Occlusion of left atrial appendage affects metabolomic profile: focus on glycolysis,tricarboxylic acid and urea metabolism

Background

Left atrial appendage (LAA) closure (LAAC) by implantation of an occlusion device is an established cardiac intervention to reduce risk of stroke while avoiding intake of oral anticoagulation medication during atrial fibrillation. Cardiac interventions can alter local or systemic gene and protein expression. Effects of LAAC on systemic metabolism have not been studied yet.

Objectives

We aimed to study the effects of interventional LAAC on systemic metabolism.

Methods

Products of glycolysis, tricarboxylic acid and urea metabolism were analyzed by ESI-LC-MS/MS and MS/MS using the AbsoluteIDQ? p180 Kit in plasma of 44 patients undergoing successful interventional LAAC at baseline (T0) and after 6 months (T1).

Results

During follow up, plasma concentrations of several parameters of glycolysis and tricarboxylic acid cycle (TCA) and urea metabolism increased (alanine, hexose, proline, sarcosine), while others decreased (aspartate, glycine, SDMA, serine). Multivariate linear regression analysis showed that time after interventional LAAC was an independent predictor for metabolite changes, including the decrease of SDMA (beta ?0.19, p?<?0.01) and the increase of sarcosine (beta 0.16, p?<?0.01).

Conclusions

Successful interventional LAAC affects different pathways of the metabolome, which are probably related to cardiac remodeling. The underlying mechanisms as well as the long term effects have to be studied in the future.

     

Prebiotics and lipid metabolism.

Prebiotics are defined as nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth or the activity of one or a limited number of bacteria (bifidobacteria, lactobacilli) in the colon. Dietary fructans are nutritionally interesting oligosaccharides that strictly conform to the definition of prebiotics and (in view of experimental studies in animals and of less numerous studies in humans) exhibit interesting serum or hepatic lipid lowering properties. Other nondigestible/fermentable nutrients, which also modulate intestinal flora activity, exhibit cholesterol or triglyceride lowering effects. Are changes in intestinal bacterial flora composition or fermentation activity responsible for those effects? What is the future of prebiotics in the nutritional control of lipidaemia and cardiovascular disease risk in humans? Those questions only receive partial response in the present review because studies of the systemic effects of prebiotics are still in their infancy, and require fundamental research devoted to elucidating the biochemical and physiological events that allow prebiotics to exert systemic effects on lipid metabolism.     

Lung delivery of nanoliposomal salbutamol sulfate dry powder inhalation for facilitated asthma therapy

Abstract

The motive behind present work was to discover a solution for overcoming the problems allied with a deprived oral bioavailability of salbutamol sulfate (SS) due to its first pass hepatic metabolism, shorter half-life, and systemic toxicity at high doses. Pulmonary delivery provides an alternative route of administration to avoid hepatic metabolism of SS, moreover facilitated diffusion and prolonged retention can be achieved by incorporation into liposomes. Liposomes were prepared by thin film hydration technique using 3² full factorial design and formulation was optimized based on the vesicle size and percent drug entrapment (PDE) of liposomes. Optimized liposomal formulation exhibited an average size of about 167.2?±?0.170?nm, with 80.68?±?0.74% drug entrapment, and 9.74?±?1.10?mV zeta potential. The liposomal dispersion was then spray dried and further characterized for in-vitro aerosol performance using Andersen Cascade Impactor. Optimized liposomal formulation revealed prolonged in-vitro drug release of more than 90% up to 14?h following Higuchi’s controlled release model. Thus, the proposed new-fangled liposomal formulation would be a propitious alternative to conventional therapy for efficient and methodical treatment of asthma and alike respiratory ailments.     

Induction of systemic stress tolerance by brassinosteroid in Cucumis sativus

? Brassinosteroids (BRs) are a new class of plant hormones that are essential for plant growth and development. Here, the involvement of BRs in plant systemic tolerance to biotic and abiotic stresses was studied. ? The effects of 24-epibrassinolide (EBR) on plant stress tolerance were studied through the assessment of symptoms of photooxidative stress by chlorophyll fluorescence imaging pulse amplitude modulation, the analysis of gene expression using quantitative real-time PCR and the measurement of hydrogen peroxide (H?O?) production using a spectrophotometric assay or confocal laser scanning microscopy. ? Treatment of primary leaves with EBR induced systemic tolerance to photooxidative stress in untreated upper and lower leaves. This was accompanied by the systemic accumulation of H?O? and the systemic induction of genes associated with stress responses. Foliar treatment of EBR also enhanced root resistance to Fusarium wilt pathogen. Pharmacological study showed that EBR-induced systemic tolerance was dependent on local and systemic H?O? accumulation. The expression of BR biosynthetic genes was repressed in EBR-treated leaves, but elevated significantly in untreated systemic leaves. Further analysis indicated that EBR-induced systemic induction of BR biosynthetic genes was mediated by systemically elevated H?O?. ? These results strongly argue that local EBR treatment can activate the continuous production of H?O?, and the autopropagative nature of the reactive oxygen species signal, in turn, mediates EBR-induced systemic tolerance.     

Acute in vitro hypoxia and high-altitude (4,559 m) exposure decreases leukocyte oxygen consumption

Hypoxia impairs metabolic functions by decreasing activity and expression of ATP-consuming processes. To separate hypoxia from systemic effects, we tested whether hypoxia at high altitude affects basal and PMA-stimulated leukocyte metabolism and how this compares to acute (15 min) and 24 h of in vitro hypoxia. Leukocytes were prepared at low altitude and ～24 h after arrival at 4559 m. Mitochondrial oxygen consumption (JO?) was measured by respirometry, oxygen radicals by electron spin resonance spectroscopy, both at a Po? = 100 mmHg (JO?,???) and 20 mmHg (JO?,??). Acute hypoxia of leukocytes decreased JO? at low altitude. Exposure to high altitude decreased JO?,???, whereas JO?,?? was not affected. Acute hypoxia of low-altitude samples decreased the activity of complexes I, II, and III. At high altitude, activity of complexes I and III were decreased when measured in normoxia. Stimulation of leukocytes with PMA increased JO?,??? at low (twofold) and high altitude (five-fold). At both locations, PMA-stimulated JO? was decreased by acute hypoxia. Basal and PMA-stimulated reactive oxygen species (ROS) production were unchanged at high altitude. Separate in vitro experiments performed at low altitude show that ～75% of PMA-induced increase in JO? was due to increased extra-mitochondrial JO? (JO?(,res); in the presence of rotenone and antimycin A). JO?(,res) was doubled by PMA. Acute hypoxia decreased basal JO?(,res) by ～70% and PMA-stimulated JO?(,res) by about 50% in cells cultured in normoxia and hypoxia (1.5% O?; 24 h). Conversely, 24 h in vitro hypoxia decreased mitochondrial JO?,??? and JO?,??, extra-mitochondrial, basal, and PMA-stimulated JO? were not affected. These results show that 24 h of high altitude but not 24 h in vitro hypoxia decreased basal leukocyte metabolism, whereas PMA-induced JO? and ROS formation were not affected, indicating that prolonged high-altitude hypoxia impairs mitochondrial metabolism but does not impair respiratory burst. In contrast, acute hypoxia impairs respiratory burst at either altitude.     

Lactobacillus plantarum promotes Drosophila systemic growth by modulating hormonal signals through TOR-dependent nutrient sensing

There is growing evidence that intestinal bacteria are important beneficial partners of their metazoan hosts. Recent observations suggest a strong link between commensal bacteria, host energy metabolism, and metabolic diseases such as diabetes and obesity. As a consequence, the gut microbiota is now considered a "host" factor that influences energy uptake. However, the impact of intestinal bacteria on other systemic physiological parameters still remains unclear. Here, we demonstrate that Drosophila microbiota promotes larval growth upon nutrient scarcity. We reveal that Lactobacillus plantarum, a commensal bacterium of the Drosophila intestine, is sufficient on its own to recapitulate the?natural microbiota growth-promoting effect. L.?plantarum exerts its benefit by acting genetically upstream of the TOR-dependent host nutrient sensing system controlling hormonal growth signaling. Our results indicate that the intestinal microbiota should also be envisaged as a factor that influences the systemic growth of its host.     

The NAD World: A New Systemic Regulatory Network for Metabolism and Aging—Sirt1, Systemic NAD Biosynthesis,and Their Importance

For the past several years, it has been demonstrated that the NAD-dependent protein deacetylase Sirt1 and nicotinamide phosphoribosyltransferase (Nampt)-mediated systemic NAD biosynthesis together play a critical role in the regulation of metabolism and possibly aging in mammals. Based on our recent studies on these two critical components, we have developed a hypothesis of a novel systemic regulatory network, named “NAD World”, for mammalian aging. Conceptually, in the NAD World, systemic NAD biosynthesis mediated by intra- and extracellular Nampt functions as a driver that keeps up the pace of metabolism in multiple tissues/organs, and the NAD-dependent deacetylase Sirt1 serves as a universal mediator that executes metabolic effects in a tissue-dependent manner in response to changes in systemic NAD biosynthesis. This new concept of the NAD World provides important insights into a systemic regulatory mechanism that fundamentally connects metabolism and aging and also conveys the ideas of functional hierarchy and frailty for the regulation of metabolic robustness and aging in mammals.     

Is cancer a metabolic rebellion against host aging?: In the quest for immortality,tumor cells try to save themselves by boosting mitochondrial metabolism

Aging drives large systemic reductions in oxidative mitochondrial function, shifting the entire body metabolically toward aerobic glycolysis, a.k.a, the Warburg effect. Aging is also one of the most significant risk factors for the development of human cancers, including breast tumors. How are these two findings connected? One simplistic idea is that cancer cells rebel against the aging process by increasing their capacity for oxidative mitochondrial metabolism (OXPHOS). Then, local and systemic aerobic glycolysis in the aging host would provide energy-rich mitochondrial fuels (such as L-lactate and ketones) to directly “fuel” tumor cell growth and metastasis. This would establish a type of parasite-host relationship or “two-compartment tumor metabolism,” with glycolytic/oxidative metabolic coupling. The cancer cells (“the seeds”) would flourish in this nutrient-rich microenvironment (“the soil”), which has been fertilized by host aging. In this scenario, cancer cells are only trying to save themselves from the consequences of aging by engineering a metabolic mutiny, through the amplification of mitochondrial metabolism. We discuss the recent findings of Drs. Ron DePinho (MD Anderson) and Craig Thomspson (Sloan-Kettering) that are also consistent with this new hypothesis, linking cancer progression with metabolic aging. Using data mining and bioinformatics approaches, we also provide key evidence of a role for PGC1a/NRF1 signaling in the pathogenesis of (1) two-compartment tumor metabolism and (2) mitochondrial biogenesis in human breast cancer cells.Key words: aging, mitochondria, cancer metabolism, autophagy, mitophagy, aerobic glycolysis, oxidative phosphorylation, Metformin, drug resistance, chemoresistance, Warburg effect, metabolic compartments, parasite, PGC1a, PGC1b, NRF1, two-compartment tumor metabolism     

The effect of circadian rhythm on pharmacokinetics and metabolism of the Cdk inhibitor,roscovitine, in tumor mice model

Roscovitine is a selective Cdk-inhibitor that is under investigation in phase II clinical trials under several conditions, including chemotherapy. Tumor growth inhibition has been previously shown to be affected by the dosing time of roscovitine in a Glasgow osteosarcoma xenograft mouse model. In the current study, we examined the effect of dose timing on the pharmacokinetics, biodistribution and metabolism of this drug in different organs in B6D2F1 mice. The drug was orally administered at resting (ZT3) or activity time of the mice (ZT19) at a dose of 300?mg/kg. Plasma and organs were removed at serial time points (10, 20 and 30?min; 1, 2, 4, 6, 8, 12 and 24?h) after the administration. Roscovitine and its carboxylic metabolite concentrations were analyzed using HPLC-UV, and pharmacokinetic parameters were calculated in different organs. We found that systemic exposure to roscovitine was 38% higher when dosing at ZT3, and elimination half-life was double compared to when dosing at ZT19. Higher organ concentrations expressed as (organ/plasma) ratio were observed when dosing at ZT3 in the kidney (180%), adipose tissue (188%), testis (132%) and lungs (112%), while the liver exposure to roscovitine was 120% higher after dosing at ZT19. The metabolic ratio was approximately 23% higher at ZT19, while the intrinsic clearance (CL_int) was approximately 67% higher at ZT19, indicating faster and more efficient metabolism. These differences may be caused by circadian differences in the absorption, distribution, metabolism and excretion processes governing roscovitine disposition in the mice. In this article, we describe for the first time the chronobiodistribution of roscovitine in the mouse and the contribution of the dosing time to the variability of its metabolism. Our results may help in designing better dosing schedules of roscovitine in clinical trials.     

Impact of heart-specific disruption of the circadian clock on systemic glucose metabolism in mice

The daily rhythm of glucose metabolism is governed by the circadian clock, which consists of cell-autonomous clock machineries residing in nearly every tissue in the body. Disruption of these clock machineries either environmentally or genetically induces the dysregulation of glucose metabolism. Although the roles of clock machineries in the regulation of glucose metabolism have been uncovered in major metabolic tissues, such as the pancreas, liver, and skeletal muscle, it remains unknown whether clock function in non-major metabolic tissues also affects systemic glucose metabolism. Here, we tested the hypothesis that disruption of the clock machinery in the heart might also affect systemic glucose metabolism, because heart function is known to be associated with glucose tolerance. We examined glucose and insulin tolerance as well as heart phenotypes in mice with heart-specific deletion of Bmal1, a core clock gene. Bmal1 deletion in the heart not only decreased heart function but also led to systemic insulin resistance. Moreover, hyperglycemia was induced with age. Furthermore, heart-specific Bmal1-deficient mice exhibited decreased insulin-induced phosphorylation of Akt in the liver, thus indicating that Bmal1 deletion in the heart causes hepatic insulin resistance. Our findings revealed an unexpected effect of the function of clock machinery in a non-major metabolic tissue, the heart, on systemic glucose metabolism in mammals.     

氨基酸转运体在肿瘤代谢中的研究进展

代谢重编程是肿瘤的重要特征,是指肿瘤细胞为满足其快速增殖的生物合成与能量需求,对其糖代谢、脂代谢以及氨基酸代谢等代谢路径进行的重编程,以维持增长速度以及补偿能量代谢所造成的氧化还原压力。虽然不同的癌症代谢变化不同,但有些特征是所有癌症共有的,氨基酸代谢重编程是其中一个重要的特征。氨基酸进出细胞需要氨基酸转运体的协助,因而在肿瘤细胞中多种特定的氨基酸转运体均过表达。靶向氨基酸转运体通过影响肿瘤细胞的氨基酸代谢从而达到抗肿瘤的目的,是目前抗肿瘤药物的研究热点之一。主要介绍了几种在肿瘤代谢中发挥重要作用的氨基酸转运体以及靶向氨基酸转运体抗肿瘤治疗的研究进展及相关作用机制,旨在了解氨基酸转运体在抗肿瘤研究中的作用,以期促进靶向氨基酸转运体抗肿瘤药物的发展。     

Copper and molybdenum absorption by rats given ammonium tetrathiomolybdate

Previous studies have shown that the tetrathiomolybdate ion [MoS_4^2?] is a potent antagonist of Cu metabolism. Effects of orally administered MoS_4^2? on the absorption and tissue distribution of ⁶⁴Cu in rats have now been investigated. Four or 12 mg Mo/kg diet, when given as MoS_4^2?, strongly inhibited ⁶⁴Cu absorption and modified the fate of absorbed Cu, decreasing hepatic and renal uptake but increasing plasma retention of ⁶⁴Cu. These effects were not induced by equivalent dietary concentrations of Mo as MoS_4^2? or when S^2? was given as CaS. Clinical and biochemical effects induced by orally administered MoS_4^2? were abolished by increasing dietary concentrations of Cu. Such treatment also inhibited the absorption and tissue retention of ⁹⁹Mo derived from ⁹⁹MoS_4^2?. Intraperitoneal administration of Cu ameliorated clinical effects attributable to MoS_4^2? but neither inhibited ⁹⁹Mo absorption nor the appearance of systemic defects in Cu metabolism. Since the absorption of MoS_4^2? (or its derivatives) from the gastrointestinal tract is inhibited by Cu, it is evident that the site of its action as an antagonist influencing either the absorption or the subsequent metabolic fate of Cu depends upon the ratio Cu/MoS_4^2? in the diet.     

Silicon modifies both a local response and a systemic response to mechanical stress in tobacco leaves

Both lignin and silicon (Si) are major players in the resistance of plants to mechanical stress (MS). Focusing on the phenolic metabolism, here we studied the short-term effects of a local MS on tobacco (Nicotiana rustica L. cv. Basmas) plants with Si (+Si, 1 mM Na₂SiO₃) and without Si (?Si) treatments in order to see how Si may modify local and systemic responses. One week after starting the Si treatment, a half of the plants were exposed to a mechanical pressure applying 980 Pa for 24 h on the upper side of the 3^rd leaf of each plant (+MS). The rest of the plants remained unstressed (?MS). Plants were harvested 24 h and 72 h after starting the MS and the leaves directly exposed to the mechanical stress (DMS) and those indirectly exposed to the mechanical stress (IMS) from below and above the DMS leaf were analyzed for phenolic metabolism along with the corresponding leaves from?MS plants. In the DMS leaf, the activities of polyphenol oxidase, phenylalanine ammonia lyase, and cytosolic and covalently-bound peroxidases increased by the MS, while decreased by Si. In accordance with this in the DMS leaf, the content of soluble and cell wall-bound phenolics and lignin were enhanced by the MS but decreased by Si. Interestingly, Si influenced the pattern of response to the MS depending on whether the leaves were directly treated by the MS or not. Silicon treatment augmented MS-induced lignin accumulation in the DMS leaf while rather inhibited lignin formation in the IMS leaves. These data show that Si modified MS-mediated changes in the phenolic metabolism differently in local and systemic leaves.     

Changes in the function and energy metabolism of the myocardium in experimental diabetes mellitus in dogs

Coronary arteries, coronary sinus, heart cavities, and great vessels were catheterized in anesthetized dogs with alloxan diabetes. Cardiac contractility, coronary and systemic circulation, myocardial energy metabolism and acid-base balance were studied. It was shown that the alterations of the cardiac function occurred in experimental dogs with severe diabetes mellitus. They consisted of a decrease in cardiac and working outputs, ejection period, maximum velocity of the left ventricular contractions and an increase in the projection period. These dysfunctions were caused by the alterations of the myocardial energy metabolism and systemic changes in the acid-base balance.     

Systemic metabolic reactions are obtained by singular value decomposition of genome-scale stoichiometric matrices

Genome-scale metabolic networks can be reconstructed. The systemic biochemical properties of these networks can now be studied. Here, genome-scale reconstructed metabolic networks were analysed using singular value decomposition (SVD). All the individual biochemical conversions contained in a reconstructed metabolic network are described by a stoichiometric matrix (S). SVD of S led to the definition of the underlying modes that characterize the overall biochemical conversions that take place in a network and rank-ordered their importance. The modes were shown to correspond to systemic biochemical reactions and they could be used to identify the groups and clusters of individual biochemical reactions that drive them. Comparative analysis of the Escherichia coli, Haemophilus influenzae, and Helicobacter pylori genome-scale metabolic networks showed that the four dominant modes in all three networks correspond to: (1) the conversion of ATP to ADP, (2) redox metabolism of NADP, (3) proton-motive force, and (4) inorganic phosphate metabolism. The sets of individual metabolic reactions deriving these systemic conversions, however, differed among the three organisms. Thus, we can now define systemic metabolic reactions, or eigen-reactions, for the study of systems biology of metabolism and have a basis for comparing the overall properties of genome-specific metabolic networks.     

Lysophosphatidylinositols in inflammation and macrophage activation: Altered levels and anti-inflammatory effects

Lysophosphatidylinositols (LPI) are bioactive lipids that are implicated in several pathophysiological processes such as cell proliferation, migration and tumorigenesis and were shown to play a role in obesity and metabolic disorders. Often, these effects of LPI were due to activation of the G protein-coupled receptor GPR55. However, the role of LPI and GPR55 in inflammation and macrophage activation remains unclear. Therefore, we thought to study the effect of macrophage activation and inflammation on LPI levels and metabolism. To do so, we used J774 and BV2 cells in culture activated with lipopolysaccharides (LPS, 100?ng/mL) as well as primary mouse alveolar and peritoneal macrophages. We also quantified LPI levels in the cerebellum, lung, liver, spleen and colon of mice with a systemic inflammation induced by LPS (300?μg/kg) and in the colon of mice with acute colitis induced by dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) and chronic DSS-induced colitis.Our data show that LPS-induced macrophage activation leads to altered LPI levels in both the cells and culture medium. We also show that cytosolic phospholipase A2α (cPLA2α) and α/β?hydrolase domain 6 (ABHD6) are among the enzymes implicated in LPI metabolism in J774 macrophages. Indeed, ABHD6 and cPLA2α inhibition increased 20:4-LPI levels in LPS-activated macrophages. Furthermore, incubation of LPS-activated cells with LPI decreased J774 activation in a GPR55-dependent manner. In vivo, LPI levels were altered by inflammation in the liver, spleen and colon. These alterations are tissue dependent and could highlight a potential role for LPI in inflammatory processes.