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Monika Dolinska, Alexandre Piccini, Wan Man Wong, Eleni Gelali, Anne-Sofie Johansson, Johannis Klang, Pingnan Xiao, Elham Yektaei-Karin, Ulla Olsson Strömberg, Satu Mustjoki, Leif Stenke, Marja Ekblom, Hong Qian
Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC...
June 13, 2017: Biochemical and Biophysical Research Communications
Tsugunobu Andoh, Ayako Harada, Yasushi Kuraishi
A recent study suggests that interleukin-31 (IL-31) exerts its effect via indirect mechanisms rather than through direct stimulation of cutaneous nerves. However, the underlying peripheral mechanisms of IL-31-induced itch in the skin remain unclear. Therefore, the present study investigated the peripheral mechanisms underlying IL-31-induced itch in mice. IL-31-induced itch-related response was inhibited by anti-allergic drugs (tranilast and azelastine), but not by an H1 histamine receptor antagonist (terfenadine)...
May 17, 2017: Acta Dermato-venereologica
D Saul, S Gleitz, H H Nguyen, R L Kosinsky, S Sehmisch, D B Hoffmann, M Wassmann, B Menger, M Komrakova
Osteoporosis is one of the most common diseases worldwide. In osteoporosis, vertebral fractures represent a major burden. Lipoxygenase (LOX) inhibitors such as baicalein and zileuton may represent a promising therapeutic option owing to their antioxidative effects and suppression of various inflammatory processes in muscle and bone. The effect of these LOX inhibitors on the spine was studied in osteopenic rats. Female Sprague-Dawley rats were divided two times into five groups: four groups each were ovariectomized (OVX) and one control group was non-ovariectomized (NON-OVX)...
April 26, 2017: Bone
Catherine Sarret, Samia Pichard, Alexandra Afenjar, Odile Boespflug-Tanguy
No abstract text is available yet for this article.
April 7, 2017: Neuropediatrics
Jian-Guo Li, Carlos Barrero, Salim Merali, Domenico Praticò
Environmental and genetic risk factors are implicated in the pathogenesis of Alzheimer's disease (AD). However, how they interact and influence its pathogenesis remains to be investigated. High level of homocysteine (Hcy) is an AD risk factor and associates with an up-regulation of the ALOX5 gene. In the current paper we investigated whether this activation is responsible for the Hcy effect on the AD phenotype and the mechanisms involved. Triple transgenic mice were randomized to receive regular chow diet, a diet deficient in folate and B vitamins (Diet), which results in high Hcy, or the Diet plus zileuton, a specific ALOX5 inhibitor, for 7 months...
April 6, 2017: Scientific Reports
Renata Gonçalves Dias, Sandra Coccuzzo Sampaio, Morena Brazil Sant'Anna, Fernando Queiroz Cunha, José María Gutiérrez, Bruno Lomonte, Yara Cury, Gisele Picolo
BACKGROUND: Arthritis is a set of inflammatory conditions that induce aching, stiffness, swelling, pain and may cause functional disability with severe consequences to the patient's lives. These are multi-mediated pathologies that cannot be effectively protected and/or treated. Therefore, the aim of this study was to establish a new model of acute arthritis, using a Lys49-PLA2 (Bothrops asper myotoxin II; MT-II) to induce articular inflammation. METHODS: The articular inflammation was induced by MT-II (10 μg/joint) injection into the left tibio-tarsal or femoral-tibial-patellar joints...
2017: Journal of Venomous Animals and Toxins Including Tropical Diseases
Alexandra Svouraki, Ulrike Garscha, Eirini Kouloura, Simona Pace, Carlo Pergola, Verena Krauth, Antonietta Rossi, Lidia Sautebin, Maria Halabalaki, Oliver Werz, Nicolas Gaboriaud-Kolar, Alexios-Leandros Skaltsounis
Among the pathways responsible for the development of inflammatory responses, the cyclooxygenase and lipoxygenase pathways are among the most important ones. Two key enzymes, namely, 5-LO and mPGES-1, are involved in the biosynthesis of leukotrienes and prostaglandins, respectively, which are considered attractive therapeutic targets, so their dual inhibition might be an effective strategy to control inflammatory deregulation. Several natural products have been identified as 5-LO inhibitors, with some also being dual 5-LO/mPGES-1 inhibitors...
February 27, 2017: Journal of Natural Products
María José Torres, Angélica Fierro, C David Pessoa-Mahana, Javier Romero-Parra, Gonzalo Cabrera, Mario Faúndez
Leukotriene A4 hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A4 to leukotriene B4 and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B4 synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B4 or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A4 Hydrolase...
March 15, 2017: European Journal of Pharmacology
Yu Zhao Lee, Khozirah Shaari, Manraj Singh Cheema, Chau Ling Tham, Mohd Roslan Sulaiman, Daud Ahmad Israf
2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a synthetic compound that is naturally found in Melicope ptelefolia. We had previously demonstrated that parenteral administration of tHGA reduces pulmonary inflammation in OVA-sensitized mice. In this study, we evaluated the effect of orally administered tHGA upon airway remodeling in a murine model of chronic asthma. Female BALB/C mice were sensitized intraperitoneally with ovalbumin (OVA) on day 0, 7 and 14, followed by aerosolized 1% OVA 3 times per week for 6 weeks...
February 15, 2017: European Journal of Pharmacology
Masanori Hijioka, Junpei Anan, Hayato Ishibashi, Yuki Kurauchi, Akinori Hisatsune, Takahiro Seki, Tomoaki Koga, Takehiko Yokomizo, Takao Shimizu, Hiroshi Katsuki
Infiltration of neutrophils has been suggested to play an important role in the pathogenesis of intracerebral hemorrhage (ICH) for which effective therapeutic interventions remain unavailable. In the present study we focused on leukotriene B4 (LTB4) as a potent chemotactic factor for neutrophils in order to address its contribution to the pathologic events associated with ICH. ICH with hematoma expansion into the internal capsule that resulted in severe sensorimotor dysfunction was induced by injection of collagenase in mouse striatum...
March 2017: Journal of Pharmacology and Experimental Therapeutics
Leyla Abueid, Ünal Uslu, Alev Cumbul, Ayliz Velioğlu Öğünç, Feriha Ercan, İnci Alican
OBJECTIVE: The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory parameters and apoptosis in ischemia/reperfusion (I/R)-induced myocardial damage in rats. For this purpose, zileuton, a selective and potent inhibitor of 5-LOX, resulting in suppression leukotriene production, was used. METHODS: Male Wistar rats (200-250 g; n=12 per group) were used in the study...
November 10, 2016: Anatolian Journal of Cardiology
Antonella Peduto, Maria Scuotto, Verena Krauth, Fiorentina Roviezzo, Antonietta Rossi, Veronika Temml, Veronica Esposito, Hermann Stuppner, Daniela Schuster, Bruno D'Agostino, Chiara Schiraldi, Mario de Rosa, Oliver Werz, Rosanna Filosa
Aiming to assess the biological activities of synthetic 1,4-benzoquinones, we previously synthesized different libraries of benzoquinones with lipophilic and bulky alkyl- or aryl-substituents that inhibited 5-lipoxygenase (5-LO). The high potency of 4,5-dimethoxy-3-alkyl-1,2-benzoquinones on 5-LO led to the idea to further modify the structures and thus to improve the inhibitory potential in vitro and in vivo as well as to investigate SARs. Systematic structural optimization through accurate structure-based design resulted in compound 30 (3-tridecyl-4,5-dimethoxybenzene-1,2-diol), an ubiquinol derivative that exhibited the strongest anti-inflammatory effect, with a 10-fold improved 5-LO inhibitory activity (IC50 = 28 nM) in activated neutrophils...
February 15, 2017: European Journal of Medicinal Chemistry
Przemysław Rzodkiewicz, Emilia Gąsińska, Michał Gajewski, Magdalena Bujalska-Zadrożny, Dariusz Szukiewicz, Sławomir Maśliński
OBJECTIVES: Esculetin (6,7-dihydroxycoumarin) is a natural coumarin with anti-oxidant, anti-inflammatory and anti-nociceptive activity. It acts as a potent inhibitor of lipoxygenases (5-LOX and 12-LOX) and decreases the production of matrix metalloproteinases (MMP-1, MMP-3 and MMP-9). Because both inhibition of lipoxygenases and inhibition of matrix metalloproteinases are effective strategies in the treatment of rheumatoid arthritis, we investigated whether esculetin may be effective in adjuvant-induced arthritis in rats...
2016: Reumatologia
Jérémie A Doiron, Luc M Leblanc, Martin J G Hébert, Natalie A Levesque, Aurélie F Paré, Jacques Jean-François, Marc Cormier, Marc E Surette, Mohamed Touaibia
Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti-LTs activity through the inhibition of 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5-LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a-i and 5a-i, respectively) were synthesized by Sonogashira and Heck cross-coupling reactions to probe the effects of flexibility and aryl substitution on 5-LO inhibition...
April 2017: Chemical Biology & Drug Design
Z I Krutetskaya, L S Milenina, A A Naumova, V G Antonov, A D Nozdrachev
Using Fura-2AM microfluorimetry, we have shown for the first time that 5-lipoxygenase specific inhibitor antiasthmatic agent zileuton significantly inhibits Ca(2+)-responses induced by glutoxim and molixan in macrophages. The results support 5-lipoxygenase involvement in the effect of glutoxim and molixan on intracellular Ca(2+) concentration in macrophages and indicate the inadvisability of a combined use of drugs glutoxim and molixan and antiasthmatic agent zileuton.
July 2016: Doklady. Biochemistry and Biophysics
Hua Yuan, Xuemei Li, Xiuying Zhang, Rui Kang, Daolin Tang
Ferroptosis, a recently identified form of non-apoptotic cell death, is involved in several physiological and pathological processes. Although lipid peroxidation plays a central role in triggering ferroptosis, the essential regulator of lipid metabolism in ferroptosis remains poorly defined. Here, we show that acyl-CoA synthetase long-chain family member 4 (ACSL4) is required for ferroptotic cancer cell death. Compared with ferroptosis-sensitive cells (e.g., HepG2 and HL60), the expression of ACSL4 was remarkably downregulated in ferroptosis-resistant cells (e...
September 23, 2016: Biochemical and Biophysical Research Communications
Tae Young Kim, Joohye Kim, Hea-Young Park Choo, Ho Jeong Kwon
5-Lipoxygenase (5-LOX) is an enzyme that converts arachidonic acid from the cell membrane into leukotriene, a signal lipid mediator. 5-LOX deficiency markedly attenuates the formation of aneurysms in knockout mice. In addition, Zileuton, a clinical drug targeting 5-LOX, is used for treatment of asthma. However, it is unclear whether 5-LOX inhibition results in anti-angiogenic effects for applications in cancer therapy. To explore the roles of 5-LOX in angiogenesis and its potential as a therapeutic target in cancer, the effects of a newly synthesized 5-LOX inhibitor, F3, on in vitro and in vivo angiogenesis were investigated...
September 23, 2016: Biochemical and Biophysical Research Communications
Giovanni Pallio, Alessandra Bitto, Gabriele Pizzino, Federica Galfo, Natasha Irrera, Letteria Minutoli, Vincenzo Arcoraci, Giovanni Squadrito, Antonio Macrì, Francesco Squadrito, Domenica Altavilla
Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) play an important role in inflammatory bowel diseases (IBDs). We investigated the effects of flavocoxid, a dual COX/LOX inhibitor, in experimental colitis induced with either dinitrobenzenesulfonic acid (DNBS) or dextrane sulphate sodium (DSS) In the first model, colitis was induced in rats by a single intra-colonic instillation (25mg in 0.8ml 50% ethanol) of DNBS; after 24h animals were randomized to receive orally twice a day, flavocoxid (10mg/kg), zileuton (50mg/kg), or celecoxib (5mg/kg)...
October 15, 2016: European Journal of Pharmacology
Xian-Kun Tu, Hua-Bin Zhang, Song-Sheng Shi, Ri-Sheng Liang, Chun-Hua Wang, Chun-Mei Chen, Wei-Zhong Yang
Previous studies from our laboratories showed that an anti-inflammatory drug, 5-lipoxygenase inhibitor zileuton, attenuates ischemic brain damage via inhibiting inflammatory reaction. However, it was elusive whether zileuton attenuates inflammatory reaction and ischemic brain damage through the modulation of PI3K/Akt signaling pathway. In the present study, we, for the first time, investigated whether PI3K/Akt pathway was involved in zileuton's anti-inflammatory and neuroprotective properties against brain damage following experimental ischemic stroke...
October 2016: Neurochemical Research
Mong Tieng Ee, Crystal Kantores, Julijana Ivanovska, Mathew J Wong, Amish Jain, Robert P Jankov
Systemically-administered bleomycin causes inflammation, arrested lung growth, and pulmonary hypertension (PHT) in the neonatal rat, similar to human infants with severe bronchopulmonary dysplasia (BPD). Leukotrienes (LTs) are inflammatory lipid mediators produced by multiple cell types in the lung. The major LTs, LTB4 and cysteinyl LTs, are suggested to contribute to BPD, but their specific roles remain largely unexplored in experimental models. We hypothesized that LTs are increased in bleomycin-induced BPD-like injury, and that inhibition of LT production would prevent inflammatory cell influx and thereby ameliorate lung injury...
August 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
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