Thematic Review Series: The Immune System and Atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease

The cellular and extracellular matrix accumulations that comprise the lesions of atherosclerosis are driven by local release of cytokines at sites of predilection for lesion formation, and by the specific attraction and activation of cells expressing receptors for these cytokines. Although cytokines were originally characterized for their potent effects on immune and inflammatory cells, they also promote endothelial cell dysfunction and alter smooth muscle cell (SMC) phenotype and function, which can contribute to or retard vascular pathologies. This review summarizes in vivo studies that have characterized endothelial- and smooth muscle-specific effects of altering cytokine signaling in vascular disease. Although multiple reports have identified cytokines as pivotal players in endothelial and SMC responses in vascular disease, they also have highlighted the need to delineate the critical genes and specific cellular functions regulated by individual cytokine signaling pathways

Electronic Properties of Molecules and Surfaces with a Self\uad-Consistent Interatomic van der Waals Density Functional.

How strong is the effect of van der Waals (vdW) interactions on the electronic properties of molecules and extended systems? To answer this question, we derived a fully self-consistent implementation of the density-dependent interatomic vdW functional of Tkatchenko and Scheffler [Phys. Rev. Lett. 102, 073005 (2009)]. Not surprisingly, vdW self-consistency leads to tiny modifications of the structure, stability, and electronic properties of molecular dimers and crystals. However, unexpectedly large effects were found in the binding energies, distances, and electrostatic moments of highly polarizable alkali-metal dimers. Most importantly, vdW interactions induced complex and sizable electronic charge redistribution in the vicinity of metallic surfaces and at organic-metal interfaces. As a result, a substantial influence on the computed work functions was found, revealing a nontrivial connection between electrostatics and long-range electron correlation effects

Are pleiotropic effects of statins real?

The clinical benefits of statins are strongly related to their low density lipoprotein-cholesterol (LDL-C) lowering properties. However, because mevalonic acid (MVA), the product of 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA) reductase reaction, is the precursor not only of cholesterol but also of nonsteroidal isoprenoid compounds, the inhibition of HMG-CoA reductase may result in pleiotropic effects, independent of their hypocholesterolemic properties. The discrimination between the pleiotropic from LDL-C lowering effects may potentially be more evident during the early phase of treatment since plasma MVA levels drop up to 70% within 1–2 hours while a reduction of LDL-C, detectable after 24 hours, became significant after 6–7 days. Therefore, the deprivation of circulating MVA-derived isoprenoids in the early phase of treatment could be the main mechanism responsible for the atheroprotective effect of statins. This early window of protection in the absence of LDL-C lowering suggests that the anti-inflammatory and the pleiotropic properties of statins may have clinical importance. Therefore, acute coronary syndromes could represent a clinical condition for addressing the early benefits of statins therapy, ie, within 24 h of the event, independent of LDL-C lowering

New sulfurated derivatives of cinnamic acids and rosmaricine as inhibitors of STAT3 and NF-kappa B transcription factors

A set of new sulfurated drug hybrids, mainly derived from caffeic and ferulic acids and rosmaricine, has been synthesized and their ability to inhibit both STAT3 and NF-kappa B transcription factors have been evaluated. Results showed that most of the new hybrid compounds were able to strongly and selectively bind to STAT3, whereas the parent drugs were devoid of this ability at the tested concentrations. Some of them were also able to inhibit the NF-kappa B transcriptional activity in HCT-116 cell line and inhibited HCT-116 cell proliferation in vitro with IC50 in micromolar range, thus suggesting a potential anticancer activity. Taken together, our study described the identification of new derivatives with dual STAT3/NF-kappa B inhibitory activity, which may represent hit compounds for developing multi-target anticancer agents

Suppressor of Cytokine Signaling-3 (SOCS-3) induces Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) expression in hepatic HepG2 cell line

The suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway activated by proinflammatory cytokines, including the tumor necrosis factor (TNF-\u3b1). SOCS3 is also implicated in hypertriglyceridemia associated to insulin resistance. Proprotein convertase subtilisin kexin type 9 (PCSK9) levels are frequently found to be positively correlated to insulin resistance and plasma very low density lipoprotein (VLDL) triglycerides concentrations. The present study aimed to investigate the possible role of TNF-\u3b1 and JAK/STAT pathway on de novo lipogenesis and PCSK9 expression in HepG2 cells. TNF-\u3b1 induced both SOCS3 and PCSK9 in a concentration-dependent manner. This effect was inhibited by transfection with siRNA anti-STAT3, suggesting the involvement of the JAK/STAT pathway. Retroviral overexpression of SOCS3 in HepG2 cells (HepG2SOCS3) strongly inhibited STAT3 phosphorylation and induced PCSK9 mRNA and protein, with no effect on its promoter activity and mRNA stability. Consistently, siRNA anti-SOCS3 reduced PCSK9 mRNA levels, whereas an opposite effect was observed with siRNA anti- STAT3. In addition, HepG2SOCS3 express higher mRNA levels of key enzymes involved in the de novo lipogenesis, such as fattyacid synthase, stearoyl-CoA desaturase (SCD)-1, and apoB. These responses were associated with a significant increase of SCD-1 protein, activation of sterol regulatory element-binding protein-1c (SREBP-1), accumulation of cellular triglycerides, and secretion of apoB. HepG2SOCS3 show lower phosphorylation levels of insulin receptor substrate 1 (IRS-1) Tyr896 and Akt Ser473 in response to insulin. Finally, insulin stimulation produced an additive effect with SOCS3 overexpression, further inducing PCSK9, SREBP-1, fatty acid synthase, and apoB mRNA. In conclusion, our data candidate PCSK9 as a gene involved in lipid metabolism regulated by proinflammatory cytokine TNF- in a SOCS3-dependent manner

Effect of a novel nutraceutical combination on serum lipoprotein functional profile and circulating PCSK9

BACKGROUND: A beneficial effect on cardiovascular risk may be obtained by improving lipid-related serum lipoprotein functions such as high-density lipoproteins (HDLs) cholesterol efflux capacity (CEC) and serum cholesterol loading capacity (CLC) and by reducing proprotein convertase subtilisin kexin type 9 (PCSK9), independently of lipoprotein concentrations. AIM: We aimed to evaluate the effect of an innovative nutraceutical (NUT) combination containing red yeast rice (monacolin K 3.3 mg), berberine 531.25 mg and leaf extract of Morus alba 200 mg (LopiGLIK®), on HDL-CEC, serum CLC and on circulating PCSK9 levels. MATERIALS AND METHODS: Twenty three dyslipidemic subjects were treated for 4 weeks with the above NUT combination. HDL-CEC was measured using specific cell-based radioisotopic assays; serum CLC and PCSK9 concentrations were measured fluorimetrically and by enzyme-linked immunosorbent assay, respectively. RESULTS: The NUT combination significantly reduced plasma level of the total cholesterol and low-density lipoprotein cholesterol (-9.8% and -12.6%, respectively). Despite no changes in HDL-cholesterol, the NUT combination improved total HDL-CEC in 83% of the patients, by an average of 16%, as a consequence of the increase mainly of the ATP-binding cassette A1-mediated CEC (+28.5%). The NUT combination significantly reduced serum CLC (-11.4%) while it did not change PCSK9 plasma levels (312.9±69.4 ng/mL vs 334.8±103.5 mg/L, before and after treatment, respectively). CONCLUSION: The present NUT combination improves the serum lipoprotein functional profile providing complementary beneficial effects, without any detrimental increase of PCSK9 plasma levels

High Density Lipoproteins Inhibit Oxidative Stress-Induced Prostate Cancer Cell Proliferation

Recent evidence suggests that oxidative stress can play a role in the pathogenesis and the progression of prostate cancer (PCa). Reactive oxygen species (ROS) generation is higher in PCa cells compared to normal prostate epithelial cells and this increase is proportional to the aggressiveness of the phenotype. Since high density lipoproteins (HDL) are known to exert antioxidant activities, their ability to reduce ROS levels and the consequent impact on cell proliferation was tested in normal and PCa cell lines. HDL significantly reduced basal and H2O2-induced oxidative stress in normal, androgen receptor (AR)-positive and AR-null PCa cell lines. AR, scavenger receptor BI and ATP binding cassette G1 transporter were not involved. In addition, HDL completely blunted H2O2-induced increase of cell proliferation, through their capacity to prevent the H2O2-induced shift of cell cycle distribution from G0/G1 towards G2/M phase. Synthetic HDL, made of the two main components of plasma-derived HDL (apoA-I and phosphatidylcholine) and which are under clinical development as anti-atherosclerotic agents, retained the ability of HDL to inhibit ROS production in PCa cells. Collectively, HDL antioxidant activity limits cell proliferation induced by ROS in AR-positive and AR-null PCa cell lines, thus supporting a possible role of HDL against PCa progression

Low- to high-velocity frictional properties of the clay-rich gouges from the slipping zone of the 1963 Vaiont slide, northern Italy

The final slip of about 450 m at about 30 m/s of the 1963 Vaiont landslide (Italy) was preceded by >3 year long creeping phase which was localized in centimeter-thick clay-rich layers (60–70% smectites, 20–30% calcite and quartz). Here we investigate the frictional properties of the clay-rich layers under similar deformation conditions as during the landslide: 1–5 MPa normal stress, 2 × 10^(−7) to 1.31 m/s slip rate and displacements up to 34 m. Experiments were performed at room humidity and wet conditions with biaxial, torsion and rotary shear apparatus. The clay-rich gouge was velocity-independent to velocity-weakening in both room humidity and wet conditions. In room humidity experiments, the coefficient of friction decreased from 0.47 at v 0.70 m/s: full lubrication results from the formation of a continuous water film in the gouge. The Vaiont landslide occurred under wet to saturated conditions. The unstable behavior of the landslide is explained by the velocity-weakening behavior of the Vaiont clay-rich gouges. The formation of a continuous film of liquid water in the slipping zone reduced the coefficient of friction to almost zero, even without invoking the activation of thermal pressurization. This explains the extraordinary high velocity achieved by the slide during the final collapse

A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility "in vitro"

The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype