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Drug-induced bronchospasm
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
K Suresh Babu, Jaymin Morjaria
Cysteinyl leukotrienes (Cys LT) are derived from arachidonic acid via the 5-lipoxygenase (5-LO) pathway. The cellular biosynthesis of leukotrienes (LTs) involves a protein named FLAP (five lipoxygenase activating protein) which transports arachidonic acid into the cytosol to be acted on by the enzyme 5-LO. Sequential catalytic action of 5-LO on arachidonic acid yields LTA4, which is further hydroxylated to LTB4 or converted into the first of the cysteinyl LTs, LTC4, by LTC4 synthase. LTC4 is exported to the extracellular space where it forms LTD4, which in turn is cleaved to form the 6-cysteinyl analogue of LTC4 known as LTE4. The cysteinyl LTs exert their biological action by binding to two types of G-protein coupled 7-transmembrane receptors, Cys LT1 and Cys LT2.
Cardiovascular Disease and Oxidative Stress
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marco Fernandes, Alisha Patel, Holger Husi
Lipoxygenases (LOXs) constitute a family of non-heme iron-containing enzymes that produce fatty acid hydroperoxides by catalysing the oxidation of poly-unsaturated fatty acids and lipids that contain a cis,cis-1,4-pentadiene structure (Neau et al., 2009). It is these hydroperoxides that form a secondary oxidation product. Lipoxygenases are involved in the synthesis of signalling molecules that contribute to structural or metabolic changes within the cell (Brash, 1999). The most relevant members in the CVD context of the lipoxygenase (LOX) family are 5-lipoxygenase (5-LOX) and 12/15-LOX isoforms which are able to convert fatty acids into several lipid mediators using arachidonic acid (AA) as substrate (Kuhn, 2004).
Cecropia pachystachya Trécul: identification, isolation of secondary metabolites, in silico study of toxicological evaluation and interaction with the enzymes 5-LOX and α-1-antitrypsin
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Penina Sousa Mourão, Rafael de Oliveira Gomes, Clara Andrezza Crisóstomo Bezerra Costa, Orlando Francisco da Silva Moura, Herbert Gonzaga Sousa, George Roberto Lemos Martins Júnior, Danniel Cabral Leão Ferreira, Antônio Luiz Martins Maia Filho, Johnnatan Duarte de Freitas, Mahendra Rai, Francisco Das Chagas Alves Lima, Antonio Euzébio Gourlart Santana, Mariana Helena Chaves, Wellington Dos Santos Alves, Valdiléia Teixeira Uchôa
Plants with antioxidant and anti-inflammatory pharmacological activities are highly targeted in studies involving the search for alternative treatments for chronic obstructive pulmonary disease (COPD) (Mourão et al. 2021). CPOD constitutes a group of chronic respiratory diseases, characterized by persistent lung inflammation, airway obstruction, and destruction of the lung alveoli (Dourado et al. 2006; Luna et al. 2020). This inflammation is marked by the presence of inflammatory cells such as lymphocytes, macrophages and neutrophils, and by interleukins 1β and 6 (Prasher et al. 2020). Leukotrienes, lipid markers of inflammation derived from arachidonic acid, are also related to lung inflammation. In leukotrienes biosynthesis the enzyme 5-lipoxygenase (5-LOX), acts as a catalyst and is expressed in various polymorphonuclear leukocytes (neutrophils and eosinophils), macrophages and lymphocytes, these being previously cited as inflammatory cells identified in COPD (Olsen and Martins 2012; Rådmark and Samuelsson 2008). The main causative factors for COPD are active and passive smoking, inhalation of noxious gases, small particles (PM2.5), and genetic deficiency of α-1-antitrypsin enzyme (Mourão et al. 2021).
Systems toxicology approach explores target-pathway relationship and adverse health impacts of ubiquitous environmental pollutant bisphenol A
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Manigandan Nagarajan, Gobichettipalayam Balasubramaniam Maadurshni, Jeganathan Manivannan
While focus on potential targets of BPA obtained from structural-similarity based search, current finding revealed various novel targets along with well-known targets such as nuclear hormone receptors. In this regard, Huang, Cang, and Liu (2019) showed that BPA exposure resulted in blockage of 5α dihydrotestosterone (DHT) induced androgen receptor (AR) nuclear translocation by diminishing DHT-dependent dissociation of AR from its co-chaperone 90-kDa heat shock protein. With respect to estrogen receptor alpha and beta interaction with BPA, Matthews, Twomey, and Zacharewski (2001) demonstrated that BPA competes more effectively for binding to ER-beta, but induces ER-alpha and ER-beta mediated gene expression with comparable efficacy. In addition, the neurite growth is closely related to the level of 5-HT6 receptor (5-HT6R) in the central nervous system and antagonism of 5-HT6R decreases excitability of the hippocampal pyramidal neurons in chronic epileptic rats by modulating the imbalance between excitatory and inhibitory neurotransmitters (Zhu et al. 2020). Further, an important predicted target of BPA is 5-lipoxygenase (5-LO), which catalyzes the first two steps in the biosynthesis of leukotrienes, a group of pro-inflammatory lipid mediators derived from arachidonic acid (Rådmark et al. 2007). In addition, BPA may plausibly target carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes involved in gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens (Supuran 2008). The members of the Bcl-2 family (including BCL-X) are designated as such due to their BCL-2 homology (BH) domains and involved in the regulation of apoptosis and play a vital role in protecting against cancer (Warren, Wong-Brown, and Bowden 2019).