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International Journal of Molecular... Dec 2021Cancer remains a leading cause of death worldwide, despite many advances being made in recent decades. Changes in the tumor microenvironment, including dysregulated... (Review)
Review
Cancer remains a leading cause of death worldwide, despite many advances being made in recent decades. Changes in the tumor microenvironment, including dysregulated immunity, may contribute to carcinogenesis and cancer progression. The cysteinyl leukotriene (CysLT) pathway is involved in several signal pathways, having various functions in different tissues. We summarized major findings of studies about the roles of the CysLT pathway in cancer. Many in vitro studies suggested the roles of CysLTs in cell survival/proliferation via CysLT receptor (CysLTR). CysLTR antagonism decreased cell vitality and induced cell death in several types of cancer cells, such as colorectal, urological, breast, lung and neurological malignancies. CysLTs were also associated with multidrug resistance of cancer, and CysLTR antagonism might reverse chemoresistance. Some animal studies demonstrated the beneficial effects of CysLTR antagonist in inhibiting tumorigenesis and progression of some cancer types, particularly colorectal cancer and lung cancer. The expression of CysLTR was shown in various cancer tissues, particularly colorectal cancer and urological malignancies, and higher expression was associated with a poorer prognosis. The chemo-preventive effects of CysLTR antagonists were demonstrated in two large retrospective cohort studies. In summary, the roles of the CysLT pathway in cancer have been delineated, whereas further studies are still warranted.
Topics: Animals; Apoptosis; Cell Proliferation; Cysteine; Humans; Leukotrienes; Neoplasms; Retrospective Studies; Signal Transduction
PubMed: 35008546
DOI: 10.3390/ijms23010120 -
Prostaglandins & Other Lipid Mediators Jun 20195-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes and specialized proresolving lipid mediators (SPM). It is mainly expressed in leukocytes and... (Review)
Review
5-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes and specialized proresolving lipid mediators (SPM). It is mainly expressed in leukocytes and is part of the innate immune system. 5-LO can shuttle between the cytosol and the nucleus. Upon cell activation the protein translocates from soluble cellular compartments to the nuclear membrane. Besides FLAP which is required for cellular leukotriene and SPM formation, 5-LO interacts with other proteins like coactosin-like protein (CLP), Dicer, β-catenin and p53. In this review, the factors involved in the regulation of 5-LO expression, the role of 5-LO in the regulation of stem cell proliferation and differentiation and its biological functions apart from leukotriene and SPM formation are summarized.
Topics: Animals; Arachidonate 5-Lipoxygenase; Gene Expression Regulation, Enzymologic; Humans; Leukotrienes; Tumor Suppressor Protein p53; Wnt Signaling Pathway
PubMed: 30930090
DOI: 10.1016/j.prostaglandins.2019.03.003 -
Current Opinion in Nephrology and... Jan 2018This review will critically highlight the role of leukotrienes as mediators of renal diseases and drug nephrotoxicity. It will also discuss the recently identified... (Review)
Review
PURPOSE OF REVIEW
This review will critically highlight the role of leukotrienes as mediators of renal diseases and drug nephrotoxicity. It will also discuss the recently identified mechanism of cysteinyl leukotrienes induction and action, and will propose clinical implementation of these findings.
RECENT FINDINGS
Since last reviewed in 1994, leukotrienes were shown to mediate drug-associated nephrotoxicity, transplant rejection and morbidity in several models of renal diseases. Although leukotrienes may be released by various infiltrating leukocytes, a recent study demonstrated that cytotoxic agents trigger production of leukotriene C4 (LTC4) in mouse kidney cells by activating a biosynthetic pathway based on microsomal glutathione-S-transferase 2 (MGST2). LTC4 then elicits nuclear accumulation of hydrogen peroxide-generating NADPH oxidase 4, leading to oxidative DNA damage and cell death. LTC4 inhibitors, commonly used as systemic asthma drugs, alleviated drug-associated damage to proximal tubular cells and attenuated mouse morbidity.
SUMMARY
Cysteinyl leukotrienes released by mast cells trigger the symptoms of asthma, including bronchoconstriction and vasoconstriction. Therefore, effective leukotriene inhibitors were approved as orally administered asthma drugs. The findings that leukotrienes mediate the cytotoxicity of nephrotoxic drugs, and are involved in numerous renal diseases, suggest that such asthma drugs may ameliorate drug-induced nephrotoxicity, as well as some renal diseases.
Topics: Animals; Anti-Asthmatic Agents; Cell Death; Cysteine; DNA Damage; Glutathione Transferase; Humans; Kidney Diseases; Leukotriene Antagonists; Leukotriene C4; Leukotrienes; NADPH Oxidase 4; Oxidative Stress
PubMed: 29059080
DOI: 10.1097/MNH.0000000000000381 -
Annual Review of Physiology Feb 2018The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic... (Review)
Review
The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic regeneration occurs physiologically in wound healing and tissue repair, pathological lymphangiogenesis has been implicated in a number of chronic diseases such as lymphedema, atherosclerosis, and cancer. Insight into the regulatory mechanisms of lymphangiogenesis and the manner in which uncontrolled inflammation promotes lymphatic dysfunction is urgently needed to guide the development of novel therapeutics: These would be designed to reverse lymphatic dysfunction, either primary or acquired. Recent investigation has demonstrated the mechanistic role of leukotriene B (LTB) in the molecular pathogenesis of lymphedema. LTB, a product of the innate immune response, is a constituent of the eicosanoid inflammatory mediator family of molecules that promote both physiological and pathological inflammation. Here we provide an overview of lymphatic development, the pathophysiology of lymphedema, and the role of leukotrienes in lymphedema pathogenesis.
Topics: Animals; Humans; Inflammation; Leukotrienes; Lymphatic System; Lymphedema
PubMed: 29029593
DOI: 10.1146/annurev-physiol-022516-034008 -
Biomolecules Feb 2022Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging... (Review)
Review
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB.
Topics: Brain; Humans; Leukotrienes; Lewy Body Disease; Parkinson Disease; Signal Transduction; Synucleinopathies; alpha-Synuclein
PubMed: 35327537
DOI: 10.3390/biom12030346 -
British Journal of Pharmacology Nov 2022Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has... (Review)
Review
Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has been an increased interest in determining how these lipid mediators orchestrate tumour development and metastasis through promoting a pro-tumour micro-environment. Up-regulation of CysLTs receptors and CysLTs production is found in a number of cancers and has been associated with increased tumorigenesis. Understanding the molecular mechanisms underlying the role of CysLTs and their receptors in cancer progression will help investigate the potential of targeting CysLTs signalling for anti-cancer therapy. This review gives an overview of the biological effects of CysLTs and their receptors, along with current knowledge of their regulation and expression. It also provides a recent update on the molecular mechanisms that have been postulated to explain their role in tumorigenesis and on the potential of anti-CysLTs in the treatment of cancer.
Topics: Carcinogenesis; Cysteine; Humans; Leukotrienes; Neoplasms; Tumor Microenvironment
PubMed: 33527344
DOI: 10.1111/bph.15402 -
Annual Review of Pharmacology and... Jan 2023Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also... (Review)
Review
Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, metabolic, and tumor diseases. Biosynthesis of leukotrienes involves release and oxidative metabolism of arachidonic acid and proceeds via a set of cytosolic and integral membrane enzymes that are typically expressed by cells of the innate immune system. In activated cells, these enzymes traffic and assemble at the endoplasmic and perinuclear membrane, together comprising a biosynthetic complex. Here we describe recent advances in our molecular understanding of the protein components of the leukotriene-synthesizing enzyme machinery and also briefly touch upon the leukotriene receptors. Moreover, we discuss emerging opportunities for pharmacological intervention and development of new therapeutics.
Topics: Humans; Leukotrienes; Inflammation; Asthma
PubMed: 36130059
DOI: 10.1146/annurev-pharmtox-051921-085014 -
Cardiovascular Drugs and Therapy Feb 2009The inflammatory process of atherosclerosis is associated with several pathophysiological reactions within the vascular wall. The arachidonic acid released by... (Review)
Review
INTRODUCTION
The inflammatory process of atherosclerosis is associated with several pathophysiological reactions within the vascular wall. The arachidonic acid released by phospholipase A(2) serves as substrate for the production of a group of lipid mediators known as the leukotrienes, which induce pro-inflammatory signaling through activation of specific BLT and CysLT receptors.
DISCUSSION
Leukotriene signaling has been implicated in early lipid retention and foam cell accumulation, as well as in the development of intimal hyperplasia and advanced atherosclerotic lesions. Furthermore, the association of leukotrienes with degradation of extracellular matrix has suggested a role in atherosclerotic plaque rupture. Finally, studies of either myocardial or cerebral ischemia and reperfusion indicate that leukotriene signaling in addition may be involved in the development of ischemic injury.
CONCLUSION
Both leukotriene synthesis inhibitors and leukotriene receptor antagonists have been suggested to induce beneficial effects at different stages of the atherosclerosis process.
Topics: Animals; Atherosclerosis; Brain Ischemia; Humans; Leukotriene Antagonists; Leukotrienes; Myocardial Ischemia; Receptors, Leukotriene; Signal Transduction
PubMed: 18949546
DOI: 10.1007/s10557-008-6140-9 -
Journal of Internal Medicine Nov 2015The immune reactions that regulate atherosclerotic plaque inflammation involve chemokines, lipid mediators and costimulatory molecules. Chemokines are a family of... (Review)
Review
The immune reactions that regulate atherosclerotic plaque inflammation involve chemokines, lipid mediators and costimulatory molecules. Chemokines are a family of chemotactic cytokines that mediate immune cell recruitment and control cell homeostasis and activation of different immune cell types and subsets. Chemokine production and activation of chemokine receptors form a positive feedback mechanism to recruit monocytes, neutrophils and lymphocytes into the atherosclerotic plaque. In addition, chemokine signalling affects immune cell mobilization from the bone marrow. Targeting several of the chemokines and/or chemokine receptors reduces experimental atherosclerosis, whereas specific chemokine pathways appear to be involved in plaque regression. Leukotrienes are lipid mediators that are formed locally in atherosclerotic lesions from arachidonic acid. Leukotrienes mediate immune cell recruitment and activation within the plaque as well as smooth muscle cell proliferation and endothelial dysfunction. Antileukotrienes decrease experimental atherosclerosis, and recent observational data suggest beneficial clinical effects of leukotriene receptor antagonism in cardiovascular disease prevention. By contrast, other lipid mediators, such as lipoxins and metabolites of omega-3 fatty acids, have been associated with the resolution of inflammation. Costimulatory molecules play a central role in fine-tuning immunological reactions and mediate crosstalk between innate and adaptive immunity in atherosclerosis. Targeting these interactions is a promising approach for the treatment of atherosclerosis, but immunological side effects are still a concern. In summary, targeting chemokines, leukotriene receptors and costimulatory molecules could represent potential therapeutic strategies to control atherosclerotic plaque inflammation.
Topics: Adaptive Immunity; Animals; Chemokines; Endothelium, Vascular; Humans; Immunity, Cellular; Inflammation; Leukotrienes; Lipoxins; Paracrine Communication; Plaque, Atherosclerotic; Receptors, Chemokine
PubMed: 25823439
DOI: 10.1111/joim.12367 -
The Journal of Allergy and Clinical... Sep 2009Leukotrienes are now established contributors to the inflammatory process in asthma, and leukotriene modifiers are mainstays in the therapy of asthma. This review... (Review)
Review
Leukotrienes are now established contributors to the inflammatory process in asthma, and leukotriene modifiers are mainstays in the therapy of asthma. This review focuses on published association studies implicating the role of leukotriene pathway genes in asthma pathogenesis and treatment response, specifically focusing on those genetic variants associated with asthma affection status, the development of aspirin-exacerbated respiratory disease, and pharmacogenetic response. Although published studies have been limited by small sample sizes and a lack of independent replication, multiple loci within multiple leukotriene pathway genes have now been associated in more than 1 study related to asthma or asthma treatment response. Those specific variants include 2 variants in the 5-lipoxygenase gene (ALOX5) that are both associated with response to 5-lipoxygenase inhibition and to leukotriene receptor antagonists, variants in genes encoding the 2 established cysteinyl leukotriene receptor antagonists (CYSLTR1 and CYSLTR2) that are both associated with asthma susceptibility in at least 2 independent populations, and a leukotriene C(4) synthase promoter polymorphism (LTC4s) that has been associated with asthma affection status and asthma-exacerbated respiratory disease. Despite these successes, genetic investigations into this pathway remain in their formative stages. Future studies aimed at providing a broader scope of investigation through increased sample sizes and through genome-wide approaches are needed.
Topics: Animals; Anti-Asthmatic Agents; Arachidonate 5-Lipoxygenase; Asthma; Humans; Leukotriene Antagonists; Leukotrienes; Receptors, Leukotriene
PubMed: 19665766
DOI: 10.1016/j.jaci.2009.06.035