Układ renina-angiotensyna-aldosteron w patogenezie miażdżycy. Wpływ na komórki śródbłonka i gromadzenie jednojądrzastych leukocytów w ścianie naczynia

Atherosclerosis is presently considered to be a type of chronic inflammatory disease in which development endothelial cell dysfunction, oxidative stress, and the fibroproliferative process within the vascular wall play very important role. Arterial hypertension, which is one of the major risk factors of atherosclerosis, may exert an important effect on many mechanisms significantly contributing to the development and progress of atherosclerosis. The article discusses in detail the role of endothelial cell dysfunction in atherosclerosis pathogenesis and mechanisms responsible for selective accumulation of mononuclear leukocytes within the vascular wall and thus for inflammation existing there. Subsequently, on the basis of the results of experimental and clinical studies, the possibilities of participation of hypertension, and in particular of angiotensin II, in these stages of development of atherosclerosis so significant for this disorder have been discussed. Morever, the article discusses how angiotensin II contributes to the intensity of inflammatory response and destabilisation of the atherosclerotic plaque and thus to the occurrence of clinical complication of atherosclerosis.Współcześnie uważa się, że miażdżyca jest rodzajemprzewlekłej choroby zapalnej, w przebiegu której istotną rolę odgrywa dysfunkcja komórek śródbłonka, stres oksydacyjny i toczący się w ścianie naczynia proces fibroproliferacyjny. Nadciśnienie tętnicze, będące jednym z głównych czynników ryzyka miażdżycy, może mieć istotny wpływ na wiele mechanizmów, które odgrywają istotną rolę w jej powstawaniu i progresji. W pracy szczegółowo omówiono rolę dysfunkcji komórek śródbłonka w patogenezie miażdżycy oraz mechanizmy odpowiedzialne za selektywne gromadzenie jednojądrzastych leukocytów w ścianie naczynia i tym samym rozwijające się tam zapalenie. Następnie na podstawie wyników badań eksperymentalnych i klinicznych przedyskutowano możliwości udziału nadciśnienia tętniczego, a szczególnie angiotensyny II, w poszczególnych etapach rozwoju miażdżycy. Ponadto omówiono sposób, w jaki angiotensyna II przyczynia się do nasilenia odpowiedzi zapalnej i destabilizacji blaszki miażdżycowej, co prowadzi do wystąpienia klinicznych powikłań miażdżycy

Antioxidant properties, anti-hepatocellular carcinoma activity and hepatotoxicity of artichoke, milk thistle and borututu

Cynara scolymus (artichoke), Silybum marianum (milk thistle) and Cochlospermum angolensis (borututu) are three plants widely used regarding hepatoprotective effects but to the best of our knowledge no anti-hepatocellular carcinoma activity has been studied in the most consumed forms: infusions and dietary supplements. Herein, antioxidant properties, anti-hepatocellular carcinoma activity and toxicity of infusions and dietary supplements of the mentioned plants were evaluated and compared. All the samples revealed antioxidant properties with EC50 values lower than the daily recommended dose, but infusions showed higher biological activity than dietary supplements. Borututu infusion gave the highest antioxidant activity (EC50 400 mu g/mL). Artichoke infusion also presented antitumour activity (GI(50) = 52 mu g/mL) but with toxicity for normal cells at a higher concentration (GI(50) = 72 mu g/mL). The antioxidant and antitumour properties were positively correlated with phenolics and flavonoids content. Overall, among the three studied species, borututu infusion proved to be the most complete sample regarding antioxidant and anti-hepatocellular carcinoma activity.The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) for financial support to the research centre CIMO (PEst-OE/AGR/UI0690/2011). L. Barros also thanks to FCT, POPH-QREN and FSE for her grant (SFRH/BPD/4609/2008)

Regulation of Inflammation by Short Chain Fatty Acids

The short chain fatty acids (SCFAs) acetate (C2), propionate (C3) and butyrate (C4) are the main metabolic products of anaerobic bacteria fermentation in the intestine. In addition to their important role as fuel for intestinal epithelial cells, SCFAs modulate different processes in the gastrointestinal (GI) tract such as electrolyte and water absorption. These fatty acids have been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of GPCRs (GPR41 and GPR43) and inhibiton of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions including production of cytokines (TNF-α, IL-2, IL-6 and IL-10), eicosanoids and chemokines (e.g., MCP-1 and CINC-2). The ability of leukocytes to migrate to the foci of inflammation and to destroy microbial pathogens also seems to be affected by the SCFAs. In this review, the latest research that describes how SCFAs regulate the inflammatory process is presented. The effects of these fatty acids on isolated cells (leukocytes, endothelial and intestinal epithelial cells) and, particularly, on the recruitment and activation of leukocytes are discussed. Therapeutic application of these fatty acids for the treatment of inflammatory pathologies is also highlighted

A RG-II type polysaccharide purified from Aconitum coreanum and their anti-inflammatory activity

Korean mondshood root polysaccharides (KMPS) isolated from the root of Aconitum coreanum (Lévl.) Rapaics have shown anti-inflammatory activity, which is strongly influenced by their chemical structures and chain conformations. However, the mechanisms of the anti-inflammatory effect by these polysaccharides have yet to be elucidated. A RG-II polysaccharide (KMPS-2E, Mw 84.8 kDa) was isolated from KMPS and its chemical structure was characterized by FT-IR and NMR spectroscopy, gas chromatography–mass spectrometry and high-performance liquid chromatography. The backbone of KMPS-2E consisted of units of [→6) -β-D-Galp (1→3)-β-L-Rhap-(1→4)-β-D-GalpA-(1→3)-β-D-Galp-(1→] with the side chain →5)-β-D-Arap (1→3, 5)-β-D-Arap (1→ attached to the backbone through O-4 of (1→3,4)-L-Rhap. T-β-D-Galp is attached to the backbone through O-6 of (1→3,6)-β-D-Galp residues and T-β-D-Ara is connected to the end group of each chain. The anti-inflammatory effects of KMPS-2E and the underlying mechanisms using lipopolysaccharide (LPS) - stimulated RAW 264.7 macrophages and carrageenan-induced hind paw edema were investigated. KMPS-2E (50, 100 and 200 µg/mL) inhibits iNOS, TLR4, phospho-NF-κB–p65 expression, phosphor-IKK, phosphor-IκB-α expression as well as the degradation of IκB-α and the gene expression of inflammatory cytokines (TNF-α, IL-1β, iNOS and IL-6) mediated by the NF-κB signal pathways in macrophages. KMPS-2E also inhibited LPS-induced activation of NF-κB as assayed by electrophorectic mobility shift assay (EMSA) in a dose-dependent manner and it reduced NF-κB DNA binding affinity by 62.1% at 200µg/mL. In rats, KMPS-2E (200 mg/kg) can significantly inhibit carrageenan-induced paw edema as ibuprofen (200 mg/kg) within 3 h after a single oral dose. The results indicate that KMPS-2E is a promising herb-derived drug against acute inflammation

Beyond Gut Instinct: Metabolic Short-Chain Fatty Acids Moderate the Pathogenesis of Alphaherpesviruses

Short-chain fatty acids (SCFA), such as sodium butyrate (SB), sodium propionate (SPr), and sodium acetate (SAc), are metabolic end-products of the fermentation of dietary fibers. They are linked with multiple beneficial effects on the general mammalian health, based on the sophisticated interplay with the host immune response. Equine herpesvirus 1 (EHV1) is a major pathogen, which primarily replicates in the respiratory epithelium, and disseminates through the body via a cell-associated viremia in leukocytes, even in the presence of neutralizing antibodies. Infected monocytic CD172a+ cells and T-lymphocytes transmit EHV1 to the endothelium of the endometrium or central nervous system (CNS), causing reproductive or neurological disorders. Here, we questioned whether SCFA have a potential role in shaping the pathogenesis of EHV1 during the primary replication in the URT, during the cell-associated viremia, or at the level of the endothelium of the pregnant uterus and/or CNS. First, we demonstrated the expression of SCFA receptors, FFA2 and FFA3, within the epithelium of the equine respiratory tract, at the cell surface of immune cells, and equine endothelium. Subsequently, EHV1 replication was evaluated in the URT, in the presence or absence of SB, SPr, or SAc. In general, we demonstrated that SCFA do not affect the number of viral plaques or virus titer upon primary viral replication. Only SB and SPr were able to reduce the plaque latitudes. Similarly, pretreatment of monocytic CD172a+ cells and T-lymphocytes with different concentrations of SCFA did not alter the number of infected cells. When endothelial cells were treated with SB, SPr, or SAc, prior to the co-cultivation with EHV1-inoculated mononuclear cells, we observed a reduced number of adherent immune cells to the target endothelium. This was associated with a downregulation of endothelial adhesion molecules ICAM-1 and VCAM-1 in the presence of SCFA, which ultimately lead to a significant reduction of the EHV1 endothelial plaques. These results indicate that physiological concentrations of SCFA may affect the pathogenesis of EHV1, mainly at the target endothelium, in favor of the fitness of the horse. Our findings may have significant implications to develop innovative therapies, to prevent the devastating clinical outcome of EHV1 infections