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Systemic trafficking and storage of essential metal ions play fundamental roles in living organisms by serving as essential cofactors in various cellular processes. Thereby metal quantification and localization are critical steps in understanding metal homeostasis, and how their dyshomeostasis might contribute to disease etiology and the ensuing pathologies. Furthermore, the amount and distribution of metals in organisms can provide insight into their underlying mechanisms of toxicity and toxicokinetics. While in vivo studies on metal imaging in mammalian experimental animals are complex, time- and resource-consuming, the nematode Caenorhabditis elegans (C. elegans) provides a suitable comparative and complementary model system. Expressing homologous genes to those inherent to mammals, including those that regulate metal homeostasis and transport, C. elegans has become a powerful tool to study metal homeostasis and toxicity. A number of recent technical advances have been made in the development and application of analytical methods to visualize metal ions in C. elegans. Here, we briefly summarize key findings and challenges of the three main techniques and their application to the nematode, namely sensing fluorophores, microbeam synchrotron radiation X-ray fluorescence as well as laser ablation ( LA) coupled to inductively coupled plasma-mass spectrometry (ICP-MS).
Obesity is a key component of equine metabolic syndrome, which is highly associated with laminitis. Feed restriction and/or exercise are known to alleviate the detrimental effects of insulin resistance in obese ponies. However, little is known about changes in the serum lipid patterns due to weight reduction and its association with disease outcomes. Therefore, the lipid patterns in the serum of 14 mature ponies before and after a 14-week body weight reduction program (BWRP) were investigated by multi-one-dimensional thin-layer chromatography (MOD-TLC). Additionally, sensitivity to insulin (SI), body condition scores (BCS) and cresty neck scores (CNS) were measured. A BWRP resulted in a significant loss of body weight (P < 0.001), which was associated with beneficial decreases in BCS and CNS (both, P < 0.001). Serum lipid compositions revealed significantly increased free fatty acid (FFA), sphingomyelin (SM; both P < 0.001), total cholesterol (C) and cholesterol ester (CE) (both P < 0.01) and triacylglycerol (TG; P < 0.05) densities. Improvement of SI after the BWRP was associated with increases in neutral lipids (C, CE and TG, all P < 0.01), FFA and the phospholipid SM (both, P < 0.001). The results show that a BWRP in obese ponies was effective and associated with changes in the concentrations of neutral lipids and the phospholipid SM, indicating that SM may play a role in insulin signaling pathways and thus in the pathogenesis of insulin resistance and the progression of metabolic syndrome in obese ponies.
Controlled delivery of corticosteroids using nanoparticles to the skin and corneal epithelium may reduce their side effects and maximize treatment effectiveness. Dexamethasone-loaded ethyl cellulose, Eudragit® RS and ethyl cellulose/Eudragit® RS nanoparticles were prepared by the solvent evaporation method. Dexamethasone release from the polymeric nanoparticles was investigated in vitro using Franz diffusion cells. Drug penetration was also assessed ex vivo using excised human skin. Nanoparticle toxicity was determined by MTT and H2DCFDA assays. Eudragit® RS nanoparticles were smaller and positively charged but had a lower dexamethasone loading capacity (0.3–0.7%) than ethyl cellulose nanoparticles (1.4–2.2%). By blending the two polymers (1:1), small (105 nm), positively charged (+37 mV) nanoparticles with sufficient dexamethasone loading (1.3%) were obtained. Dexamethasone release and penetration significantly decreased with decreasing drug to polymer ratio and increased when Eudragit® RS was blended with ethyl cellulose. Ex vivo, drug release and penetration from the nanoparticles was slower than a conventional cream. The nanoparticles bear no toxicity potentials except ethyl cellulose nanoparticles had ROS generation potential at high concentration. In conclusion, the nanoparticles showed great potential to control the release and penetration of corticosteroids on the skin and mucus membrane and maximize treatment effectiveness.
BACKGROUNDProduction and the quality of tomato fruits have a strong economic relevance. Microorganisms such as the plant growth-promoting bacterium (PGPB) Kosakonia radicincitans (DSM 16656) have been demonstrated to improve shoot and root growth of young tomato plants, but data on yield increase and fruit quality by K. radicincitans are lacking. RESULTSThis study investigated how K. radicincitans affects tomato fruits. After inoculation of tomato seeds with K. radicincitans or a sodium chloride buffer control solution, stalk length, first flowering and the amount of ripened fruits produced by inoculated and non-inoculated plants were monitored over a period of 21 weeks. Inoculation of tomato seeds with K. radicincitans accelerated flowering and ripening of tomato fruits. Sugars, acidity, amino acids, volatile organic compounds and carotenoids in the fruits were also analyzed. CONCLUSIONIt was found that the PGPBK. radicincitans affected the amino acid, sugar and volatile composition of ripened fruits, contributing to a more pleasant-tasting fruit without forfeiting selected quality indicators. (c) 2017 Society of Chemical Industry
Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR- based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2 production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.
Adulteration of food and mislabeled products in global market is a major financial and reputational risk for food manufacturers and trade companies. Consequently, there is a necessity to develop analytical methods to meet these issues. An analytical strategy to check the authenticity of wheat, spelt and rye addition in bread products was developed based on database research, in silico digestion confirming peptide specificity and finally quantification by liquid chromatography-tandem mass spectrometry analysis. Peptide markers for wheat (SQQQISQQPQQLPQQQQIPQQPQQF; QQHQIPQQPQQFPQQQQF and QPHQPQQPYPQQ), spelt (ASIVVGIGGQ; SQQPGQIIPQQPQQPSPL) and rye (LPQSHKQHVGQGAL; AQVQGIIQPQQL and QQFPQQPQQSFPQQPQQPVPQQPL) were identified, verified by protein Basic Local Alignment Search Tool and database research and used for quantification in bread. The specific use of multi-reaction monitoring transitions of selected peptides permitted the identification of closely related species wheat and spelt. Other cereal species (emmer, einkorn, barley, maize, rye and oat) were also checked. The target peptides were quantified at different levels using own reference baked products (bread) after in-solution chymotryptic digestion. Sensitivity of the identification was 0.5-1% using flour-based (0-25%) matrix calibration and the analytical recovery in bread was 80-125%. The analytical strategy described here supplies an emerging, independent and flexible tool in controlling the labeling of bread.
Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-κB). We have examined the gene expression of the subunits NF-κBp65 and NF-κBp50, as well as NF-κBp65 and NF-κBp50 binding, the gene expression of pro-inflammatory mediators under NF-κB control (IL-1β, IL-6, INF-γ, TNF-α, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-κBp65 and its target genes expression (TNF-α, IL-1β, MCP-1 and IκB-α) were significantly higher in cachectic cancer patients. Moreover, NF-κBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-κB pathway plays a role in the promotion of WAT inflammation during cachexia.
White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho)physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e.g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance.
Identification of Endodormancy Release for Cherries (Prunus Avium L.) by
Abscisic Acid and Sugars
(2017)
In order to develop reliable and physiologically sound models for the plant development in spring, the date of endodormancy release is always a crucial and mostly unknown model parameter. Until present, classical approaches - such as climate chamber experiments - are used to derive this unknown parameter. In these experiments, progressive plant development or significant changes in bud’s fresh weight or water content are measurable markers for dormancy release. This study presents an alternative approach, which is based on four well-known metabolites. For 5 seasons (2011/12-2015/16), the content of abscisic acid (ABA) and sugars such as fructose, sucrose and glucose in sweet cherry flower buds (cultivar ‘Summit’) were weekly analysed between beginning of October and April. These data allow comparing the annual course of these metabolites with the date of endodormancy release, derived from a classical climate chamber experiment, published in a previous study. Results showed that ABA and sucrose are two important metabolites which can help to identify the date of endodormancy release of sweet cherries. On average, ABA content reached a plateau of 5.65 μg g-1 DW-1 during endodormancy, which was maintained for 3-6 weeks. The significant reduction of the ABA content after this period to 4.41 μg g-1 DW-1 on average during ecodormancy was nearly in agreement with the date of endodormancy release of ‘Summit’ on 28 November (332 DOY).
The annual cycle of sucrose, which has a cryoprotective effect during winter, is well comprehensible and showed a close relationship to
the annual course of minimum air temperature after leaf fall(r=-0.90). The nearly constant level of sucrose during ecodormancy (21.0 mg g-1 DW-1, 5 yr. mean) did not only allow deriving the date of endodormancy release but can also be helpful to define the beginning of ontogenetic development.
Preclinical assessment of penetration not only in intact, but also in barrier‐disrupted skin is important to explore the surplus value of novel drug delivery systems, which can be specifically designed for diseased skin. Here, we characterized physical and chemical barrier disruption protocols for short‐term ex vivo skin cultures with regard to structural integrity, physiological and biological parameters. Further, we compared the penetration of dexamethasone (Dex) in different nanoparticle‐based formulations in stratum corneum, epidermis and dermis extracts of intact vs. barrier‐disrupted skin as well as by dermal microdialysis at 6, 12 and 24 hours after topical application. Dex was quantified by liquid‐chromatography ‐ tandem‐mass spectrometry (LC‐MS/MS). Simultaneously, we investigated the Dex efficacy by interleukin (IL) analysis. Tape‐stripping (TS) and 4 hours sodium lauryl sulfate 5 % (SLS) exposure were identified as highly effective barrier disruption methods assessed by reproducible transepidermal water loss (TEWL) changes and IL‐6/8 increase which was more pronounced in SLS‐treated skin. The barrier state has also a significant impact on the Dex penetration kinetics: for all formulations, TS highly increased dermal Dex concentration despite the fact that nanocrystals quickly and effectively penetrated both, intact and barrier‐disrupted skin reaching significantly higher dermal Dex concentration after 6 hours compared to Dex cream. The surplus value of encapsulation in ethyl cellulose nanocarriers could mostly be observed when applied on intact skin, in general showing a delayed Dex penetration. Estimation of cytokines was limited due to the trauma caused by probe insertion. In summary, ex vivo human skin is a highly interesting short‐term preclinical model for the analysis of penetration and efficacy of novel drug delivery systems.
Fortsetzung aus Ernährungs Umschau Heft 9/2017
Fettsäurenverteilung
Die Gehalte an den wichtigsten Fettsäuren (FS) sind in • Tabelle 4 und 5 aufgeführt, in g/100 g sowie in Prozent des Fettanteils (Etherextrakt bzw. g FS-Methylester pro 100 g der Summe der FS-Methylester). Erbsen und Ackerbohnen spielen als Fett- und FS-Quelle praktisch keine Rolle. Sojabohnen sind eine wesentliche Quelle für Linolsäure, die häufigste n-6-FS. An zweiter Stelle steht die Ölsäure. Aber auch der Gehalt an der n-3-FS α-Linolensäure (ALA) ist hoch, womit sich Sojaöl in die Reihe der Fette mit mittlerem ALA-Gehalt, wie Raps- und Walnussöl einreiht. Im Gegensatz zu Rapsöl entspricht jedoch das Linolsäure/α-Linolensäure- Verhältnis nicht dem empfohlenen Verhältnis von 5:1 in der Gesamt- Diät [13]. Zum Ausgleich für die Fette aus der übrigen Nahrung (Getreide, Lebensmittel tierischer Herkunft) sollten Pflanzenöle besser noch ein engeres Verhältnis als 5:1 aufweisen. Das trifft für Lupinen-Öl schon eher zu, wenngleich der absolute Beitrag an ALA hier eher gering ist.
Background/Aims:
Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6).
Methods:
The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS).
Results:
Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25).
Conclusion:
LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.
A protease called Mauritanicain was isolated from the latex of Euphorbia mauritanica L. (Euphorbiaceae) by combining ion exchange chromatography, ultrafiltration, and gel filtration chromatography. It has a high proteolytic activity against casein. The activity was only inhibited by specific serine protease inhibitors, classifying it to the serine protease family. An optimal degradation of the substrate casein takes place at a temperature of 55-65 degrees C and a pH of 5.5-6.5, and is unstable at pH < 5 and pH > 9. The protease is stable at temperatures from 20-70 degrees C, whereby the activity decreases drastically to less than 20% at 75 degrees C. SDS-PAGE and matrix-assisted laser desorption time-of-flight analysis yielded a molecular weight of 73 kDa; possibly, it is natively present as a non-covalently linked dimer of a higher molecular mass > 132 kDa. Without heat denaturation, a breakdown in fractions of 73 kDa and 52 kDa was observed in SDS-PAGE. Only in some properties it shows a similarity to other characterized proteases in the plant family Euphorbiaceae, such that Mauritanicain can be presented as a new isolated protease.
Background: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study.
Methods and Results: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT.
Conclusions: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage.
The degeneration of the retinal pigment epithelium caused by oxidative damage is a stage of development in age related macular degeneration (AMD). The carotenoid lutein is a major macular pigment that may reduce the incidence and progression of AMD, but the underlying mechanism is currently not fully understood. Carotenoids are known to be direct antioxidants. However, carotenoids can also activate cellular pathways resulting in indirect antioxidant effects. Here, we investigate the influence of lutein on the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes in human retinal pigment epithelial cells (ARPE-19 cells) using lutein-loaded Tween40 micelles. The micelles were identified as a suitable delivery system since they were nontoxic in APRE-19 cells up to 0.04% Tween40 and led to a cellular lutein accumulation of 62 mu M +/- 14 mu M after 24 h. Lutein significantly enhanced Nrf2 translocation to the nucleus 1.5 +/- 0.4-fold compared to that of unloaded micelles after 4 h. Furthermore, lutein treatment for 24 h significantly increased the transcripts of NAD(P)H:quinone oxidoreductase 1 (NQO1) by 1.7 +/- 0.1-fold, glutamate-cysteine ligase regulatory subunit (GCLm) by 1.4 +/- 0.1-fold, and heme oxygenase-1 (HO-1) by 1.8 +/- 0.3-fold. Moreover, we observed a significant enhancement of NQO1 activity by 1.2 +/- 0.1-fold. Collectively, this study indicates that lutein not only serves as a direct antioxidant but also activates Nrf 2 in ARPE-19 cells.
To study the role of the TTR-RBP4-ROH complex components (transthyretin, serum retinol binding protein, retinol) and of angiogenic factors PlGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1) in pregnancies complicated by small for gestational age infants (SGA). Case control study conducted on maternal serum collected between 11 + 0 to 13 + 6 weeks of gestation. TTR, RBP4, ROH, PlGF and sFlt-1 were measured in SGA patients (birth weight < 10%) who delivered at term (n = 37) and before 37 weeks of gestation (n = 17) and in a matched control group with uneventful pregnancies (n = 37). We found decreased RBP4 in SGA patients that delivered fetuses < 3% and in fetuses delivered after the 37 weeks of gestation compared to controls [1.50 (95% CI 1.40-1.75) vs 1.62 (95% CI 1.47-1.98), p < 0.05]. Further, we found lower PlGF and sFlt-1 concentrations in SGA that delivered before 37 weeks of gestation compared to controls (respectively, PIGF and sFlt-1: 39.7 pg/ml (95% CI 32.3-66.3) vs 62.9 pg/ml (95% CI 45.2-78.4) and 906 pg/ml (95% CI 727-1626) vs 1610 pg/ml (95% CI 1088-212), p < 0.05). First trimester maternal serum RBP4 and angiogenic factors PlGF and sFlt-1 can differently predict the timing of delivery of pregnancies complicated by SGA fetuses.
Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery.
Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery.