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The primary objective of this study was to investigate the pharmacokinetics of inhaled argon in young pigs using mechanical ventilation. Also a physiologically based model of argon pharmacokinetics (PBPK) is validated with human data for xenon from the literature and the new data from juvenile pigs. The inherent difficulty in performing pharmacokinetics studies of argon makes the use of the PBPK model especially relevant. The model is used to investigate argon pharmacokinetics for adult and neonate applications. Juvenile pigs (n = 4) were anesthetized, submitted to endotracheal intubation, and mechanical ventilation using a conventional ventilator. Argon inhalation was achieved by switching the animal from the first mechanical ventilator (with air/oxygen) to a second one that was supplied with 75% argon and 25% oxygen from premixed gas cylinders. This administration yielded blood samples that were analyzed using a quadrupole based technique for determining argon concentration. The range of blood:gas partition coefficient corresponding to the average measured Cmax of 190-872 μM is 0.005-0.022. Based on the average curve, T1/2= 75 seconds. The PBPK is shown to be in general agreement with the experimental data in pigs. Inhaled argon administration exhibited an on-off nature such that AUC was proportional to administration time. Confidence in the PBPK model and the remarkably robust and stable on-off nature of argon pharmacokinetics, notwithstanding intersubject variability and comorbidity, suggests that inhaled argon could readily be applied to any treatment regime., (Copyright © 2024 Copyright: © 2024 Medical Gas Research.)

The noble gas argon has demonstrated biological activity that may prove useful as a medical intervention. Pharmacokinetics, the disposition of the drug molecule in the body through time, is fundamental necessary knowledge to drug discovery, development and even post-marketing. The fundamental measurement in pharmacokinetic studies is blood concentration of the molecule (and its metabolites) of interest. While a physiologically based model of argon pharmacokinetics has appeared in the literature, no experimental data have been published. Thus, argon pharmaceutical development requires measurement of argon solubility in blood. This paper reports on the development of a technique based on mass spectrometry for measuring argon solubility in liquids, including blood, to be further employed in pharmacokinetics testing of argon. Based on a prototype, results are reported from sensitivity experiments using ambient air, water and rabbit blood. The key takeaway is that the system was sensitive to argon during all of the testing. We believe the technique and prototype of the quadrupole mass spectrometer gas analyzer will be capable of inferring argon pharmacokinetics through the analysis of blood samples., Competing Interests: None

The bacteriostatic and/or bactericidal properties of few phosphoramide-based amphiphilic compounds on human pathogenic bacteria were previously reported. In this study, the potential of two cationic ( BSV36 and KLN47 ) and two zwitterionic ( 3 and 4 ) amphiphiles as inhibitors of marine bacterial growth and biofilm formation were investigated. Results showed that the four compounds have little impact on the growth of a panel of 18 selected marine bacteria at a concentration of 200 µM, and up to 700 µM for some bacterial strains. Interestingly, cationic lipid BSV36 and zwitterionic lipids 3 and 4 effectively disrupt biofilm formation of Paracoccus sp. 4M6 and Vibrio sp. D02 at 200 µM and to a lesser extent of seven other bacterial strains tested. Moreover, ecotoxicological assays on four species of microalgae highlighted that compounds 3 and 4 have little impact on microalgae growth with EC50 values of 51 µM for the more sensitive species and up to 200 µM for most of the others. Amphiphilic compounds, especially zwitterionic amphiphiles 3 and 4 seem to be promising candidates against biofilm formation by marine bacteria.

Several studies based on in vivo or in vitro models have found promising results for the noble gas argon in neuroprotection against ischaemic pathologies. The development of argon as a medicinal product includes the requirement for toxicity testing through non-clinical studies. The long exposure period of animals (rats) during several days results in technical and logistic challenges related to the gas administration. In particular, a minimum of 10 air changes per hour (ACH) to maintain animal welfare results in extremely large volumes of experimental gas required if the gas is not recirculated. The difficulty with handling the many cylinders prompted the development of such a recirculation-based design. To distribute the recirculating gas to individually ventilated cages and monitor them properly was deemed more difficult than constructing a single large enclosure that will hold several open cages. To address these concerns, a computational fluid dynamics (CFD) analysis of the preliminary design was performed. A purpose-made exposure chamber was designed based on the CFD simulations. Comparisons of the simulation results to measurements of gas concentration at two cage positions while filling show that the CFD results compare well to these limited experiments. Thus, we believe that the CFD results are representative of the gas distribution throughout the enclosure. The CFD shows that the design provides better gas distribution (i.e. a higher effective air change rate) than predicted by 10 ACH.

Argon inhalation attenuates multiorgan failure (MOF) after experimental ischemic injury. We hypothesized that this protection could involve decreased High Mobility Group Box 1 (HMGB1) systemic release. We investigated this issue in an animal model of MOF induced by aortic cross-clamping. Anesthetized rabbits were submitted to supra-coeliac aortic cross-clamping for 30 min, followed by 300 min of reperfusion. They were randomly divided into three groups ( n = 7/group). The Control group inhaled nitrogen (70%) and oxygen (30%). The Argon group was exposed to a mixture of argon (70%) and oxygen (30%). The last group inhaled nitrogen/oxygen (70/30%) with an administration of the HMGB1 inhibitor glycyrrhizin (4 mg/kg i.v.) 5 min before aortic unclamping. At the end of follow-up, cardiac output was significantly higher in Argon and Glycyrrhizin vs. Control (60 ± 4 and 49 ± 4 vs. 33 ± 8 mL/kg/min, respectively). Metabolic acidosis was attenuated in Argon and Glycyrrhizin vs. Control, along with reduced amount of norepinephrine to reverse arterial hypotension. This was associated with reduced interleukin-6 and HMGB1 plasma concentration in Argon and Glycyrrhizin vs. Control. End-organ damages were also attenuated in the liver and kidney in Argon and Glycyrrhizin vs. Control, respectively. Argon inhalation reduced HMGB1 blood level after experimental aortic cross-clamping and provided similar benefits to direct HMGB1 inhibition.

A novel anaerobic methylotrophic halophilic methanogen strain SLHTYRO T was isolated from a deep hypersaline anoxic basin called "Tyro" located in the Eastern Mediterranean Sea. Cells of SLHTYRO T were motile cocci. The strain SLHTYRO T grew between 12 and 37 °C (optimum 30 °C), at pH between 6.5 and 8.2 (optimum pH 7.5) and salinity from 45 to 240 g L -1 NaCl (optimum 135 g L -1 ). Strain SLHTYRO T was methylotrophic methanogen able to use methylated compounds (trimethylamine, dimethylamine, monomethylamine and methanol). Strain SLHTYRO T was able to grow at in situ hydrostatic pressure and temperature conditions (35 MPa, 14 °C). Phylogenetic analysis based on 16S rRNA gene and mcrA gene sequences indicated that strain SLHTYRO T was affiliated to genus Methanohalophilus within the order Methanosarcinales. It shared >99.16% of the 16S rRNA gene sequence similarity with strains of other Methanohalophilus species. Based on ANIb, AAI and dDDH measurements, and the physiological properties of the novel isolate, we propose that strain SLHTYRO T should be classified as a representative of a novel species, for which the name Methanohalophilus profundi sp. nov. is proposed; the type strain is SLHTYRO T (=DSM 108854 = JCM 32768 = UBOCC-M-3308)., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

When administered in relatively high concentrations the mechanical properties of inhaled gas can become significantly different from air. This fact has implications in mechanical ventilation where adequate respiration and injury to the lungs or respiratory muscles can worsen morbidity and mortality. Here we use an engineering pressure loss model to analyze the administration of medical gas mixtures in newborns. The model is used to determine the pressure distribution along the gas flow path. Numerical experiments comparing medical gas mixtures with helium, nitrous oxide, argon, xenon, and medical air as a control, with and without an endotracheal tube obstruction were performed. The engineering pressure loss model was incorporated into a model of mechanical ventilation during pressure control mode, a ventilator mode that is often used for neonates. Results are presented in the form of Rohrer equations relating pressure loss to flow rate for each gas mixture with and without obstruction. These equations were incorporated into a model for mechanical ventilation resulting in pressure, flow rate, and volume curves for the inhalation-exhalation cycle. In terms of accuracy, published values of airway resistance range from 50 to 150 cmH 2 O/L per second for a normal 3 kg infant. With air, the current results are 55 to 80 cmH 2 O/L per second for 0.3 to 5 L/min. It is shown that density through inertial pressure losses has a greater influence on airway resistance than viscosity in spite of relatively low flow rates and small airway dimensions of newborns. The results indicate that the high-density xenon mixture can be problematic during mechanical ventilation. On the other hand, low density heliox (a mixture of helium and oxygen) provides a wider margin of safety for mechanical ventilation than the other gas mixtures. The argon or nitrous oxide mixtures considered are only slightly different from air in terms of mechanical ventilation performance.

Microplastics (<5 mm) exhibit intrinsic features such as density, hydrophobic surface, or high surface/volume ratio, that are known to promote microbial colonization and biofilm formation in marine ecosystems. Yet, a relatively low number of studies have investigated the nature of microplastic associated bacterial communities in coastal ecosystems and the potential factors influencing their composition and structure. Here, we characterized microplastics collected in the Bay of Brest by manual sorting followed by Raman spectroscopy and studied their associated bacterial assemblages using 16S amplicon high-throughput sequencing. Our methodology allowed discriminating polymer type (polyethylene, polypropylene and polystyrene) within small size ranges (0.3-1 vs. 1-2 vs. 2-5 mm) of microplastics collected. Data showed high species richness and diversity on microplastics compared to surrounding seawater samples encompassing both free living and particle attached bacteria. Even though a high proportion of operational taxonomic units (OTU; 94 ± 4%) was shared among all plastic polymers, polystyrene fragments exhibited distinct bacterial assemblages as compared to polyethylene and polypropylene samples. No effect of microplastic size was revealed regardless of polymer type, site and date of collection. The Vibrio genus was commonly detected in the microplastic fraction and specific PCR were performed to determine the presence of potentially pathogenic Vibrio strains (namely V. aestuarianus and the V. splendidus polyphyletic group). V. splendidus related species harboring putative oyster pathogens were detected on most microplastic pools (77%) emphasizing the need of further research to understand the role of microplastics on pathogen population transport and ultimate disease emergence., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Juglans regia (walnut) is a species belonging to the family Juglandaceae. Broadly spread in diverse temperate and subtropical regions, walnut is primarily cultivated for its nuts. In France, Colletotrichum sp. on walnut was detected for the first time in 2007; in 2011 the disease led to 50-70% losses in nut production. A combined approach of metabarcoding analysis and multi-locus genetic characterization of isolated strains has been used for taxonomic designation and to study the genetic variability of this pathogen in France. Evidence indicates that four Colletotrichum species are associated with walnut in France: 3 belong to the C. acutatum species complex and 1 to the C. gloeosporioides species complex. Results also show that C. godetiae is the most abundant species followed by C. fioriniae; while C. nymphaeae and another Colletotrichum sp. belonging to the C. gloeosporioides complex are found rarely. Representative isolates of detected species were also used to confirm pathogenicity on walnut fruits. The results show a high variability of lesion's dimensions among isolates tested. This study highlights the genetic and pathogenic heterogeneity of Colletotrichum species associated with walnut anthracnose in France providing useful information for targeted treatments or selection of resistant cultivars, in order to better control the disease.

Harmful Algal Blooms are worldwide occurrences that can cause poisoning in human seafood consumers as well as mortality and sublethal effets in wildlife, propagating economic losses. One of the most widespread toxigenic microalgal taxa is the dinoflagellate Genus Alexandrium, that includes species producing neurotoxins referred to as PST (Paralytic Shellfish Toxins). Blooms cause shellfish harvest restrictions to protect human consumers from accumulated toxins. Large inter-individual variability in toxin load within an exposed bivalve population complicates monitoring of shellfish toxicity for ecology and human health regulation. To decipher the physiological pathways involved in the bivalve response to PST, we explored the whole transcriptome of the digestive gland of the Pacific oyster Crassostrea gigas fed experimentally with a toxic Alexandrium minutum culture. The largest differences in transcript abundance were between oysters with contrasting toxin loads (1098 transcripts), rather than between exposed and non-exposed oysters (16 transcripts), emphasizing the importance of toxin load in oyster response to toxic dinoflagellates. Additionally, penalized regressions, innovative in this field, modeled accurately toxin load based upon only 70 transcripts. Transcriptomic differences between oysters with contrasting PST burdens revealed a limited suite of metabolic pathways affected, including ion channels, neuromuscular communication, and digestion, all of which are interconnected and linked to sodium and calcium exchanges. Carbohydrate metabolism, unconsidered previously in studies of harmful algal effects on shellfish, was also highlighted, suggesting energy challenge in oysters with high toxin loads. Associations between toxin load, genotype, and mRNA levels were revealed that open new doors for genetic studies identifying genetically-based low toxin accumulation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Argon (Ar) is a noble gas with known organoprotective effects in rodents and in vitro models. In a previous study we failed to find a postconditioning effect of Ar during ex vivo lung perfusion (EVLP) on warm-ischemic injury in a porcine model. In this study, we further investigated a prolonged exposure to Ar to decrease cold ischemia-reperfusion injury after lung transplantation in a porcine model with EVLP assessment. Domestic pigs ( n = 6/group) were pre-conditioned for 6 hours with 21% O 2 and 79% N 2 (CONTR) or 79% Ar (ARG). Subsequently, lungs were cold flushed and stored inflated on ice for 18 hours inflated with the same gas mixtures. Next, lungs were perfused for 4 hours on EVLP (acellular) while ventilated with 12% O 2 and 88% N 2 (CONTR group) or 88% Ar (ARG group). The perfusate was saturated with the same gas mixture but with the addition of CO 2 to an end-tidal CO 2 of 35-45 mmHg. The saturated perfusate was drained and lungs were perfused with whole blood for an additional 2 hours on EVLP. Evaluation at the end of EVLP did not show significant effects on physiologic parameters by prolonged exposure to Ar. Also wet-to-dry weight ratio did not improve in the ARG group. Although in other organ systems protective effects of Ar have been shown, we did not detect beneficial effects of a high concentration of Ar on cold pulmonary ischemia-reperfusion injury in a porcine lung model after prolonged exposure to Ar in this porcine model with EVLP assessment., Competing Interests: Conflicts of interest None.

Halophilic archaea were isolated from different chotts and sebkha, dry salt lakes and salt flat respectively, of the Algerian Sahara and characterized using phenotypic and phylogenetic approaches. From 102 extremely halophilic strains isolated, forty three were selected and studied. These strains were also screened for their antagonistic potential and the production of hydrolytic enzymes. Sequencing of the 16S rRNA genes and phylogenetic analysis allowed the identification of 10 archaeal genera within the class Halobacteria: Natrinema (13 strains), Natrialba (12 strains), Haloarcula (4 strains), Halopiger (4 strains), Haloterrigena (3 strains), Halorubrum (2 strains), Halostagnicola (2 strains), Natronococcus, Halogeometricum and Haloferax (1 strain each). The most common producers of antimicrobial compounds belong to the genus Natrinema while the most hydrolytic isolates, with combined production of several enzymes, belong to the genus Natrialba. The strain affiliated to Halopiger djelfamassilliensis was found to produce some substances of interest (halocins, anti-Candida, enzymes). After partial purification and characterization of one of the strains Natrinema gari QI1, we found similarities between the antimicrobial compound and the halocin C8. Therefore, the gene encoding halocin C8 was amplified and sequenced., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Background: In kidney transplantation, the conditions of organ preservation following removal influence function recovery. Current static preservation procedures are generally based on immersion in a cold-storage solution used under atmospheric air (approximately 78 kPa N2, 21 kPa O2, 1 kPa Ar). Research on static cold-preservation solutions has stalled, and modifying the gas composition of the storage medium for improving preservation was considered. Organoprotective strategies successfully used noble gases and we addressed here the effects of argon and xenon on graft preservation in an established preclinical pig model of autotransplantation., Methods: The preservation solution Celsior saturated with pure argon (Argon-Celsior) or xenon (Xenon-Celsior) at atmospheric pressure was tested versus Celsior saturated with atmospheric air (Air-Celsior). The left kidney was removed, and Air-Celsior (n = 8 pigs), Argon-Celsior (n = 8) or Xenon-Celsior (n = 6) was used at 4 °C to flush and store the transplant for 30 h, a duration that induced ischemic injury in our model when Air-Celsior was used. Heterotopic autotransplantation and contralateral nephrectomy were performed. Animals were followed for 21 days., Results: The use of Argon-Celsior vs. Air-Celsior: (1) improved function recovery as monitored via creatinine clearance, the fraction of excreted sodium and tubulopathy duration; (2) enabled diuresis recovery 2-3 days earlier; (3) improved survival (7/8 vs. 3/8 pigs survived at postoperative day-21); (4) decreased tubular necrosis, interstitial fibrosis, apoptosis and inflammation, and preserved tissue structures as observed after the natural death/euthanasia; (5) stimulated plasma antioxidant defences during the days following transplantation as shown by monitoring the "reduced ascorbic acid/thiobarbituric acid reactive substances" ratio and Hsp27 expression; (6) limited the inflammatory response as shown by expression of TNF-alpha, IL1-beta and IL6 as observed after the natural death/euthanasia. Conversely, Xenon-Celsior was detrimental, no animal surviving by day-8 in a context where functional recovery, renal tissue properties and the antioxidant and inflammation responses were significantly altered. Thus, the positive effects of argon were not attributable to the noble gases as a group., Conclusions: The saturation of Celsior with argon improved early functional recovery, graft quality and survival. Manipulating the gas composition of a preservation medium constitutes therefore a promising approach to improve preservation.

Growing evidence suggests that hepatic-insulin resistance is sufficient to promote progression to cardiovascular disease. We have shown previously that liver-specific protein-tyrosine-phosphatase 1B (PTP1B) deficiency improves hepatic-insulin sensitivity and whole-body glucose homeostasis. The aim of this study was to investigate the impact of liver-specific PTP1B-deficiency (L-PTP1B-/-) on cardiac and peripheral vascular function, with special emphasis on endothelial function in the context of high-fat diet (HFD)-induced obesity. L-PTP1B-/- mice exhibited an improved glucose and lipid homeostasis and increased insulin sensitivity, without changes in body weight. HFD-feeding increased systolic blood pressure (BP) in both L-PTP1B-/- and control littermates; however, this was significantly lower in L-PTP1B-/- mice. HFD-feeding increased diastolic BP in control mice only, whilst the L-PTP1B-/- mice were completely protected. The analysis of the function of the left ventricle (LV) revealed that HFD-feeding decreased LV fractional shortening in control animals, which was not observed in L-PTP1B-/- mice. Importantly, HFD feeding significantly impaired endothelium-dependent vasorelaxation in response to acetylcholine in aortas from control mice, whilst L-PTP1B-/- mice were fully protected. This was associated with alterations in eNOS phosphorylation. Selective inhibition of COX-2, using NS-398, decreased the contractile response in response to serotonin (5-HT) only in vessels from control mice. HFD-fed control mice released enhanced levels of prostaglandin E, a vasoconstrictor metabolite; whilst both chow- and HFD-fed L-PTP1B-/- mice released higher levels of prostacylin, a vasorelaxant metabolite. Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Red wine polyphenol compounds (RWPC) exert paradoxical effects depending on the dose on post-ischemic neovascularisation. Low dose RWPC (0.2 mg/kg/day) is pro-angiogenic, whereas high dose (20 mg/kg/day) is anti-angiogenic. We recently reported that the endothelial effect of RWPC is mediated through the activation of a redox-sensitive pathway, mitochondrial biogenesis and the activation of α isoform of the estrogen receptor (ERα). Here, we investigated the implication of ERα on angiogenic properties of RWPC. Using ovariectomized mice lacking ERα treated with high dose of RWPC after hindlimb ischemia, we examined blood flow reperfusion, vascular density, nitric oxide (NO) production, expression and activation of proteins involved in angiogenic process and muscle energy sensing network. As expected, high dose of RWPC treatment reduced both blood flow and vascular density in muscles of mice expressing ERα. These effects were associated with reduced NO production resulting from diminished activity of eNOS. In the absence of RWPC, ERα deficient mice showed a reduced neo-vascularisation associated with a decreased NO production. Surprisingly in mice lacking ERα, high dose of RWPC increased blood flow and capillary density in conjunction with increased NO pathway and production as well as VEGF expression. Of particular interest is the activation of Sirt-1, AMPKα and PGC-1α/β axis in ischemic hindlimb from both strains. Altogether, the results highlight a pro-angiogenic property of RWPC via an ERα-independent mechanism that is associated with an up-regulation of energy sensing network. This study brings a corner stone of a novel pathway for RWPC to correct cardiovascular diseases associated with failed neovascularisation.

A novel, strictly anaerobic, methylotrophic marine methanogen, strain SLH33(T), was isolated from deep sediment samples covered by an orange microbial mat collected from the Napoli Mud Volcano. Cells of strain SLH33(T) were Gram-stain-negative, motile, irregular cocci that occurred singly. Cells utilized trimethylamine, dimethylamine, monomethylamine, methanol, betaine, N,N-dimethylethanolamine and choline (N,N,N-trimethylethanolamine) as substrates for growth and methanogenesis. The optimal growth temperature was 30 °C; maximum growth rate was obtained at pH 7.0 in the presence of 0.5 M Na(+). The DNA G+C content of strain SLH33(T) was 43.4 mol%. Phylogenetic analyses based on 16S rRNA gene sequences placed strain SLH33(T) within the genus Methanococcoides. The novel isolate was related most closely to Methanococcoides methylutens TMA-10(T) (98.8% 16S rRNA gene sequence similarity) but distantly related to Methanococcoides burtonii DSM 6242(T) (97.6%) and Methanococcoides alaskense AK-5(T) (97.6%). DNA-DNA hybridization studies indicated that strain SLH33(T) represents a novel species, given that it shared less than 16% DNA-DNA relatedness with Methanococcoides methylutens TMA-10(T). The name Methanococcoides vulcani sp. nov. is proposed for this novel species, with strain SLH33(T) ( = DSM 26966(T) = JCM 19278(T)) as the type strain. An emended description of the genus Methanococcoides is also proposed., (© 2014 IUMS.)

A novel strictly anaerobic thermophilic heterotrophic bacterium, strain SLHLJ1(T), was isolated from a Pacific hydrothermal sediment. Cells were Gram-negative coccobacilli (approximately 1.0 × 0.6 μm) with a toga. It grew at temperatures between 33 and 78 °C (optimum 70 °C). Elemental sulphur and L-cystine stimulated its growth. It contained C16:0, C16:1 ω11c, C18:0 and C18:1 ω9c as major fatty acids (>5%), 3 phospholipids and 2 glycolipids as polar lipids. Its DNA G+C content was 43.7 mol%. Phylogenetic analyses based on 16S rRNA gene sequences placed strain SLHLJ1(T) within the family Thermotogaceae. The novel isolate was most closely related to Kosmotoga arenicorallina (97.93 % 16S rRNA gene sequence similarity), K. olearia (92.43%) and K. shengliensis (92.17 %). On the basis of phenotypic, chemotaxonomic and phylogenetic comparisons with its closest relatives, we propose its assignment to a novel species of the genus Kosmotoga. The name Kosmotoga pacifica sp. nov. is proposed with strain SLHLJ1(T) (=DSM 26965(T) = JCM 19180(T) = UBOCC 3254(T)) as the type species.

Aims: Obesity is a primary contributor to acquired insulin resistance leading to the development of type 2 diabetes and cardiovascular alterations. The carnitine derivate, propionyl-L-carnitine (PLC), plays a key role in energy control. Our aim was to evaluate metabolic and cardiovascular effects of PLC in diet-induced obese mice., Methods: C57BL/6 mice were fed a high-fat diet for 9 weeks and then divided into two groups, receiving either free- (vehicle-HF) or PLC-supplemented water (200 mg/kg/day) during 4 additional weeks. Standard diet-fed animals were used as lean controls (vehicle-ST). Body weight and food intake were monitored. Glucose and insulin tolerance tests were assessed, as well as the HOMA(IR), the serum lipid profile, the hepatic and muscular mitochondrial activity and the tissue nitric oxide (NO) liberation. Systolic blood pressure, cardiac and endothelial functions were also evaluated., Results: Vehicle-HF displayed a greater increase of body weight compared to vehicle-ST that was completely reversed by PLC treatment without affecting food intake. PLC improved the insulin-resistant state and reversed the increased total cholesterol but not the increase in free fatty acid, triglyceride and HDL/LDL ratio induced by high-fat diet. Vehicle-HF exhibited a reduced cardiac output/body weight ratio, endothelial dysfunction and tissue decrease of NO production, all of them being improved by PLC treatment. Finally, the decrease of hepatic mitochondrial activity by high-fat diet was reversed by PLC., Conclusions: Oral administration of PLC improves the insulin-resistant state developed by obese animals and decreases the cardiovascular risk associated to this metabolic alteration probably via correction of mitochondrial function.

Despite significant expression level in cancer cells, the role of the angiotensin II Type 2 receptor (AT2R) in cancer progression remains poorly understood. We aimed to investigate the involvement of AT2R in tumorigenesis, hypothesizing a role in tumor cell proliferation and/or tumor angiogenesis. Two animal tumor models were used: fibrosarcoma induced by 3-methylcholanthrene (3-MCA) in FVB/N mice invalidated for AT2R (AT2R-KO) and carcinoma LL/2 cells injected in C57BL/6N mice treated with AT2R antagonist PD123,319. Tumor growth was monitored, microvascular density (MVD) evaluated by CD31 staining. Proliferation index of LL/2 and 3-MCA tumor cells was evaluated by expression of Ki-67. Angiogenesis was assessed by aorta ring assay and angiogenic mediators' expression by real-time RT-PCR. Tumor induction by 3-MCA was significantly delayed in AT2R-KO compared to wild-type mice (56 days vs. 28 days). Tumorigenesis following LL/2 cell injection in mice was also significantly reduced by early administration of the antagonist PD123,319. In vitro, inactivation or invalidation of AT2R inhibited proliferation of LL/2 and 3-MCA tumor cells, respectively. Tumor MVD was reduced in mice treated early with PD123,319. Ex vivo experiments revealed a significant decrease in angiogenesis after PD123,319 treatment or in AT2R-KO mice. Finally, we identified vascular endothelial growth factor (VEGF) as a soluble proangiogenic factor produced by LL/2 cells and we showed that in LL/2 and 3-MCA tumor cells, inhibition or deficiency of AT2R was associated with impaired production of proangiogenic factors included VEGF. This study uncovered novel mechanisms by which AT2R would promote tumor development, favoring both malignant cell proliferation and tumor angiogenesis.

Background: A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERalpha) could be involved in the transduction of the vascular benefits of polyphenols., Methodology/principal Findings: Here, we used ERalpha deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERalpha. Indeed, Provinols, delphinidin and ERalpha agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERalpha Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERalpha completely prevented the effects of Provinols and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERalpha activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERalpha deficient mice., Conclusions/significance: This study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERalpha activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies.