Human Apolipoprotein A-I-Derived Amyloid: Its Association with Atherosclerosis

Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA-I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis

Anti-Inflammatory and Antioxidant Chinese Herbal Medicines: Links between Traditional Characters and the Skin Lipoperoxidation “Western” Model

The relationship between lipid peroxidation and inflammation has been accepted as a paradigm in the field of topical inflammation. The underlying biochemical mechanisms may be summarised as unspecific oxidative damage followed by specific oxidative processes as the physio pathological response in skin tissues. In this experimental review we hypothesise that the characteristics attributed by Traditional Chinese Medicine (TCM) to herbal drugs can be linked to their biomolecular activities within the framework of the above paradigm. To this end, we review and collect experimental data from several TCM herbal drugs to create 2D-3D pharmacological and biochemical spaces that are further reduced to a bidimensional combined space. When multivariate analysis is applied to the latter, it unveils a series of links between TCM herbal characters and the skin lipoperoxidation “Western” model. With the help of these patterns and a focused review on their chemical, pharmacological and antioxidant properties we show that cleansing herbs of bitter and cold nature acting through removal of toxins—including P. amurense, Coptis chinensis, S. baicalensis and F. suspensa—are highly correlated with strong inhibition of both lipid peroxidation and eicosanoids production. Sweet drugs—such as A. membranaceus, A. sinensis and P. cocos—act through a specific inhibition of the eicosanoids production. The therapeutic value of the remaining drugs—with low antioxidant or anti-inflammatory activity—seems to be based on their actions on the Qi with the exception of furanocoumarin containing herbs—A. dahurica and A. pubescens—which “expel wind”. A further observation from our results is that the drugs present in the highly active “Cleansing herbs” cluster are commonly used and may be interchangeable. Our work may pave the way to a translation between two medical systems with radically different philosophies and help the prioritisation of active ingredients with specific biomolecular activities of interest for the treatment of skin conditions

Is the protection against ischemia induced by red wine linked to its antioxidant capacity?

Objective: To establish whether the total antioxidant capacity of nonalcoholic extracts of three Argentine red wines (RWE) is correlated with their protection against ischemia-reperfusion injury. Animals and methods: The antioxidant properties of three RWE were determined using different free radicalgenerating systems. To examine the effects of these RWE during a 20 min global ischemic period followed by 30 min of reperfusion, isolated rat hearts received 50 µg/mL of RWE 1 (cabernetsauvignon), RWE 2 (malbec) or RWE 3 (a commercial mixture of cabernet-sauvignon, malbec and merlot) 10 min before and after ischemia. Left ventricular developed pressure (LVDP), maximal velocity of rise of left ventricular pressure (+dP/dtmax) and left ventricular end-diastolic pressure (LVEDP) were used to assess contractility and diastolic function. Results: All RWE inhibited lipid peroxidation induced by the Cl4C/NADPH system in a similar proportion (42±4%, 47±9% and 43±14% for RWE 1, RWE 2 and RWE 3, respectively). The scavenging activity of superoxide anion and 2,2-diphenyl-1-picrylhydrazyl radical was about the same with the three RWE. In hearts without RWE treatment, LVDP and +dP/dtmax were 61±4% and 62±5%, respectively, at the end of the reperfusion period. Infusion of RWE 1 and RWE 2 significantly improved postischemic recovery (LVDP and +dP/dtmax were 102±4% and 101±4% for RWE 1 and 92±5% and 91±5% for RWE 2, respectively) and attenuated the increase of LVEDP. RWE 3 did not improve either systolic or diastolic dysfunction. Conclusion: These data show that although the three nonalcoholic RWE exhibit a similar total antioxidant capacity, only two of them protect the heart against myocardial stunning, suggesting that the protective effect is not primarily linked to the antioxidant properties of the extracts.Centro de Investigaciones Cardiovasculare

Modulation of Diabetes by Natural Products and Medicinal Plants via Incretins

Incretins are metabolic hormones released after a meal that increase insulin secretion from pancreatic β-cells. The two main incretins are the intestinal peptides glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Both induce a decrease in glycemia, slow down the absorption of nutrients, and are inactivated by the enzyme dipeptidyl peptidase-4. Recently, incretin-based therapies have become a useful tool to treat diabetic patients, and different studies have focused on the identification of glucagon-like peptide-1 receptor agonists, including those of natural origin. This review focuses on the new findings of medicinal plants and natural products as possible active agents on the potentiation of incretin receptor signaling. Among these, soluble fiber from species of Plantago and guar gum show promising effects, iridoid derivatives are relevant activators of incretin receptors, and derivatives of cyanidin, especially diglycosylated ones, are an interesting source of dipeptidyl peptidase-4 inhibitors.Sin financiación2.687 JCR (2019) Q1, 7/28 Integrative & Complementary Medicine0.572 SJR (2019) Q1, 19/111 Complementary and Alternative MedicineNo data IDR 2019UE

Participation of mitochondrial permeability transition pore in the effects of ischemic preconditioning in hypertrophied hearts: Role of NO and mitoKATP

Background: The mitochondrial permeability transition pore (mPTP) plays an important role in ischemia–reperfusion in normotensive animals. Our study aims to define their participation in the ischemic preconditioning (IP) in hypertrophied hearts and to assess the role played by NO and mitochondrial ATP-dependent K channels (mitoKATP). Material and methods: Isolated hearts from spontaneously hypertensive rats (SHR) and age-matched normotensive rats Wistar Kyoto (WKY) were subjected to 35-min or 50-min global ischemia (GI) followed by 2-hour reperfusion (R). IP was induced by a single cycle of 5-min GI and 10-min R (IP1) or three cycles of 2-min GI and 5-min R (IP3) applied before to prolonged ischemia. L-NAME (NOS inhibitor) or 5-HD (mitoKATP blocker) to investigate the role played by NO and mitoKATP, respectively were administered. Infarct size (IS), myocardial function, reduced glutathione (GSH) — as marker of oxidative stress and MnSOD cytosolic activity — as an index of mPTP opening were determined. Results: IP1 significantly decreased the IS in WKY hearts at both ischemia duration times. In SHR, IP1 decreased the IS observed in GI35 but it did not modify that detected at 50-min GI, which was limited by IP3. IP preserved GSH content and decreased MnSOD cytosolic activity in both rat strains. These protective effects were annulled by L-NAME and 5-HD for both ischemic periods in SHR, whereas in WKY they were only effective for 50-min GI. Conclusion: Our data demonstrate that the cardioprotection achieved by ischemic preconditioning in hearts from SHR hearts involves an attenuation of mPTP opening NO and mitoKATP-mediated.Fil: Fantinelli, Juliana Catalina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; ArgentinaFil: Pérez Nuñez, Ignacio Adrián. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; ArgentinaFil: González Arbeláez, Luisa Fernanda. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina. Ministerio de Ciencia, Tecnología e Innovación Productiva. Agencia Nacional de Promoción Cientifíca y Tecnológica; ArgentinaFil: Schinella, Guillermo R.. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; ArgentinaFil: Mosca, Susana Maria. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentin

Human Apolipoprotein A-I-Derived Amyloid: Its Association with Atherosclerosis

Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA-I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis

Chemical unfolding of apoA-I variants.

<p>Dark circles represent the experimental data for Wt. Gray and white symbols correspond to Lys107-0 and Gly26Arg respectively. A) Equilibrium unfolding of apoA-I variants as followed by intrinsic Trp fluorescence. Spectral centers of mass are plotted as a function of [GndHCl]. Final protein concentration was 0.1 mg/mL; excitation was set at 295 nm and emission recorded between 310 and 420 nm. Continuous lines are fits to the data, in the same order using a sigmoidal model. B) Dependence of bis-ANS fluorescence as a function of [GndHCl]. Proteins were diluted to 0.1 mg/mL and incubated with bis-ANS at a molar ration probe: protein 1∶5. GndHCl was added stepwise. Fluorescence was registered as the Wavelength of Maximum Fluorescence at each [GndHCl]. C) Overlap of GndHCl-mediated denaturation curves for Wt apoA-I as followed by Trp (panel A) and bis-ANS fluorescence (panel B).</p