scholarly journals Membrane Phospholipids and Polyphosphates as Cofactors and Binding Molecules of SERPINA12 (vaspin)

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1992
Author(s):  
Catherine A. Tindall ◽  
Sebastian Dommel ◽  
Veronika Riedl ◽  
David Ulbricht ◽  
Stefanie Hanke ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Membrane Trafficking ◽  
Intracellular Signaling ◽  
Membrane Lipids ◽  
Heparin Binding ◽  
Functional Protein ◽  
Beneficial Effects ◽  
High Affinity ◽  
Phosphatidylinositol Phosphates ◽  
Insulin Stability

Visceral adipose tissue derived serine protease inhibitor (vaspin) is a member of the serpin family and has been shown to have beneficial effects on glucose tolerance, insulin stability as well as adipose tissue inflammation, parameters seriously affected by obesity. Some of these effects require inhibition of target proteases such as kallikrein 7(KLK7) and many studies have demonstrated vaspin-mediated activation of intracellular signaling cascades in various cells and tissues. So far, little is known about the exact mechanism how vaspin may trigger these intracellular signaling events. In this study, we investigated and characterized the interaction of vaspin with membrane lipids and polyphosphates as well as their potential regulatory effects on serpin activity using recombinant vaspin and KLK7 proteins and functional protein variants thereof. Here, we show for the first time that vaspin binds to phospholipids and polyphosphates with varying effects on KLK7 inhibition. Vaspin binds strongly to monophosphorylated phosphatidylinositol phosphates (PtdInsP) with no effect on vaspin activation. Microscale thermophoresis (MST) measurements revealed high-affinity binding to polyphosphate 45 (KD: 466 ± 75 nM) and activation of vaspin in a heparin-like manner. Furthermore, we identified additional residues in the heparin binding site in β-sheet A by mutating five basic residues resulting in complete loss of high-affinity heparin binding. Finally, using lipid overlay assays, we show that these residues are additionally involved in PtdInsP binding. Phospholipids play a major role in membrane trafficking and signaling whereas polyphosphates are procoagulant and proinflammatory agents. The identification of phospholipids and polyphosphates as binding partners of vaspin will contribute to the understanding of vaspins involvement in membrane trafficking, signaling and beneficial effects associated with obesity.

Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1356-1363 ◽  
Author(s):  
Barbara P. Schick ◽  
David Maslow ◽  
Adrianna Moshinski ◽  
James D. San Antonio
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Tandem Repeats ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
High Affinity ◽  
Binding Peptides

Abstract Patients given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious bleeding. We showed previously that peptides containing 3 or more tandem repeats of heparin-binding consensus sequences have high affinity for LMWH and neutralize LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified the (ARKKAAKA)n tandem repeat peptides by cyclization or by inclusion of hydrophobic tails or cysteines to promote multimerization. These peptides exhibit high-affinity binding to LMWH (dissociation constant [Kd], ≈ 50 nM), similar potencies in neutralizing anti–Factor Xa activity of UFH and enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater than protamine. Peptide (ARKKAAKA)3VLVLVLVL was most effective in all plasmas from enoxaparin-treated patients, and was 4- to 20-fold more effective than protamine. Several other peptide structures were effective in some patients' plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti–Factor Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure and heart rate measurements showed little or no hemodynamic effect. These heparin-binding peptides, singly or in combination, are potential candidates for clinical reversal of UFH and LMWH in humans.

scholarly journals Melatonin in Wine and Beer: Beneficial Effects

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 343
Author(s):  
Javier Marhuenda ◽  
Débora Villaño ◽  
Raúl Arcusa ◽  
Pilar Zafrilla
Keyword(s):  
Intracellular Signaling ◽  
Plasma Concentrations ◽  
Radical Scavenging ◽  
Direct Interaction ◽  
Melatonin Receptors ◽  
Current Evidence ◽  
Sleep Cycle ◽  
Beneficial Effects ◽  
Neuroprotective Actions ◽  
Radical Scavenging Properties

Melatonin is a hormone secreted in the pineal gland with several functions, especially regulation of circadian sleep cycle and the biological processes related to it. This review evaluates the bioavailability of melatonin and resulting metabolites, the presence of melatonin in wine and beer and factors that influence it, and finally the different benefits related to treatment with melatonin. When administered orally, melatonin is mainly absorbed in the rectum and the ileum; it has a half-life of about 0.45–1 h and is extensively inactivated in the liver by phase 2 enzymes. Melatonin (MEL) concentration varies from picograms to ng/mL in fermented beverages such as wine and beer, depending on the fermentation process. These low quantities, within a dietary intake, are enough to reach significant plasma concentrations of melatonin, and are thus able to exert beneficial effects. Melatonin has demonstrated antioxidant, anticarcinogenic, immunomodulatory and neuroprotective actions. These benefits are related to its free radical scavenging properties as well and the direct interaction with melatonin receptors, which are involved in complex intracellular signaling pathways, including inhibition of angiogenesis and cell proliferation, among others. In the present review, the current evidence on the effects of melatonin on different pathophysiological conditions is also discussed.

scholarly journals Xylo-Oligosaccharides in Prevention of Hepatic Steatosis and Adipose Tissue Inflammation: Associating Taxonomic and Metabolomic Patterns in Fecal Microbiomes with Biclustering

2021 ◽  
Vol 18 (8) ◽  
pp. 4049
Author(s):  
Jukka Hintikka ◽  
Sanna Lensu ◽  
Elina Mäkinen ◽  
Sira Karvinen ◽  
Marjaana Honkanen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Insulin Signaling ◽  
Aromatic Amino Acids ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Beneficial Effects ◽  
Male Wistar Rats ◽  
Branched Chain

We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms associated with these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12 weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.

scholarly journals Current Status of Human Adipose–Derived Stem Cells: Differentiation into Hepatocyte-Like Cells

2011 ◽  
Vol 11 ◽  
pp. 1568-1581 ◽  
Author(s):  
Feras Al Battah ◽  
Joery De Kock ◽  
Tamara Vanhaecke ◽  
Vera Rogiers
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Study Drug ◽  
Current Status ◽  
Human Organ ◽  
Beneficial Effects ◽  
Stems Cells

The shortage of human organ donors and the low cell quality of available liver tissues represent major obstacles for the clinical application of orthotropic liver transplantation and hepatocyte transplantation, respectively. Therefore, worldwide research groups are investigating alternative extrahepatic cell sources. Recentin vitrostudies have demonstrated that mesenchymal stem cells (MSCs) from various sources, including human bone marrow, adipose tissue, and umbilical cord, can be differentiated into hepatocyte-like cells when appropriate conditions are used. In particular, interest exists for human adipose–derived stems cells (hASCs) as an attractive cell source for generating hepatocyte-like cells. The hASCs are multipotent MSCs that reside in adipose tissue, with the ability to self-renew and differentiate into multiple cell lineages. Moreover, these cells can secrete multiple growth factors and cytokines that exert beneficial effects on organ or tissue injury. In this review, we will not only present recent data regarding hASC biology, their isolation, and differentiation capability towards hepatocytes, but also the potential application of hASC-derived hepatocytes to study drug toxicity. Additionally, this review will discuss the therapeutic potential of hASCs as undifferentiated cells in liver regeneration.

scholarly journals Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis factor-α

2007 ◽  
Vol 97 (2) ◽  
pp. 389-398 ◽  
Author(s):  
Patricia Pérez-Matute ◽  
Nerea Pérez-Echarri ◽  
J. Alfredo Martínez ◽  
Amelia Marti ◽  
María J. Moreno-Aliaga
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Body Weight Gain ◽  
Control Diet ◽  
Cafeteria Diet ◽  
High Fat ◽  
Beneficial Effects

n-3 PUFA have shown potential anti-obesity and insulin-sensitising properties. However, the mechanisms involved are not clearly established. The aim of the present study was to assess the effects of EPA administration, one of the n-3 PUFA, on body-weight gain and adiposity in rats fed on a standard or a high-fat (cafeteria) diet. The actions on white adipose tissue lipolysis, apoptosis and on several genes related to obesity and insulin resistance were also studied. Control and cafeteria-induced overweight male Wistar rats were assigned into two subgroups, one of them daily received EPA ethyl ester (1 g/kg) for 5 weeks by oral administration. The high-fat diet induced a very significant increase in both body weight and fat mass. Rats fed with the cafeteria diet and orally treated with EPA showed a marginally lower body-weight gain (P = 0·09), a decrease in food intake (P < 0·01) and an increase in leptin production (P < 0·05). EPA administration reduced retroperitoneal adipose tissue weight (P < 0·05) which could be secondary to the inhibition of the adipogenic transcription factor PPARγ gene expression (P < 0·001), and also to the increase in apoptosis (P < 0·05) found in rats fed with a control diet. TNFα gene expression was significantly increased (P < 0·05) by the cafeteria diet, while EPA treatment was able to prevent (P < 0·01) the rise in this inflammatory cytokine. Adiposity-corrected adiponectin plasma levels were increased by EPA. These actions on both TNFα and adiponectin could explain the beneficial effects of EPA on insulin resistance induced by the cafeteria diet.

scholarly journals Two Things about COVID-19 Might Need Attention

2020 ◽  
Author(s):  
Xiaodong Jia ◽  
Chengliang Yin ◽  
Shanshan Lu ◽  
Yan Chen ◽  
Qingyan Liu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Affinity Binding ◽  
High Affinity Binding ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Network Database ◽  
Tumor Tissues ◽  
The World ◽  
Different Types ◽  
Novel Coronavirus

The spread of 2019 novel coronavirus disease (COVID-19) throughout the world has been a severe challenge for public health. The human angiotensin-converting enzyme 2 (ACE2) has a remarkably high affinity binding to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the search for network database and re-analysis of pubic data, we found the level of ACE2 expression in adipose tissue was higher than that in lung tissue, which indicated the adipose tissue might be vulnerable to SARS-CoV-2 as well; the levels of ACE2 expressed by adipocytes and adipose progenitor cells were similar between non-obese individuals and obese individuals, but obese individuals have more adiposes so as to increase the number of ACE2-expressing cells; the expression of ACE2 in tumor tissues posed by five different types of cancers increased significantly compared with that in adjacent tissues. Thus, we suggest that more attentions might be given to obese individuals and the five types of cancer patients during the outbreak of COVID-19.

Abstract 1588: Midkine Gene Transfer Ameliorates Ischemic Cardiomyopathy through Enhancements of Neovascularization via Akt/PI3 Kinase and ERK Pathways and Anti-Apoptosis by Regulating Bcl-2 and Bax

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Arihiro Sumida ◽  
Mitsuru Horiba ◽  
Hisaaki Ishiguro ◽  
Hiroharu Takenaka ◽  
Norihiro Ueda ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Wistar Rat ◽  
Capillary Density ◽  
Heparin Binding ◽  
Intramyocardial Injection ◽  
Beneficial Effects ◽  
Erk Phosphorylation

Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, e.g. neural survival, carcinogenesis and tissue repair. We have demonstrated recently that MK ameliorates acute myocardial injury by ischemia/reperfusion through prevention of apoptotic reactions. Chronic effects of MK on the ventricular remodeling after myocardial infarction (MI) remain to be confirmed. MI was created in Wistar rat by ligation of the left anterior discending coronary artery. Rats of MK overexpression were prepared by intramyocardial injection of adenoviruses encoding MK (AdMK, n=12) at the onset of MI. Control rats were injected with adenoviruses encoding beta-galactosidase (AdLacZ, n=12). In echocardiography 4w after MI, AdMK showed smaller LVESD and LVEDD than AdLacZ (LVESD: 6.7±0.7 vs. 9.3±0.7mm, LVEDD: 8.7±0.7 vs. 10.7±0.7mm, p<0.01). AdMK had better FS than AdLacZ (FS: 23.0±2.8 vs. 12.4±2.1%, p<0.01). Better preservation of systolic/diastolic function in AdMK than AdLacZ was also recognized in the LV catheterization 6w after MI (dP/dt max : 3092±619 vs. 2171±763mmHg/s, dP/dt min : −2525±878 vs. −1700±722mmHg/s, LVEDP: 3.3±0.9 vs. 8.3±2.2mmHg, p<0.01). Morphological study on AdMK 6w after MI revealed less fibrosis (collagen deposition area: 10.2±5.3 vs. 15.3±4.5%, p<0.05) and a higher vWF-positive capillary density in the perinfarct zone (32±11 vs. 21±5/mm 2 , p<0.01) compared with AdLacZ. In Western blotting, the levels of Akt and ERK phosphorylation and PI3K were elevated in AdMK compared with AdLacZ (pAkt; 2.08-fold increase, pERK; 1.43-fold increase, PI3K; 2.36-fold increase, relative to AdLacZ, p<0.05). In addition, the level of Bcl-2 increased and the level of Bax decreased in AdMK compared with AdLacZ (Bcl-2; 2.15-fold increase, Bax; 3.63-fold decrease, relative to AdLacZ, p<0.01). Overexpression of MK has long-term beneficial effects to reduce the progression of LV remodeling and dysfunction after MI. This amelioration is attributable in part to an enhancement of neovascularization via PI3K/Akt and ERK pathways, and in part to anti-apoptotic actions regulating Bcl-2 and Bax. MK gene transfer might be a new therapeutic strategy for treatment of ischemic heart disease.

Acceleration of trophoblast differentiation by heparin-binding EGF-like growth factor is dependent on the stage-specific activation of calcium influx by ErbB receptors in developing mouse blastocysts

Development ◽  
2000 ◽  
Vol 127 (1) ◽  
pp. 33-44 ◽  
Author(s):  
J. Wang ◽  
L. Mayernik ◽  
J.F. Schultz ◽  
D.R. Armant
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Intracellular Signaling ◽  
Erbb Receptors ◽  
Apical Surface ◽  
Heparin Binding ◽  
Trophoblast Cells ◽  
Trophoblast Differentiation ◽  
Kinase C

Heparin-binding EGF-like growth factor (HB-EGF) is expressed in the mouse endometrial epithelium during implantation exclusively at sites apposed to embryos and accelerates the development of cultured blastocysts, suggesting that it may regulate peri-implantation development in utero. We have examined the influence of HB-EGF on mouse trophoblast differentiation in vitro and the associated intracellular signaling pathways. HB-EGF both induced intracellular Ca2+ signaling and accelerated trophoblast development to an adhesion-competent stage, but only late on gestation day 4 after ErbB4, a receptor for HB-EGF, translocated from the cytoplasm to the apical surface of trophoblast cells. The acceleration of blastocyst differentiation by HB-EGF was attenuated after inhibition of protein tyrosine kinase activity or removal of surface heparan sulfate, as expected. Chelation of intracellular Ca2+ blocked the ability of HB-EGF to accelerate development, as did inhibitors of protein kinase C or calmodulin. The absence of any effect by a phospholipase C inhibitor and the requirement for extracellular Ca2+ suggested that the accrued free cytoplasmic Ca2+ did not originate from inositol phosphate-sensitive intracellular stores, but through Ca2+ influx. Indeed, N-type Ca2+ channel blockers specifically inhibited the ability of HB-EGF to both induce Ca2+ signaling and accelerate trophoblast development. We conclude that HB-EGF accelerates the differentiation of trophoblast cells to an adhesion-competent stage by inducing Ca2+ influx, which activates calmodulin and protein kinase C. An upstream role for ErbB4 in this pathway is implicated by the timing of its translocation to the trophoblast surface.

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