Arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo.

Based on its capacity to inhibit in vitro HIV-1 replication in T cells and the release of pro-inflammatory cytokines in monocytes, the prenylated heterodimeric phloroglucinyl α-pyrone arzanol was identified as the major anti-inflammatory and anti-viral constituent from Helichrysum italicum. We have now investigated the activity of arzanol on the biosynthesis of pro-inflammatory eicosanoids, evaluating its anti-inflammatory efficacy in vitro and in vivo. Arzanol inhibited 5-lipoxygenase (EC 7.13.11.34) activity and related leukotriene formation in neutrophils, as well as the activity of cyclooxygenase (COX)-1 (EC 1.14.99.1) and the formation of COX-2-derived prostaglandin (PG)E(2)in vitro (IC(50)=2.3-9μM). Detailed studies revealed that arzanol primarily inhibits microsomal PGE(2) synthase (mPGES)-1 (EC 5.3.99.3, IC(50)=0.4μM) rather than COX-2. In fact, arzanol could block COX-2/mPGES-1-mediated PGE(2) biosynthesis in lipopolysaccharide-stimulated human monocytes and human whole blood, but not the concomitant COX-2-derived biosynthesis of thromboxane B(2) or of 6-keto PGF(1α), and the expression of COX-2 or mPGES-1 protein was not affected. Arzanol potently suppressed the inflammatory response of the carrageenan-induced pleurisy in rats (3.6mg/kg, i.p.), with significantly reduced levels of PGE(2) in the pleural exudates. Taken together, our data show that arzanol potently inhibits the biosynthesis of pro-inflammatory lipid mediators like PGE(2)in vitro and in vivo, providing a mechanistic rationale for the anti-inflammatory activity of H. italicum, and a rationale for further pre-clinical evaluation of this novel anti-inflammatory lead

Structural optimization and biological evaluation of 2-substituted 5-hydroxyindole-3-carboxylates as potent inhibitors of human 5-lipoxygenase.

Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5- hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC50 values of 0.23 and 0.086 μM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC50 = 0.83-1.6 μM) and significantly prevented leukotriene B4 production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics

Análisis del Comportamiento del Cojinete de Longitud Finita usando el Método de Perturbación Regular

El estudio del funcionamiento de cojinetes hidrodinámicos lleva directamente a analizar el comportamiento de flujo de una película de fluido que, si es newtoniano, queda descrito por la ecuación de Reynolds. Esta ecuación surge de la integración de las ecuaciones de conservación de cantidad de movimiento en el fluido (ecuaciones de Navier – Stokes) una vez introducidas en la ecuación de continuidad. De esta manera se obtiene una ecuación diferencial para la presión (P). El proceso exige un riguroso análisis de orden de magnitud basado en las relaciones entre las dimensiones del cojinete. De la etapa de adimensionalización surge que hay tres parámetros que rigen el comportamiento del sistema: el número de Sommerfeld (S), la relación longitud a diámetro al cuadrado (L/D)² y, menos directamente, la excentricidad relativa (η). La ecuación de Reynolds, resultante de este tratamiento, es una ecuación diferencial de segundo orden en derivadas parciales, cuya solución analítica ha sido estudiada ampliamente desde su formulación pero aún no ha sido hallada. Afortunadamente, para el caso especial de flujo en régimen estacionario y a temperatura constante se han encontrado aproximaciones a dos situaciones geométricas particulares: el caso del cojinete de longitud infinita (L/D→∞) y el caso del cojinete de longitud nula (L/D→0). Los cojinetes de longitud finita deben tratarse numéricamente. En este trabajo se analiza el caso del cojinete de longitud finita haciendo uso del método de perturbación regular usando la relación (L/D)² como parámetro de perturbación. Lo novedoso del tratamiento realizado es el estudio del comportamiento del cojinete corto efectuando la expansión en serie no sólo de P sino también de S. Dado que el número de Sommerfeld sólo aparece como un factor de un término de la ecuación de Reynolds en el que también está presente el parámetro de perturbación, la metodología propuesta permite ampliar el rango de valores que el parámetro S puede tomar, y por ende, el rango de η. Hasta el presente se han considerado diversos valores de la relación L/D y se han comparado los resultados analíticos aproximados del método propuesto con la solución de orden cero, la solución perturbada sin expandir S y la solución numérica obtenida mediante diferencias finitas. Se han analizado los perfiles de presión, velocidades axial y tangencial y tensiones en función de la posición tangencial y axial, como así también la capacidad portante y las variables de proceso en función de S. Los resultados obtenidos muestran muy buenas predicciones hasta valores de η = ½ y L/D = 1.Fil: Vignolo, Gustavo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; ArgentinaFil: Barilá, Daniel O.. Universidad Nacional de la Patagonia; ArgentinaFil: Quinzani, Lidia Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentin

Myrtucommulone from Myrtus communis exhibits potent anti-inflammatory effectiveness in vivo.

Myrtucommulone a nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis), has been reported to suppress the biosynthesis of eicosanoids by inhibition of 5-lipoxygenase and cyclooxygenase-1 in vitro and to inhibit the release of elastase and the formation of reactive oxygen species in activated polymorphonuclear leukocytes. Here, in view of the ability of MC to suppress typical proinflammatory cellular responses in vitro, we have investigated the effects of MC in in vivo models of inflammation. MC was administered to mice intraperitoneally, and paw edema and pleurisy were induced by the subplantar and intrapleural injection of carrageenan, respectively. MC (0.5, 1.5, and 4.5 mg/kg i.p.) reduced the development of mouse carrageenan-induced paw edema in a dose-dependent manner. Moreover, MC (4.5 mg/kg i.p. 30 min before and after carrageenan) exerted anti-inflammatory effects in the pleurisy model. In particular, 4 h after carrageenan injection in the pleurisy model, MC reduced: 1) the exudate volume and leukocyte numbers; 2) lung injury (histological analysis) and neutrophil infiltration (myeloperoxidase activity); 3) the lung intercellular adhesion molecule-1 and P-selectin immunohistochemical localization; 4) the cytokine levels (tumor necrosis factor-α and interleukin-1 β in the pleural exudate and their immunohistochemical localization in the lung; 5) the leukotriene B 4, but not prostaglandin E2, levels in the pleural exudates; and 6) lung peroxidation (thiobarbituric acid-reactant substance) and nitrotyrosine and poly (ADP-ribose) immunostaining. In conclusion, our results demonstrate that MC exerts potent anti-inflammatory effects in vivo and offer a novel therapeutic approach for the management of acute inflammation. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics

Development of the New Method of the Melted Cheese Products Without Salt-melters Using Cryomechanolysis

The aim of the work is elaboration of the principally new method of deep processing of rennet cheeses to the melting using the complex action of freezing and cryomechanolysis on the raw material that gives a possibility to destruct the hardly soluble biopolymers and to transform them into soluble form.The principally new method of the deep processing of rennet cheeses for receiving the melt cheese products without salts-smelters was elaborated. It differs from the traditional ones by the complete exclusion of the salts-smelters. This method is based on the use of the influence of freezing and fine-dispersed comminution on the raw material. It allows open biological potential of the rennet cheeses more fully and to extract the hidden (bound) protein forms from nanocomplexes of lipids and mineral substances. It allows destruct the proteins of rennet cheeses to the separate polymers and dipeptides and tripeptides. The used technological methods gave a possibility to exclude the salts-smelters at the rennet cheeses manufacturing. They favor the transformation of lipid-proteins paracaseinate calcium phosphate complexes to the separate amino acids and peptides and allow receive homogenous plastic mass.It was established, that at the complex action of freezing and fine-dispersed comminution on the rennet cheese the destruction of hardly soluble lipid-protein nanocomplexes and release of protein from the bound state into free one – nanoform (by 33,5…35 % more) takes place. The mechanisms of this process, connected with cryomechanodestruction of connections between lipids and proteins and non-fermented catalysis of nanocomplexes were described.It was established, that cryomechanodestruction and non-fermented catalysis of protein to the separate monomers – α-amino acids (by 55…60 %) takes place at freezing and fine-dispersed comminution of rennet cheese before melting. The mechanism of freezing and non-fermented analysis, connected with cryomechanocracking of protein molecules at the expanse of peptide protein connections destruction to the separate α-amino acids and their transformation into the free form was described. It was also demonstrated, that the conformational changes of protein molecules take place synchronously.The offered and elaborated nanotechnology of melt cheese products on the base of rennet cheeses without salts-smelters includes complex action of freezing and fine-dispersed comminution. The mechanisms of processes, connected with cryomechanodestruction of connections between lipids and protein to the separate α-amino acids are described.The cheese fillings for “Pancake” confectionary and cheese snacks – falafels were manufactured on the base of cheese mass, received using the new method and enriching vegetable nanoadditives. They exceed the well-known analogs by chemical composition and are remarkable for the storage life, increased in 2 times. At the same time the significant part of substances (BAS and biopolymers) in cheese filings is in nanodimensional form (55…60 % of protein), especially, free α-amino acids, easily assimilated by the human organism. The recipes and technologies of sauces-dressings, sauces-deeps, cheese snacks and so on are also elaborated on the base of cheese mass, received by the new method

The novel Sinupret® dry extract exhibits anti-inflammatory effectiveness in vivo

Sinupret® is frequently used as a herbal medicinal product to treat sinusitis, and it was assumed that anti-inflammatory effects might contribute to its overall beneficial properties. Here, we investigated the effects of a Sinupret® drug mixture (SIN) as well as of the novel Sinupret® dry extract (SIN DE) with the latter containing higher concentrations of active ingredients, in an in vivo model of acute inflammation, the carrageenan-induced pleurisy in rats. Both SIN and SIN DE were administered to rats orally at doses of 100mg/kg (low dose) and 500mg/kg (high dose) 1h prior to intrapleural injection of carrageenan. Although both SIN and SIN DE significantly reduced the exudate volume and leukocyte numbers in the pleural exudate at the high and the low dose 4h after carrageenan injection, the novel SIN DE was more efficient than SIN at the low dose, implying higher efficiency. In parallel, the novel dry extract SIN DE, but not SIN, at 500mg/kg significantly lowered the levels of prostaglandin (PG)E(2) in the exudates and reduced the amounts of cyclooxygenase (COX)-2 protein in the lungs. Together, SIN and SIN DE exert significant oral anti-inflammatory effects, which rationalize their therapeutic use in the management of sinusitis and other viral/microbial nasal infections that are associated with inflammation. Moreover, our results suggest that based on the higher efficiency and the accompanied reduction of COX-2 expression and PGE(2) formation, the novel dry extract SIN DE might be superior over the former SIN drug mixture

2-(4-(Biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52) - a novel type 5-lipoxygenase inhibitor with favorable molecular pharmacology and efficacy in vivo.

BACKGROUND AND PURPOSE: 5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) representing a potential target for pharmacological intervention with inflammation and allergic disorders. Although many LT synthesis inhibitors are effective in simple in vitro test systems, they frequently fail in vivo due to lack of efficacy. Here, we attempted to assess the pharmacological potential of the previously identified 5-LO inhibitor 2-(4-(biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52). EXPERIMENTAL APPROACH: We evaluated the efficacy of HZ52 in vivo using carrageenan-induced pleurisy in rats and platelet-activating factor (PAF)-induced lethal shock in mice. We also characterized 5-LO inhibition by HZ52 at the cellular and molecular level in comparison with other types of 5-LO inhibitor, that is, BWA4C, ZM230487 and hyperforin. KEY RESULTS: HZ52, 1.5 mg·kg⁻¹ i.p., prevented carrageenan-induced pleurisy accompanied by reduced LTB(4) levels and protected mice (10 mg·kg⁻¹, i.p.) against PAF-induced shock. Detailed analysis in cell-based and cell-free assays revealed that inhibition of 5-LO by HZ52 (i) does not depend on radical scavenging properties and is reversible; (ii) is not impaired by an increased peroxide tone or by elevated substrate concentrations; and (iii) is little affected by the cell stimulus or by phospholipids, glycerides, membranes or Ca²⁺. CONCLUSIONS AND IMPLICATIONS: HZ52 is a promising new type of 5-LO inhibitor with efficacy in vivo and with a favourable pharmacological profile. It possesses a unique 5-LO inhibitory mechanism different from classical 5-LO inhibitors and seemingly lacks the typical disadvantages of former classes of LT synthesis blockers

Epidemics in partially overlapped multiplex networks

Many real networks exhibit a layered structure in which links in each layer reflect the function of nodes on different environments. These multiple types of links are usually represented by a multiplex network in which each layer has a different topology. In real-world networks, however, not all nodes are present on every layer. To generate a more realistic scenario, we use a generalized multiplex network and assume that only a fraction $q$ of the nodes are shared by the layers. We develop a theoretical framework for a branching process to describe the spread of an epidemic on these partially overlapped multiplex networks. This allows us to obtain the fraction of infected individuals as a function of the effective probability that the disease will be transmitted $T$. We also theoretically determine the dependence of the epidemic threshold on the fraction $q > 0$ of shared nodes in a system composed of two layers. We find that in the limit of $q \to 0$ the threshold is dominated by the layer with the smaller isolated threshold. Although a system of two completely isolated networks is nearly indistinguishable from a system of two networks that share just a few nodes, we find that the presence of these few shared nodes causes the epidemic threshold of the isolated network with the lower propagating capacity to change discontinuously and to acquire the threshold of the other network.Comment: 13 pages, 4 figure

Physicochemical evaluation of cooking and dessert bananas (Musa sp.) varieties

In México, banana (Musa sp.) varieties are used for human consumption as well as for traditional medicine, but the literature lacks information on local diversity and functional justification for their use. Three varieties of dessert bananas (Valery, Morado, and Enano) and one cooking banana (Macho) were collected in a commercial farm in Tuxtepec, Oaxaca, México, at the agronomic maturity stage, and they were physically and chemically evaluated. A random sampling, ANOVA, and Tukey tests were used. As compared to the dessert bananas, the cooking banana (Macho) showed a lower number of hands per banana bunch (6) and of fingers per hands (6), one of the smallest bunch yields (about 12.4 kg), a higher average finger weight (349 g), length (31.7 cm), girth (17 cm), starch amount (75.7 %, dry basis), resistant starch (59.2 % db), and greater firmness (10.2 N). Values of extractable polyphenols (EP), condensed tannins (CT), and hydrolysable tannins (HT) were higher for Morado variety, followed by Macho. The antioxidant capacity of EP, CT, and HT fluctuated among varieties. The Morado variety exhibited the lowest pasting temperature, lowest onset temperature, highest peak viscosity, and highest breakdown than those of the other varieties. The cooking variety exhibited the highest pasting and onset temperature (86.2 and 74.8 °C), and cooking ability (88.6 s) (p£0.05). The resuts revealed the differentiation of edible Mexican banana varieties and for their potential acceptability. (Résumé d'auteur

The molecular pharmacology and in vivo activity of 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase.

The microsomal prostaglandin E2 synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E2 biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of pirinixic acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of α-(n-hexyl)- substituted pirinixic acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino) pyrimidin-2-ylthio)octanoic acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC 50 = 3.4 μM), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 (KD = 10-14 μM). In lipopolysaccharide-stimulated human whole blood, PGE2 formation was concentration dependently inhibited (IC50 =2 μM), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B2 and 6-keto PGF1α and the COX-1-derived 12(S)-hydroxy-5-cis-8,10- transheptadecatrienoic acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE2 and leukotriene B4 but also of 6-keto PGF 1α. Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo