino Acid Metabolism-Related Signature and Its Implication for Immunosuppressive Microenvironment.

Amino acid metabolism has been implicated in tumorigenesis and tumor progression. Alterations in intracellular and extracellular metabolites associated with metabolic reprogramming in cancer have profound effects on gene expression, cell differentiation, and tumor immune microenvironment. However, the prognostic significance of amino acid metabolism in head and neck cancer remains to be further investigated. In this study, we identified 98 differentially expressed genes related to amino acid metabolism in head and neck cancer in The Cancer Genome Atlas. Using batch univariate Cox regression and Lasso regression, we extracted nine amino acid metabolism-related genes. Based on that, we developed the amino acid metabolism index. The prognostic value of this index was validated in two Gene Expression Omnibus cohorts. The results show that this model can help predict tumor recurrence and prognosis. The infiltration of immune cells in the tumor microenvironment was analyzed, and it was discovered that the high index is associated with an immunosuppressive microenvironment. In addition, this study demonstrated the impact of the amino acid metabolism index on clinical indicators, survival of patients with head and neck cancer, and the prediction of treatment response to immune checkpoint inhibitors. We conducted several cell experiments and demonstrated that epigenetic drugs could affect the index and enhance tumor immunity. In conclusion, our study demonstrates that the index not only has important prognostic value in head and neck cancer patients but also facilitates patient stratification for immunotherapy.

The regulation of necroptosis by ubiquitylation.

Necroptosis is a programmed necrosis that is mediated by receptor-interacting protein kinases RIPK1, RIPK3 and the mixed lineage kinase domain-like protein, MLKL. Necroptosis must be strictly regulated to maintain normal tissue homeostasis, and dysregulation of necroptosis leads to the development of various inflammatory, infectious, and degenerative diseases. Ubiquitylation is a widespread post-translational modification that is essential for balancing numerous physiological processes. Over the past decade, considerable progress has been made in the understanding of the role of ubiquitylation in regulating necroptosis. Here, we will discuss the regulatory functions of ubiquitylation in necroptosis signaling pathway. An enhanced understanding of the ubiquitylation enzymes and regulatory proteins in necroptotic signaling pathway will be exploited for the development of new therapeutic strategies for necroptosis-related diseases.

A Universal Biofilm Reactor Sensor for the Determination of Biochemical Oxygen Demand of Different Water Areas.

In this study, we developed a simple strategy to prepare a biofilm reactor (BFR) sensor for the universal biochemical oxygen demand (BOD) determination. The microorganisms in fresh water were domesticated by artificial seawater with different salinity gradients successively to prepare the BFR sensor. The prepared BFR sensor exhibits an efficient ability to degrade a variety of organic substances. The linear range of BOD determination by the BFR sensor is 1.0-10.0 mg/L-1 with a correlation coefficient of 0.9951. The detection limit is 0.30 mg/L according to three times of signal-to-noise ratio. What is more, the BFR sensor displayed excellent performances for the BOD determination of different water samples, including both fresh water and seawater. The 16S-rRNA gene sequencing technology was used to analyze the microbial species before and after the domestication. The results show that it is a general approach for the rapid BOD determination in different water samples.

Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses.

RATIONALE: A hallmark of chronic inflammatory disorders is persistence of proinflammatory macrophages in diseased tissues. In atherosclerosis, this is associated with dyslipidemia and oxidative stress, but mechanisms linking these phenomena to macrophage activation remain incompletely understood. OBJECTIVE: To investigate mechanisms linking dyslipidemia, oxidative stress, and macrophage activation through modulation of immunometabolism and to explore therapeutic potential targeting specific metabolic pathways. METHODS AND RESULTS: Using a combination of biochemical, immunologic, and ex vivo cell metabolic studies, we report that CD36 mediates a mitochondrial metabolic switch from oxidative phosphorylation to superoxide production in response to its ligand, oxidized LDL (low-density lipoprotein). Mitochondrial-specific inhibition of superoxide inhibited oxidized LDL-induced NF-κB (nuclear factor-κB) activation and inflammatory cytokine generation. RNA sequencing, flow cytometry, 3H-labeled palmitic acid uptake, lipidomic analysis, confocal and electron microscopy imaging, and functional energetics revealed that oxidized LDL upregulated effectors of long-chain fatty acid uptake and mitochondrial import, while downregulating fatty acid oxidation and inhibiting ATP5A (ATP synthase F1 subunit alpha)-an electron transport chain component. The combined effect is long-chain fatty acid accumulation, alteration of mitochondrial structure and function, repurposing of the electron transport chain to superoxide production, and NF-κB activation. Apoe null mice challenged with high-fat diet showed similar metabolic changes in circulating Ly6C+ monocytes and peritoneal macrophages, along with increased CD36 expression. Moreover, mitochondrial reactive oxygen species were positively correlated with CD36 expression in aortic lesional macrophages. CONCLUSIONS: These findings reveal that oxidized LDL/CD36 signaling in macrophages links dysregulated fatty acid metabolism to oxidative stress from the mitochondria, which drives chronic inflammation. Thus, targeting to CD36 and its downstream effectors may serve as potential new strategies against chronic inflammatory diseases such as atherosclerosis.

An Activity-Based Sensing Fluorogenic Probe for Monitoring Ethylene in Living Cells and Plants.

Ethylene (ET) is an important gaseous plant hormone. It is highly desirable to develop fluorescent probes for monitoring ethylene in living cells. We report an efficient RhIII -catalysed coupling of N-phenoxyacetamides to ethylene in the presence of an alcohol. The newly discovered coupling reaction exhibited a wide scope of N-phenoxyacetamides and excellent regioselectivity. We successfully developed three fluorophore-tagged RhIII -based fluorogenic coumarin-ethylene probes (CEPs) using this strategy for the selective and quantitative detection of ethylene. CEP-1 exhibited the highest sensitivity with a limit of detection of ethylene at 52 ppb in air. Furthermore, CEP-1 was successfully applied for imaging in living CHO-K1 cells and for monitoring endogenous-induced changes in ethylene biosynthesis in tobacco and Arabidopsis thaliana plants. These results indicate that CEP-1 has great potential to illuminate the spatiotemporal regulation of ethylene biosynthesis and ethylene signal transduction in living biological systems.

Regulation of Na/K-ATPase expression by cholesterol: isoform specificity and the molecular mechanism.

We have reported that the reduction in plasma membrane cholesterol could decrease cellular Na/K-ATPase α1-expression through a Src-dependent pathway. However, it is unclear whether cholesterol could regulate other Na/K-ATPase α-isoforms and the molecular mechanisms of this regulation are not fully understood. Here we used cells expressing different Na/K-ATPase α isoforms and found that membrane cholesterol reduction by U18666A decreased expression of the α1-isoform but not the α2- or α3-isoform. Imaging analyses showed the cellular redistribution of α1 and α3 but not α2. Moreover, U18666A led to redistribution of α1 to late endosomes/lysosomes, while the proteasome inhibitor blocked α1-reduction by U18666A. These results suggest that the regulation of the Na/K-ATPase α-subunit by cholesterol is isoform specific and α1 is unique in this regulation through the endocytosis-proteasome pathway. Mechanistically, loss-of-Src binding mutation of A425P in α1 lost its capacity for regulation by cholesterol. Meanwhile, gain-of-Src binding mutations in α2 partially restored the regulation. Furthermore, through studies in caveolin-1 knockdown cells, as well as subcellular distribution studies in cell lines with different α-isoforms, we found that Na/K-ATPase, Src, and caveolin-1 worked together for the cholesterol regulation. Taken together, these new findings reveal that the putative Src-binding domain and the intact Na/K-ATPase/Src/caveolin-1 complex are indispensable for the isoform-specific regulation of Na/K-ATPase by cholesterol.

Bioactive-guided structural optimization of 1,2,3-triazole phenylhydrazones as potential fungicides against Fusarium graminearum.

The phytopathogenic fungus Fusarium graminearum is the major causal agent of fusarium head blight (FHB), which is one of the most serious diseases in wheat. Based on our previous work, the 1,2,3-triazole phenylhydrazone scaffold was further optimized at three modification sites to improve its antifungal activity against F. graminearum. The optimization yielded compound 8d was discovered to be a potent fungicidal agent with an EC50 value of 0.28 µg/mL against F. graminearum, which is 3.6 times lower than previously reported. In addition, 8d also exhibited good inhibitory activities against Rhizoctonia solani and Sclerotinia sclerotiorum with EC50 values of 0.86 and 1.66 µg/mL, respectively. In vivo testing demonstrated that 8d could effectively suppress the disease development of FHB at 200 µg/mL with a protection efficacy of 80.6%. Scanning electron micrographs and transmission electron micrographs showed that the external morphology and internal contents of F. graminearum hyphae were abnormal after 24 h of 8d treatment. Therefore, compound 8d was a promising fungicide candidate for further development.

Oxidant-Induced Alterations in the Adipocyte Transcriptome: Role of the Na,K-ATPase Oxidant Amplification Loop.

(1) Background: Recently we have noted that adipocyte specific expression of the peptide, NaKtide, which was developed to attenuate the Na,K-ATPase oxidant amplification loop, could ameliorate the phenotypical features of uremic cardiomyopathy. We performed this study to better characterize the cellular transcriptomes that are involved in various biological pathways associated with adipocyte function occurring with renal failure. (2) Methods: RNAseq was performed on the visceral adipose tissue of animals subjected to partial nephrectomy. Specific expression of NaKtide in adipocytes was achieved using an adiponectin promoter. To better understand the cause of gene expression changes in vivo, 3T3L1 adipocytes were exposed to indoxyl sulfate (IS) or oxidized low density lipoprotein (oxLDL), with and without pNaKtide (the cell permeant form of NaKtide). RNAseq was also performed on these samples. (3) Results: We noted a large number of adipocyte genes were altered in experimental renal failure. Adipocyte specific NaKtide expression reversed most of these abnormalities. High correlation with some cardiac specific phenotypical features was noted amongst groups of these genes. In the murine adipocytes, both IS and oxLDL induced similar pathway changes as were noted in vivo, and pNaKtide appeared to reverse these changes. Network analysis demonstrated tremendous similarities between the network revealed by gene expression analysis with IS compared with oxLDL, and the combined in vitro dataset was noted to also have considerable similarity to that seen in vivo with experimental renal failure. (4) Conclusions: This study suggests that the myriad of phenotypical features seen with experimental renal failure may be fundamentally linked to oxidant stress within adipocytes.

Feasible Green Strategy for the Quantitative Bioaccumulation of Heavy Metals by Lemna minor: Application of the Self-Thinning Law.

This study involved the development of mathematical linear regression models to describe the relationships between mean plant biomass (M) and population density (D), M and frond diameter (L), frond numbers (N) and L of Lemna minor under different initial population densities (3200, 4450, and 6400 plants/m2), respectively, from the perspective of the self-thinning law. Our results revealed that the value of the allometric exponents for M and D were - 3/2. Further, the concentrations of Zn, Pb, Cu, Fe, and Ni accumulated in L. minor plants were 0.86, 0.32, 0.36, 0.62, and 0.39 mg/kg, respectively. Based on these developed equations and the heavy metal accumulations by L. minor, the phytoremediation capacity of L. minor was quantified via its frond diameters. Overall, the present study provides a cost-effective green method for managing the phytoremediation of heavy metal-contaminated aquatic environments.

Platelet CD36 promotes thrombosis by activating redox sensor ERK5 in hyperlipidemic conditions.

Atherothrombosis is a process mediated by dysregulated platelet activation that can cause life-threatening complications and is the leading cause of death by cardiovascular disease. Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in oxidized low-density lipoprotein (oxLDL) particles, a process that induces an overt prothrombotic phenotype. The mechanisms by which CD36 promotes platelet activation and thrombosis remain incompletely defined. In this study, we identify a mechanism for CD36 to promote thrombosis by increasing activation of MAPK extracellular signal-regulated kinase 5 (ERK5), a protein kinase known to be exquisitely sensitive to redox stress, through a signaling pathway requiring Src kinases, NADPH oxidase, superoxide radical anion, and hydrogen peroxide. Pharmacologic inhibitors of ERK5 blunted platelet activation and aggregation in response to oxLDL and targeted genetic deletion of ERK5 in murine platelets prevented oxLDL-induced platelet deposition on immobilized collagen in response to arterial shear. Importantly, in vivo thrombosis experiments after bone marrow transplantation from platelet-specific ERK5 null mice into hyperlipidemic apolipoprotein E null mice showed decreased platelet accumulation and increased thrombosis times compared with mice transplanted with ERK5 expressing control bone marrows. These findings suggest that atherogenic conditions critically regulate platelet CD36 signaling by increasing superoxide radical anion and hydrogen peroxide through a mechanism that promotes activation of MAPK ERK5.

Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase.

OBJECTIVE: Circulating levels of cardiotonic steroids (CTS) are elevated in various chronic inflammatory conditions, but the role of CTS in inflammation remains largely unknown. We have previously shown that the CTS ouabain stimulates proinflammatory responses in murine macrophages. In this study, we aim to explore the mechanism how CTS induce proinflammatory responses in primary murine and human macrophages. APPROACH AND RESULTS: Using both murine peritoneal macrophages and human monocyte-derived macrophages, we demonstrated that ouabain activated NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), leading to proinflammatory cytokine (eg, MCP-1 [monocyte chemotactic protein 1], TNF-α [tumor necrosis factor-α], IL-1ß [interleukin-1ß], and IL-6) production. By applying siRNA techniques and murine peritoneal macrophages isolated from genetically modified mice, we showed that macrophages partially deficient in Na/K-ATPase, the receptor for CTS, or fully deficient in the scavenger receptor CD36 or TLR4 (Toll-like receptor) were resistant to ouabain-induced NF-κB activation, suggesting an indispensable role of these 3 receptors in this pathway. Mechanistically, this effect of ouabain was independent of the ion transport function of the Na/K-ATPase. Instead, ouabain stimulated a signaling complex, including Na/K-ATPase, CD36, and TLR4. Subsequently, TLR4 recruited MyD88 adaptor protein for NF-κB activation. Furthermore, intraperitoneal injection of ouabain into mice specifically recruited Ly6C+CCR2+ monocyte subtypes to the peritoneal cavities, indicating that the CTS ouabain triggers inflammation in vivo. CONCLUSIONS: CTS activate NF-κB leading to proinflammatory cytokine production in primary macrophages through a signaling complex, including CD36, TLR4, and Na/K-ATPase. These findings warrant further studies on endogenous CTS in chronic inflammatory diseases, such as atherosclerosis.

The global dynamics for a stochastic SIS epidemic model with isolation.

In this paper, we investigate the dynamical behavior for a stochastic SIS epidemic model with isolation which is as an important strategy for the elimination of infectious diseases. It is assumed that the stochastic effects manifest themselves mainly as fluctuation in the transmission coefficient, the death rate and the proportional coefficient of the isolation of infective. It is shown that the extinction and persistence in the mean of the model are determined by a threshold value R 0 S . That is, if R 0 S < 1 , then disease dies out with probability one, and if R 0 S > 1 , then the disease is stochastic persistent in the means with probability one. Furthermore, the existence of a unique stationary distribution is discussed, and the sufficient conditions are established by using the Lyapunov function method. Finally, some numerical examples are carried out to confirm the analytical results.

Extracellular Vesicles Activate a CD36-Dependent Signaling Pathway to Inhibit Microvascular Endothelial Cell Migration and Tube Formation.

OBJECTIVE: Literature on the effect of cell-derived extracellular vesicles (EV), ≤1 µm vesicles shed from various cell types during activation or apoptosis, on microvascular endothelial cell (MVEC) signaling is conflicting. Thrombospondin-1 and related proteins induce anti-angiogenic signals in MVEC via CD36. CD36 binds EV via phosphatidylserine exposed on their surface but the effects of this interaction on MVEC functions are not known. We hypothesized that EV would inhibit angiogenic MVEC functions via CD36. APPROACH AND RESULTS: EV generated in vitro from various cell types or isolated from plasma inhibited MVEC tube formation in in vitro matrigel assays and endothelial cell migration in Boyden chamber assays. Exosomes derived from the same cells did not have inhibitory activity. Inhibition of migration required endothelial cell expression of CD36. In mouse in vivo matrigel plug assays, EV inhibited cell migration into matrigel plugs in wild type but not in cd36 null animals. Annexin V, an anionic phospholipid binding protein, when incubated with EV partially reversed inhibition of migration, suggesting a phosphatidylserine-dependent effect. EV exposure induced reactive oxygen species generation in MVEC in a NADPH oxidase and Src family kinase-dependent manner, and their inhibition by apocynin and PP2, respectively, partially reversed the EV-mediated inhibition of migration. Annexin V partially reversed EV-induced reactive oxygen species generation in murine CD36 cDNA-transfected HVUEC but not in CD36-negative human umbilical vein endothelial cell. CONCLUSIONS: These studies establish a general inhibitory effect of EV on endothelial cell proangiogenic responses and identify a CD36-mediated mechanistic pathway through which EV inhibit MVEC migration and tube formation.

Energy replacement using glucose does not increase postprandial lipemia after moderate intensity exercise.

BACKGROUND: Aerobic exercise can decrease postprandial triglyceride (TG) concentrations but the relationship between exercise-induced energy deficits and postprandial lipemia is still unclear. The aim of the present study was to examine the effect of a single bout of aerobic exercise, with and without energy replacement, on postprandial lipemia and on peripheral blood mononuclear cell (PBMC) mRNA expression of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) receptors and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). METHODS: Nine healthy male humans completed three two-day trials in a random order. On day 1, volunteers rested (CON), completed 60 minutes of treadmill walking at 50% of VO2peak (EX) or completed the same bout of walking but with the energy replaced afterwards with a glucose solution (EXG). On day 2, volunteers rested and consumed a high fat test meal in the morning. RESULTS: Total and incremental TG AUC were significantly lower on the EXG (P < 0.05) and EX (P < 0.05) trials than the CON trial with no difference between the two exercise trials. No significant difference was observed in VLDL or LDL receptor mRNA expression among the trials (P > 0.05). CONCLUSIONS: In conclusion, energy replacement by glucose did not affect the decrease in postprandial TG concentrations observed after moderate intensity exercise and exercise does not affect changes in PBMC HMGCR, VLDL and LDL receptor mRNA expression.