The cellular mechanisms associated with the anesthetic and neuroprotective properties of xenon: a systematic review of the preclinical literature.

Introduction: Xenon exhibits significant neuroprotection against a wide range of neurological insults in animal models. However, clinical evidence that xenon improves outcomes in human studies of neurological injury remains elusive. Previous reviews of xenon's method of action have not been performed in a systematic manner. The aim of this review is to provide a comprehensive summary of the evidence underlying the cellular interactions responsible for two phenomena associated with xenon administration: anesthesia and neuroprotection. Methods: A systematic review of the preclinical literature was carried out according to the PRISMA guidelines and a review protocol was registered with PROSPERO. The review included both in vitro models of the central nervous system and mammalian in vivo studies. The search was performed on 27th May 2022 in the following databases: Ovid Medline, Ovid Embase, Ovid Emcare, APA PsycInfo, and Web of Science. A risk of bias assessment was performed utilizing the Office of Health Assessment and Translation tool. Given the heterogeneity of the outcome data, a narrative synthesis was performed. Results: The review identified 69 articles describing 638 individual experiments in which a hypothesis was tested regarding the interaction of xenon with cellular targets including: membrane bound proteins, intracellular signaling cascades and transcription factors. Xenon has both common and subtype specific interactions with ionotropic glutamate receptors. Xenon also influences the release of inhibitory neurotransmitters and influences multiple other ligand gated and non-ligand gated membrane bound proteins. The review identified several intracellular signaling pathways and gene transcription factors that are influenced by xenon administration and might contribute to anesthesia and neuroprotection. Discussion: The nature of xenon NMDA receptor antagonism, and its range of additional cellular targets, distinguishes it from other NMDA antagonists such as ketamine and nitrous oxide. This is reflected in the distinct behavioral and electrophysiological characteristics of xenon. Xenon influences multiple overlapping cellular processes, both at the cell membrane and within the cell, that promote cell survival. It is hoped that identification of the underlying cellular targets of xenon might aid the development of potential therapeutics for neurological injury and improve the clinical utilization of xenon. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: 336871.

Phylogeography of hydrothermal vent stalked barnacles: a new species fills a gap in the Indian Ocean 'dispersal corridor' hypothesis.

Phylogeography of animals provides clues to processes governing their evolution and diversification. The Indian Ocean has been hypothesized as a 'dispersal corridor' connecting hydrothermal vent fauna of Atlantic and Pacific oceans. Stalked barnacles of the family Eolepadidae are common associates of deep-sea vents in Southern, Pacific and Indian oceans, and the family is an ideal group for testing this hypothesis. Here, we describe Neolepas marisindica sp. nov. from the Indian Ocean, distinguished from N. zevinae and N. rapanuii by having a tridentoid mandible in which the second tooth lacks small elongated teeth. Morphological variations suggest that environmental differences result in phenotypic plasticity in the capitulum and scales on the peduncle in eolepadids. We suggest that diagnostic characters in Eolepadidae should be based mainly on more reliable arthropodal characters and DNA barcoding, while the plate arrangement should be used carefully with their intraspecific variation in mind. We show morphologically that Neolepas specimens collected from the South West Indian Ridge, the South East Indian Ridge and the Central Indian Ridge belong to the new species. Molecular phylogeny and fossil evidence indicated that Neolepas migrated from the southern Pacific to the Indian Ocean through the Southern Ocean, providing key evidence against the 'dispersal corridor' hypothesis. Exploration of the South East Indian Ridge is urgently required to understand vent biogeography in the Indian Ocean.

α-Glucosidase inhibitory activity of marine sponges collected in Mauritius waters.

This report describes the use of α-glucosidase to evaluate the anti-diabetic potential of extracts from marine sponges collected in the Mauritius waters. Initial screening at 1.0 mg/mL of 141 extracts obtained from 47 sponge species revealed 10 extracts with inhibitory activity greater than 85%. Seven of the 10 extracts were further tested at 0.1 and 0.01 mg/mL and only the methanol extract of two sponges namely Acanthostylotella sp. (ASSM) and Echinodictyum pykei (EPM) showed inhibition activity greater than 60% at 0.1 mg/mL with an IC50 value of 0.16 ± 0.02 and 0.04 ± 0.01 mg/mL, respectively, while being inactive at 0.01 mg/mL.

Evaluation of hexane and ethyl acetate extracts of the sponge Jaspis diastra collected from Mauritius Waters on HeLa cells.

OBJECTIVES: Based on previous screening results, the cytotoxic effect of the hexane (JDH) and ethyl acetate extracts (JDE) of the marine sponge Jaspis diastra were evaluated on HeLa cells and the present study aimed at determining their possible mechanism of cell death. METHODS: Nuclear staining, membrane potential change, flow cytometry analysis of cell cycle distribution and annexin V staining were undertaken to investigate the effects of JDE and JDH. Electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance were used to characterize an isolated bioactive molecule. KEY FINDINGS: JDE displayed an IC50 25 times more significant than the JDH. Flow cytometry analysis revealed JDE induced apoptosis in HeLa cells accompanied by the collapse of mitochondrial membrane potential. Fractionation of JDE resulted in the isolation of the known cytotoxic cyclodepsipeptide, Jaspamide. CONCLUSIONS: Taking our results together suggest that JDE can be valuable for the development of anticancer drugs, especially for cervical cancer. Further investigations are currently in progress with the aim to determine and isolate other bioactive compounds from this extract.

High connectivity of animal populations in deep-sea hydrothermal vent fields in the Central Indian Ridge relevant to its geological setting.

Dispersal ability plays a key role in the maintenance of species in spatially and temporally discrete niches of deep-sea hydrothermal vent environments. On the basis of population genetic analyses in the eastern Pacific vent fields, dispersal of animals in the mid-oceanic ridge systems generally appears to be constrained by geographical barriers such as trenches, transform faults, and microplates. Four hydrothermal vent fields (the Kairei and Edmond fields near the Rodriguez Triple Junction, and the Dodo and Solitaire fields in the Central Indian Ridge) have been discovered in the mid-oceanic ridge system of the Indian Ocean. In the present study, we monitored the dispersal of four representative animals, Austinograea rodriguezensis, Rimicaris kairei, Alviniconcha and the scaly-foot gastropods, among these vent fields by using indirect methods, i.e., phylogenetic and population genetic analyses. For all four investigated species, we estimated potentially high connectivity, i.e., no genetic difference among the populations present in vent fields located several thousands of kilometers apart; however, the direction of migration appeared to differ among the species, probably because of different dispersal strategies. Comparison of the intermediate-spreading Central Indian Ridge with the fast-spreading East Pacific Rise and slow-spreading Mid-Atlantic Ridge revealed the presence of relatively high connectivity in the intermediate- and slow-spreading ridge systems. We propose that geological background, such as spreading rate which determines distance among vent fields, is related to the larval dispersal and population establishment of vent-endemic animal species, and may play an important role in controlling connectivity among populations within a biogeographical province.

Ethyl acetate extract of the Mauritian sponge Jaspis sp. induces cell arrest in human promyelocytic leukemia cells.

Marine sponges are considered as a gold mine of new natural products possessing numerous biological activities. We examined the cytotoxic properties of the ethyl acetate extract (JDE) of the previously unrecorded sponge, Jaspis sp. collected from Mauritius Waters. JDE displayed an interesting IC50 of 0.057±0.04µg/mL on HL-60 cells evaluated by MTS assay. Mitochondrial membrane potential change, microscopic analysis and DNA fragmentation assays also confirmed JDE induced apoptosis on HL-60 cells. Annexin V staining demonstrated that JDE induced apoptosis at different concentrations. Treatment with 100ng/mL of JDE led to an accumulation of cells in G2/M phase after 24 h, causing a significant increase of cells (24h: 5.84%; 48h: 13.41%) in sub-G1 phase suggesting that JDE can induce cell cycle arrest in G2/M phase.

Acetylcholinesterase-inhibitory activities of the extracts from sponges collected in mauritius waters.

Patients diagnosed with Alzheimer's disease (AD) show a characteristic neurochemical deficit of acetylcholine, especially in the basal forebrains. The use of acetylcholinesterase (AChE) inhibitors to retard the hydrolysis of acetylcholine has been suggested as a promising strategy for AD treatment. In this study, we evaluated the acetylcholinesterase inhibitory (AChEI) activities of 134 extracts obtained from 45 species of marine sponges. Thin-layer chromatography (TLC) and microplate assays reveal potent acetylcholinsterase inhibitory activities of two AcOEt extracts from the sponges Pericharax heteroraphis and Amphimedon navalis PULITZER-FINALI. We further investigated the inhibitory kinetics of the extracts and found them to display mixed competitive/noncompetitive inhibition and associated their inhibitory activity partly to terpenoids. Acetylcholinesterase inhibitors from marine organisms have been rarely studied, and this study demonstrated the potential of marine sponges as a source of pharmaceutical leads against neurodegenerative diseases.

Cytotoxic activities of hexane, ethyl acetate and butanol extracts of marine sponges from Mauritian Waters on human cancer cell lines.

The ocean is an exceptional source of natural products with many of them exhibiting novel structural features and bioactivity. As one of the most interesting phylum with respect to pharmacological active marine compounds, Poriferas have been investigated widely in the last few decades. A total of 60 organic extracts (hexane, ethyl acetate and butanol) from 20 species of marine sponges from Mauritius were screened at 50µg/ml in an in vitro screening assay against 9 human cancer cell lines. From these tested extracts, many exhibited pronounced cytotoxic effect at least in one of the cell lines and cell type cytotoxic specificity was observed. 27% of ethyl acetate, 11% of hexane and 2% of butanol extracts were found to possess a cytotoxicity ≥75% on 9 different cancer cell lines with the sponges Petrosia sp. 1, Petrosia sp. 2, Pericharax heteroraphis and Jaspis sp. being the most active. Overall, the HL-60cells were much more sensitive to most of the extracts than the other cell lines. We further evaluated the properties of the ethyl acetate (JDE) and hexane extract (JDH) of one sponge, Jaspis sp. on KB cells. JDE displayed a smaller IC(50) than JDH. Clonogenic assay confirmed the antiproliferative effect of both extracts while mitochondrial membrane potential change and microscopic analysis demonstrated extracts-induced apoptosis. Treatment with 100ng/ml of JDE led to a significant increase of cells (24h: 4.02%; 48h: 26.23%) in sub-G1 phase. The cytotoxic properties of the tested extracts from these sponges suggest the presence of compounds with pharmacological potential and are currently undergoing fractionation to isolate the active constituents.

Discovery of new hydrothermal activity and chemosynthetic fauna on the Central Indian Ridge at 18°-20° S.

Indian Ocean hydrothermal vents are believed to represent a novel biogeographic province, and are host to many novel genera and families of animals, potentially indigenous to Indian Ocean hydrothermal systems. In particular, since its discovery in 2001, much attention has been paid to a so-called 'scaly-foot' gastropod because of its unique iron-sulfide-coated dermal sclerites and the chemosynthetic symbioses in its various tissues. Despite increasing interest in the faunal assemblages at Indian Ocean hydrothermal vents, only two hydrothermal vent fields have been investigated in the Indian Ocean. Here we report two newly discovered hydrothermal vent fields, the Dodo and Solitaire fields, which are located in the Central Indian Ridge (CIR) segments 16 and 15, respectively. Chemosynthetic faunal communities at the Dodo field are emaciated in size and composition. In contrast, at the Solitaire field, we observed faunal communities that potentially contained almost all genera found at CIR hydrothermal environments to date, and even identified previously unreported taxa. Moreover, a new morphotype of 'scaly-foot' gastropod has been found at the Solitaire field. The newly discovered 'scaly-foot' gastropod has similar morphological and anatomical features to the previously reported type that inhabits the Kairei field, and both types of 'scaly-foot' gastropods genetically belong to the same species according to analyses of their COI gene and nuclear SSU rRNA gene sequences. However, the new morphotype completely lacks an iron-sulfide coating on the sclerites, which had been believed to be a novel feature restricted to 'scaly-foot' gastropods. Our new findings at the two newly discovered hydrothermal vent sites provide important insights into the biodiversity and biogeography of vent-endemic ecosystems in the Indian Ocean.

Frizzled 4 regulates arterial network organization through noncanonical Wnt/planar cell polarity signaling.

RATIONALE: A growing body of evidence supports the hypothesis that the Wnt/planar cell polarity (PCP) pathway regulates endothelial cell proliferation and angiogenesis, but the components that mediate this regulation remain elusive. OBJECTIVE: We investigated the involvement of one of the receptors, Frizzled4 (Fzd4), in this process because its role has been implicated in retinal vascular development. METHODS AND RESULTS: We found that loss of fzd4 function in mice results in a striking reduction and impairment of the distal small artery network in the heart and kidney. We report that loss of fzd4 decreases vascular cell proliferation and migration and decreases the ability of the endothelial cells to form tubes. We show that fzd4 deletion induces defects in the expression level of stable acetylated tubulin and in Golgi organization during migration. Deletion of fzd4 favors Wnt noncanonical AP1-dependent signaling, indicating that Fzd4 plays a pivotal role favoring PCP signaling. Our data further demonstrate that Fzd4 is predominantly localized on the top of the plasma membrane, where it preferentially induces Dvl3 relocalization to promote its activation and α-tubulin recruitment during migration. In a pathological mouse angiogenic model, deletion of fzd4 impairs the angiogenic response and leads to the formation of a disorganized arterial network. CONCLUSIONS: These results suggest that Fzd4 is a major receptor involved in arterial formation and organization through a Wnt/PCP pathway.

Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome.

Filaminopathies A caused by mutations in the X-linked FLNA gene are responsible for a wide spectrum of rare diseases including 2 main phenotypes, the X-linked dominant form of periventricular nodular heterotopia (FLNA-PVNH) and the otopalatodigital syndrome spectrum of disorders. In platelets, filamin A (FLNa) tethers the principal receptors ensuring the platelet-vessel wall interaction, glycoprotein Ibα and integrin αIIbß3, to the underlying cytoskeleton. Hemorrhage, coagulopathy, and thrombocytopenia are mentioned in several reports on patients with FLNA-PVNH. Abnormal platelet morphology in 2 patients with FLNA-PVNH prompted us to examine a third patient with similar platelet morphology previously diagnosed with immunologic thrombocytopenic purpura. Her enlarged platelets showed signs of FLNa degradation in Western blotting, and a heterozygous missense mutation in FLNA was detected. An irregular distribution of FLNa within the total platelet population was shown by confocal microscopy for all 3 patients. In vitro megakaryocyte cultures showed an abnormal differentiation, including an irregular distribution of FLNa with a frayed aspect, the presence of enlarged α-granules, and an abnormal fragmentation of the cytoplasm. Mutations in FLNA may represent an unrecognized cause of macrothrombocytopenia with an altered platelet production and a modified platelet-vessel wall interaction.

Secreted frizzled-related protein-1 improves postinfarction scar formation through a modulation of inflammatory response.

OBJECTIVE: The inflammatory response after myocardial infarction plays a crucial role in the healing process. Lately, there is accumulating evidence that the Wnt/Frizzled pathway may play a distinct role in inflammation. We have shown that secreted frizzled-related protein-1 (sFRP-1) overexpression reduced postinfarction scar size, and we noticed a decrease in neutrophil infiltration in the ischemic tissue. We aimed to further elucidate the role of sFRP-1 in the postischemic inflammatory process. METHODS AND RESULTS: We found that in vitro, sFRP-1 was able to block leukocyte activation and cytokine production. We transplanted bone marrow cells (BMCs) from transgenic mice overexpressing sFRP-1 into wild-type recipient mice and compared myocardial healing with that of mice transplanted with wild-type BMCs. These results were compared with those obtained in transgenic mice overexpressing sFRP-1 specifically in endothelial cells or in cardiomyocytes to better understand the spatiotemporal mechanism of the sFRP-1 effect. Our findings indicate that when overexpressed in the BMCs, but not in endothelial cells or cardiomyocytes, sFRP-1 was able to reduce neutrophil infiltration after ischemia, by switching the balance of pro- and antiinflammatory cytokine expression, leading to a reduction in scar formation and better cardiac hemodynamic parameters. CONCLUSION: sFRP-1 impaired the loop of cytokine amplification and decreased neutrophil activation and recruitment into the scar, without altering the neutrophil properties. These data support the notion that sFRP-1 may be a novel antiinflammatory factor protecting the heart from damage after myocardial infarction.

Mapping 3-dimensional neovessel organization steps using micro-computed tomography in a murine model of hindlimb ischemia-brief report.

OBJECTIVE: Studying the mechanisms of neovascularization and evaluating the effects of proangiogenic strategies require accurate analysis of the neovascular network. We sought to evaluate the contribution of the microcomputed tomography (mCT) providing high-resolution 3-dimensional (3D) structural data, to a better comprehension of the well-studied mouse hindlimb postischemic neovascularization. METHODS AND RESULTS: We showed a predominant arteriogenesis process in the thigh and a predominant angiogenesis-related process in the tibiofibular region, in response to ischemia during the first 15 days. After 15 days, mCT quantitative analysis reveals a remodeling of arterial neovessels and a regression depending on the restoration of the blood flow. We provided also new mCT data on the rapid and potent angiogenic effects of mesenchymal stem cell therapy on vessel formation and organization. We discussed the contribution of this technique compared with or in addition to data generated by the more conventional approaches. CONCLUSIONS: This study demonstrated that optimized mCT is a robust method for providing new insights into the 3D understanding of postischemic vessel formation.

Secreted frizzled-related protein-1 enhances mesenchymal stem cell function in angiogenesis and contributes to neovessel maturation.

Mesenchymal stem cell (MSC) transplantation offers a great angiogenic opportunity in vascular regenerative medicine. The canonical Wnt/beta-catenin signaling pathway has been demonstrated to play an essential role in stem cell fate. Recently, genetic studies have implicated the Wnt/Frizzled (Fz) molecular pathway, namely Wnt7B and Fz4, in blood growth regulation. Here, we investigated whether MSC could be required in shaping a functional vasculature and whether secreted Frizzled-related protein-1 (sFRP1), a modulator of the Wnt/Fz pathway, could modify MSC capacities, endowing MSC to increase vessel maturation. In the engraftment model, we show that murine bone marrow-derived MSC induced a beneficial vascular effect through a direct cellular contribution to vascular cells. MSC quickly organized into primitive immature vessel tubes connected to host circulation; this organization preceded host endothelial cell (EC) and smooth muscle cell (SMC) recruitment to later form mature neovessel. MSC sustained neovessel organization and maturation. We report here that sFRP1 forced expression enhanced MSC surrounding neovessel, which was correlated with an increase in vessel maturation and functionality. In vitro, sFRP1 strongly increased platelet-derived growth factor-BB (PDGF-BB) expression in MSC and enhanced beta-catenin-dependent cell-cell contacts between MSC themselves and EC or SMC. In vivo, sFRP1 increased their functional integration around neovessels and vessel maturation through a glycogen synthase kinase 3 beta (GSK3beta)-dependent pathway. sFRP1-overexpressing MSC compared with control MSC were well elongated and in a closer contact with the vascular wall, conditions required to achieve an organized mature vessel wall. We propose that genetically modifying MSC to overexpress sFRP1 may be potentially effective in promoting therapeutic angiogenesis/arteriogenesis processes. Disclosure of potential conflicts of interest is found at the end of this article.

Epicardial deposition of endothelial progenitor and mesenchymal stem cells in a coated muscle patch after myocardial infarction in a murine model.

OBJECTIVES: To assess, using an in vivo engraftment strategy combining bone marrow cell (BMC) transplantation and tissue cardiomyoplasty, the functional outcome of distinct vascular progenitor cell therapy (endothelial progenitor (EPC) and mesenchymal stem (MSC) cells) at distance of myocardium infarction (MI). The study was also designed to test whether scaffold mixing progenitors with unfractionated BMC could improve progenitor recruitment in the damaged myocardium. METHODS: To track engrafted progenitor cells in vivo, cultured murine MSC and EPC were transduced with eGFP lentiviruses. Thirty days after cryogenical induction of MI, C57BL/6J mice were randomized to receive muscle patch placement coated or not (control group), labeled EPC or MSC mixed to the ration of 1:10, or not with unfractionated BMC. Two weeks after transplantation, cardiac function was recorded and heart sections were examined to detect GFP-labeled progenitor cells and analyze cell differentiation. RESULTS: This study showed that either type of mono cell therapy improved angiogenesis and cell survival in the scar but only MSC exhibited the capacity to invade the scar. We found no evidence of myocardial or vascular regeneration from progenitor cells. Engraftment of the progenitors/unfractionated BMC mix increased repopulation and thickness of the scar. CONCLUSION: Combined therapy with unfractionated BMC and expanded MSC appeared thus promising for scar repopulation.

Association between semicarbazide-sensitive amine oxidase, a regulator of the glucose transporter, and elastic lamellae thinning during experimental cerebral aneurysm development: laboratory investigation.

OBJECT: Amine oxidases play a key role in the polymerization and cross-linking of the collagens and elastic lamellae of the arterial wall. The loss of elastic lamellae integrity is one of the first steps in the genesis of a cerebral aneurysm. The authors investigated the relation between semicarbazide-sensitive amine oxidase (SSAO) and the organization of the cerebral arterial wall during aneurysm development. METHODS: Intracranial aneurysms were induced in rats via unilateral carotid artery ligation and renovascular hypertension. This modified Hashimoto model was used to create elevated blood pressure associated with shear stress in cerebral arteries. The authors immunohistologically investigated some markers of the extracellular matrix (Types I, III, and IV collagen and elastin), vascular smooth muscle cell differentiation (smooth muscle myosin heavy chain [sm-MHC], alpha-smooth muscle actin, and desmin), and amine oxidases (SSAO and lysyl oxidase [LOX]) in the cerebral arterial wall in control and treated rats 1, 2, 3, 4, and 6 months after the surgical procedure. RESULTS: The authors found severe disorganization and thinning of the elastic lamellae and a dramatic reduction in SSAO activity and immunostaining during cerebral aneurysm development. In contrast, LOX markers were slightly increased. Elastic lamellae thinning was highly correlated with decreases in SSAO (r = 0.76, p < 0.0001). There was also a correlation between sm-MHC and SSAO levels. CONCLUSIONS: The data suggested that cerebral hemodynamic modifications induce decreases in SSAO activity resulting in cell dedifferentiation and inducing dysregulation of glucose transport.

Regulation of endothelial cell cytoskeletal reorganization by a secreted frizzled-related protein-1 and frizzled 4- and frizzled 7-dependent pathway: role in neovessel formation.

Consistent with findings of Wnt pathway members involved in vascular cells, a role for Wnt/Frizzled signaling has recently emerged in vascular cell development. Among the few Wnt family members implicated in vessel formation in adult, Wnt7b and Frizzled 4 have been shown as involved in vessel formation in the lung and in the retina, respectively. Our previous work has shown a role for secreted Frizzled-related protein-1 (sFRP-1), a proposed Wnt signaling inhibitor, in neovascularization after an ischemic event and demonstrated its role as a potent angiogenic factor. However the mechanisms involved have not been investigated. Here, we show that sFRP-1 treatment increases endothelial cell spreading on extracellular matrix as revealed by actin stress fiber reorganization in an integrin-dependent manner. We demonstrate that sFRP-1 can interact with Wnt receptors Frizzled 4 and 7 on endothelial cells to transduce downstream to cellular machineries requiring Rac-1 activity in cooperation with GSK-3beta. sFRP-1 overexpression in endothelium specifically reversed the inactivation of GSK-3 beta and increased neovascularization in ischemia-induced angiogenesis in mouse hindlimb. This study illustrates a regulated pathway by sFRP-1 involving GSK-3beta and Rac-1 in endothelial cell cytoskeletal reorganization and in neovessel formation.

Modifications of arterial phenotype in response to amine oxidase inhibition by semicarbazide.

Semicarbazide-sensitive amine oxidase (SSAO)-deficient mice present no alteration in elastin cross-linking processes and carotid mechanical properties. In contrast, previous studies have shown that SSAO inhibitors induced marked anomalies in arterial structure and function. The aim of the present study was to examine the effect of semicarbazide (SCZ), an efficient SSAO inhibitor, on the arterial phenotype of the carotid artery in relation to modulation of SSAO and lysyl oxidase activities in growing rats. We first show that after 6 weeks of SCZ treatment (100 mg/kg per day), SSAO activity was reduced by 90%, whereas lysyl oxidase activity was only partially inhibited (<60%) in carotid artery, compared with controls. There was significant growth inhibition and no difference in mean arterial pressure but an increase in pulse pressure with a smaller arterial diameter in SCZ-treated rats. SCZ decreased aortic insoluble elastin without a change in total collagen. In addition, extracellular proteins other than insoluble elastin and collagen were increased in SCZ-treated rats. All of the elastic lamellae presented globular masses along their periphery, and focal disorganization was observed in the ascending aorta. Carotid artery mechanical strength was lower in SCZ-treated rats, and the elastic modulus-wall stress curve was shifted leftward compared with controls, indicating increased stiffness. Thus, SCZ modifies arterial geometry and mechanical properties, alters elastic fiber structure, and reduces the content of cross-linked elastin. Because these abnormalities are essentially absent in SSAO-deficient mice, our results suggest that lysyl oxidase inhibition is responsible for the major part of the vascular phenotype of SCZ-treated rats.

Constituents of Psiadia terebinthina A.J. Scott, an endemic Asteraceae from Mauritius.

Kaemferol-3-methyl ether (1), quercetin-3-methyl ether (2), kaemferol-3,7-dimethyl ether (3), 3-caffeoyl quinic acid (4) and 3,4-O-dicaffeoyl quinic acid (5) have been isolated for the first time from the leaves of Psiadia terebinthina A.J. Scott (Asteraceae). The identity of the compounds 1-5 were confirmed by various spectroscopic methods.

Activation of the Ca(2+)/calcineurin/NFAT2 pathway controls smooth muscle cell differentiation.

Cellular mechanisms controlling smooth muscle cells (SMCs) phenotypic modulation are largely unknown. Intracellular Ca2+ movements are essential to ensure SMC functions; one of the roles of Ca2+ is to regulate calcineurin, which in turn induces nuclear localization of the nuclear factor of activated T-cell (NFAT). In order to investigate, during phenotypic differentiation of SMCs, the effect of calcineurin inhibition on NFAT2 nuclear translocation, we used a culture model of SMC differentiation in serum-free conditions. We show that the treatment of cultured SMC with the calcineurin inhibitor cyclosporine A induced their dedifferentiation while preventing their differentiation. These findings suggest that nuclear translocation of NFAT2 is dependent of calcineurin activity during the in vitro SMC differentiation kinetic and that the nuclear presence of NFAT2 is critical in the acquisition and maintenance of SMC differentiation.