DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

Prostaglandin (PG) D2 is the ligand for the G‐protein coupled receptors DP1 (D‐type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro‐inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor‐mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which—as a consequence—sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti‐apoptotic gene BCL‐XL, but also induced pro‐inflammatory genes, such as VLA‐4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti‐apoptotic, early‐response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro‐inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti‐inflammatory therapy in eosinophilic diseases

Acute reduction of serum 8-iso-PGF2-alpha and advanced oxidation protein products in vivo by a polyphenol-rich beverage; a pilot clinical study with phytochemical and in vitro antioxidant characterization

<p>Abstract</p> <p>Background</p> <p>Measuring the effects of the acute intake of natural products on human biomarker concentrations, such as those related to oxidation and inflammation, can be an advantageous strategy for early clinical research on an ingredient or product.</p> <p>Methods</p> <p>31 total healthy subjects were randomized in a double-blinded, placebo-controlled, acute pilot study with post-hoc subgroup analysis on 20 of the subjects. The study examined the effects of a single dose of a polyphenol-rich beverage (PRB), commercially marketed as "SoZo^®", on serum anti-inflammatory and antioxidant markers. In addition, phytochemical analyses of PRB, and <it>in vitro </it>antioxidant capacity were also performed.</p> <p>Results</p> <p>At 1 hour post-intake, serum values for 8-iso-PGF2-alpha and advanced oxidation protein products decreased significantly by 40% and 39%, respectively. Additionally, there was a trend toward decreased C-reactive protein, and increased nitric oxide levels. Both placebo and PRB treatment resulted in statistically significant increases in hydroxyl radical antioxidant capacity (HORAC) compared to baseline; PRB showed a higher percent change (55-75% versus 23-74% in placebo group), but the two groups did not differ significantly from each other.</p> <p>Conclusions</p> <p>PRB produced statistically significant changes in several blood biomarkers related to antioxidant/anti-inflammatory effects. Future studies are justified to verify results and test for cumulative effects of repeated intakes of PRB. The study demonstrates the potential utility of acute biomarker measurements for evaluating antioxidant/anti-inflammatory effects of natural products.</p

Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products

Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin. Copyright: © 2014 Milutinovic et al

Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group

The conjugation of siRNA to molecules, which can be internalized into the cell via natural transport mechanisms, can result in the enhancement of siRNA cellular uptake. Herein, the carrier-free cellular uptake of nuclease-resistant anti-MDR1 siRNA equipped with lipophilic residues (cholesterol, lithocholic acid, oleyl alcohol and litocholic acid oleylamide) attached to the 5′-end of the sense strand via oligomethylene linker of various length was investigated. A convenient combination of H-phosphonate and phosphoramidite methods was developed for the synthesis of 5′-lipophilic conjugates of siRNAs. It was found that lipophilic siRNA are able to effectively penetrate into HEK293, HepG2 and KB-8-5 cancer cells when used in a micromolar concentration range. The efficiency of the uptake is dependent upon the type of lipophilic moiety, the length of the linker between the moiety and the siRNA and cell type. Among all the conjugates tested, the cholesterol-conjugated siRNAs with linkers containing from 6 to 10 carbon atoms demonstrate the optimal uptake and gene silencing properties: the shortening of the linker reduces the efficiency of the cellular uptake of siRNA conjugates, whereas the lengthening of the linker facilitates the uptake but retards the gene silencing effect and decreases the efficiency of the silencing

The Discovery of LOX-1, its Ligands and Clinical Significance

LOX-1 is an endothelial receptor for oxidized low-density lipoprotein (oxLDL), a key molecule in the pathogenesis of atherosclerosis.The basal expression of LOX-1 is low but highly induced under the influence of proinflammatory and prooxidative stimuli in vascular endothelial cells, smooth muscle cells, macrophages, platelets and cardiomyocytes. Multiple lines of in vitro and in vivo studies have provided compelling evidence that LOX-1 promotes endothelial dysfunction and atherogenesis induced by oxLDL. The roles of LOX-1 in the development of atherosclerosis, however, are not simple as it had been considered. Evidence has been accumulating that LOX-1 recognizes not only oxLDL but other atherogenic lipoproteins, platelets, leukocytes and CRP. As results, LOX-1 not only mediates endothelial dysfunction but contributes to atherosclerotic plaque formation, thrombogenesis, leukocyte infiltration and myocardial infarction, which determine mortality and morbidity from atherosclerosis. Moreover, our recent epidemiological study has highlighted the involvement of LOX-1 in human cardiovascular diseases. Further understandings of LOX-1 and its ligands as well as its versatile functions will direct us to ways to find novel diagnostic and therapeutic approaches to cardiovascular disease

Impaired cholesterol efflux capacity in patients with Helicobacter pylori infection and its relation with inflammation

Background: Gut microorganisms are associated with atherosclerosis and related cardiovascular disease. Helicobacter pylori (H. pylori) infection is associated with dyslipidemia and inflammation contributing to the progression of atherosclerosis. Objective: Several studies have reported reduced HDL-C levels in H. pylori infected patients, but HDL cholesterol efflux capacity (CEC) as the most important function of HDL has not been evaluated yet. Methods: This cross-sectional study was conducted with 44 biopsy confirmed H. pylori patients and 43 controls. ABCA1-mediated, non-ABCA1 and total CEC were measured in ApoB-depleted serum and levels of ApoA-I, ApoB and hsCRP were estimated using ELISA technique. Results: Total and ABCA1 mediated-CEC were reduced in patients compared to controls, independent of age, sex, body mass index and HDL-C (p < 0.001), while non-ABCA1 CEC indicated no significant change between the groups. In addition, patients showed lower serum levels of ApoA-I but increased levels of hsCRP when compared to controls. Total CEC and ABCA1-mediated CEC positively correlated with ApoA-I and HDL-C, furthermore, ABCA1-mediated CEC as well as ApoA-I inversely correlated with hsCRP. Conclusion: The results of the present study indicate reduced CECs in H. pylori infected patients, especially ABCA1-mediated CEC which is associated with decreased ApoA-I and increased inflammation. © 2020 National Lipid Associatio

Historical evolution and Middle to Late Holocene environmental changes in Lake Shkodra (Albania): new evidences from ostracod analysis

The 7.5 m long SK13 sediment core, drilled at Lake Shkodra (Albania) bottom depth of 7 m in the central southern part of the lake, was selected for multidisciplinary analysis. Ostracods, Characeae, pollens, and stable isotopes were studied with the aim to reconstruct the past biodiversity and the palaeoenvironmental and palaeoclimatic changes occurred during the Middle-Late Holocene. The chronological framework of SK13 was already known and well constrained through radiometric datings. The sediment core age spans from 4560 cal year BP to present. Thirteen ostracod and five charophyte species were identified. Among them, the ostracods Candona montenigrina and Limnocythere scutariense are endemic of the lake; Candona meridionalis and Paralimnocythere georgevitschi have been collected for the first time in the Lake Shkodra while formerly were considered endemic respectively of Lake Dojran and Lake Prespa; Metacypris cordata, ?Carpathocandona sp., and Cyclocypris sp. were never recorded in the lake and were found only in the lower portion of the sediment core. Among the charopytes, Lychnothamnus barbatus and N. hyalina are recorded for the first time in the lake and occurs with high frequency throughout interval A of core. The faunal composition is quite homogeneous, with the percentages of the different species varying along the sediment core. The main change occurs between 1274 and 1197 cal yr BP, where charophytes disappear abruptly as well as 8 ostracod species out of 13, and the frequency of the remaining 5 species dramatically increases. Moreover at that moment, it occurs also the appearance of a peculiar not-tuberculate morphotypes of Ilyocypris monstrifica. The micropaleontological data suggest a decrease of the lake biodiversity since around 1200 cal years BP linked to the transition between an ancient marshland to a lacustrine environment. This drastic change seems to be independent from any global or local climate changes and could be related to the co-occurrence of two phenomena: 1) the Adriatic sea level rise during the Middle and Late Holocene, that that would have uplifted the base level of the River Bojana causing a decrease of its discharge and, consequently, reducing the drainage of the water from the Shkodra swamp; 2) the periodical change of the River Drin course over the last five centuries, which, when deviated into the Bojana river, blocked the River Bojana outflow