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Pulmonary fibrosis cancer pharmacology

Alexios N Matralis, Antreas Afantitis, Vassilis Aidinis
Several years after its isolation from melanoma cells, an increasing body of experimental evidence has established the involvement of Autotaxin (ATX) in the pathogenesis of several diseases. ATX, an extracellular enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) into the bioactive lipid lysophosphatidic acid (LPA), is overexpressed in a variety of human metastatic cancers and is strongly implicated in chronic inflammation and liver toxicity, fibrotic diseases, and thrombosis. Accordingly, the ATX-LPA signaling pathway is considered a tractable target for therapeutic intervention substantiated by the multitude of research campaigns that have been successful in identifying ATX inhibitors by both academia and industry...
November 21, 2018: Medicinal Research Reviews
Tejinder Pal Khaket, Sun Chul Kang, Tapan Kumar Mukherjee
The receptor for advanced glycation end products (RAGE) is a multi-ligand pattern recognition receptor that is highly expressed in lung epithelial cells. It helps alveolar epithelial cells to maintain their morphology and specific architecture. However, in various pathophysiological conditions, pulmonary tissues express supraphysiological level of RAGE and its ligands including advanced glycation end products, high mobility group box 1 proteins and S100 proteins. These ligands on interaction with RAGE stimulate various downstream signaling pathways that generate inflammation and oxidative stress leading to asthma, chronic obstructive pulmonary disease, lung cancers, idiopathic pulmonary fibrosis, acute lung injury, pneumonia, bronchopulmonary dysplasia, cystic fibrosis and sepsis...
November 19, 2018: Current Drug Targets
Maria Assunta Chiacchio, Daniela Iannazzo, Roberto Romeo, Salvatore V Giofrè, Laura Legnani
Pyridine and pyrimidine derivatives have received great interest in recent pharmacological research, being effective in the treatment of various malignancies, such as myeloid leukemia, breast cancer and idiopathic pulmonary fibrosis. Most of the FDA approved drugs show a pyridine or pyrimidine core bearing different substituents. Aim of this review is to describe the most recent reports in this field, with reference to the new discovered pyridine- or pyrimidine-based drugs, to their synthesis and to the evaluation of the most biologically active derivatives...
September 4, 2018: Current Medicinal Chemistry
Paloma Millan-Billi, Candela Serra, Ana Alonso Leon, Diego Castillo
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal disease. The treatment is challenging and nowadays a comprehensive approach based not only in pharmacological strategies is necessary. Identification and control of comorbidities, non-pharmacological treatment, prevention and management of exacerbations as well as other areas of care (social, psychological) are fundamental for a holistic management of IPF. Gastroesophageal reflux, pulmonary hypertension, obstructive sleep apnea, combined with emphysema, lung cancer and cardiovascular involvement are the main comorbidities associated with IPF...
July 24, 2018: Medical Sciences: Open Access Journal
Philippe Lachapelle, Meina Li, Jo Douglass, Alastair Stewart
The transforming growth factor (TGF)-β cytokines play a central role in development and progression of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including asthma, COPD, lung cancer and idiopathic pulmonary fibrosis. Despite the overwhelming burden of respiratory diseases in the world, new pharmacological therapies have been limited in impact...
July 2018: Pharmacology & Therapeutics
Wioletta Skronska-Wasek, Reinoud Gosens, Melanie Königshoff, Hoeke Abele Baarsma
The WNT signalling cascades have emerged as critical regulators of a wide variety of biological aspects involved in lung development as well as in physiological and pathophysiological processes in the adult lung. WNTs (secreted glycoproteins) interact with various transmembrane receptors and co-receptors to activate signalling pathways that regulate transcriptional as well as non-transcriptional responses within cells. In physiological conditions, the majority of WNT receptors and co-receptors can be detected in the adult lung...
July 2018: Pharmacology & Therapeutics
Jian Wang, Fangzheng Zhou, Zhenyu Li, Hong Mei, Ye Wang, Hong Ma, Liangliang Shi, Ai Huang, Tao Zhang, Zhenyu Lin, Gang Wu
Radiation-induced lung injury has restricted radiotherapy for thoracic cancer. The purpose of this study was to investigate the radioprotective effects of bromodomain and extra terminal (BET) inhibitor JQ1 in a murine model of pulmonary damage. Chest computed tomography (CT) was performed in a rat model after 20 Gy radiation of the right thorax. And histological evaluation and protein expressions of irradiated tissue were analyzed to confirm the potential anti-fibrosis effect of JQ1 and its underlying mechanisms...
January 17, 2018: Scientific Reports
Hamza M Al-Tamari, Swati Dabral, Anja Schmall, Pouya Sarvari, Clemens Ruppert, Jihye Paik, Ronald A DePinho, Friedrich Grimminger, Oliver Eickelberg, Andreas Guenther, Werner Seeger, Rajkumar Savai, Soni S Pullamsetti
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo -cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro-fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF-β1)...
February 2018: EMBO Molecular Medicine
Guodong Deng, Ning Liang, Jian Xie, Hui Luo, Lili Qiao, Jingxin Zhang, Dawei Wang, Jiandong Zhang
Radiation-induced lung injury (RILI) remains a major obstacle for thoracic radiotherapy for the treatment of lung cancer, esophageal cancer and lymphoma. It is the principal dose-limiting complication, and can markedly impair the therapeutic ratio as well as a patient's quality of life. The current review presents the relevant concepts associated with RILI, including the pathogenic mechanisms and the potential treatment strategies, so as to achieve a general understanding of this issue. RILI comprises an acute radiation pneumonitis phase and subsequent late lung fibrosis...
July 2017: Oncology Letters
Elena Bargagli, Viola Bonti, Katia Ferrari, Elisabetta Rosi, Alessandra Bindi, Maurizio Bartolucci, Moroni Chiara, Luca Voltolini
Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease limited to the lung with an undefined etiopathogenesis and a very short life expectancy (less than 5 years). IPF susceptibility has been associated with several genetic and environmental risk factors and the prognosis is conditioned by comorbidities such as gastro-esophageal reflux, depression, venous thromboembolism, pulmonary hypertension and lung cancer. At 5 years follow-up, 15% of IPF patients develop lung cancer, which can significantly reduce their survival...
July 2017: In Vivo
Soo Jung Cho, Jong-Seok Moon, Chang-Min Lee, Augustine M K Choi, Heather W Stout-Delgado
Aging is associated with metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, cancer, and neurodegeneration. Aging contributes to common processes including metabolic dysfunction, DNA damage, and reactive oxygen species generation. Although glycolysis has been linked to cell growth and proliferation, the mechanisms by which the activation of glycolysis by aging regulates fibrogenesis in the lung remain unclear. The objective of this study was to determine if glucose transporter 1 (GLUT1)-induced glycolysis regulates age-dependent fibrogenesis of the lung...
April 2017: American Journal of Respiratory Cell and Molecular Biology
Steffen T Simon, Irene J Higginson, Sara Booth, Richard Harding, Vera Weingärtner, Claudia Bausewein
BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2010, on 'Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults'. Breathlessness is one of the most common symptoms experienced in the advanced stages of malignant and non-malignant disease. Benzodiazepines are widely used for the relief of breathlessness in advanced diseases and are regularly recommended in the literature. At the time of the previously published Cochrane review, there was no evidence for a beneficial effect of benzodiazepines for the relief of breathlessness in people with advanced cancer and chronic obstructive pulmonary disease (COPD)...
October 20, 2016: Cochrane Database of Systematic Reviews
Christopher S King, Steven D Nathan
Despite the development of pharmacological therapies that are effective in slowing the progression of idiopathic pulmonary fibrosis (IPF), it remains a debilitating and lethal condition. In addition to the adverse effects caused by pulmonary fibrosis, most patients with IPF have associated comorbid conditions, which might negatively affect functional status, quality of life, and survival. Comorbid conditions can be pulmonary or extrapulmonary. Pulmonary comorbidities include pulmonary hypertension, emphysema, and lung cancer, while non-pulmonary conditions include venous thromboembolism, coronary artery disease, congestive heart failure, sleep-disordered breathing, gastro-oesophageal reflux disease, and anxiety or depression...
January 2017: Lancet Respiratory Medicine
R Köhler, A Oliván-Viguera, H Wulff
Endothelial calcium/calmodulin-gated K channels of small (KCa2.3) and intermediate conductance (KCa3.1) produce membrane hyperpolarization and endothelium-dependent hyperpolarization (EDH)-mediated vasodilation. Dysfunctions of the two channels and ensuing EDH impairments are found in several cardiovascular pathologies such as diabetes, atherosclerosis, postangioplastic neointima formation, but also inflammatory disease, cancer, and organ fibrosis. Moreover, KCa3.1 plays an important role in endothelial barrier dysfunction, edema formation in cardiac and pulmonary disease, and in ischemic stroke...
2016: Advances in Pharmacology
Florian Wirsdörfer, Simone de Leve, Federica Cappuccini, Therese Eldh, Alina V Meyer, Eva Gau, Linda F Thompson, Ning-Yuan Chen, Harry Karmouty-Quintana, Ute Fischer, Michael Kasper, Diana Klein, Jerry W Ritchey, Michael R Blackburn, Astrid M Westendorf, Martin Stuschke, Verena Jendrossek
Radiation-induced pulmonary fibrosis is a severe side effect of thoracic irradiation, but its pathogenesis remains poorly understood and no effective treatment is available. In this study, we investigated the role of the extracellular adenosine as generated by the ecto-5'-nucleotidase CD73 in fibrosis development after thoracic irradiation. Exposure of wild-type C57BL/6 mice to a single dose (15 Gray) of whole thorax irradiation triggered a progressive increase in CD73 activity in the lung between 3 and 30 weeks postirradiation...
May 15, 2016: Cancer Research
Toru Kimura, Takashi Nojiri, Jun Hino, Hiroshi Hosoda, Koichi Miura, Yasushi Shintani, Masayoshi Inoue, Masahiro Zenitani, Hiroyuki Takabatake, Mikiya Miyazato, Meinoshin Okumura, Kenji Kangawa
BACKGROUND: Pulmonary fibrosis has high rates of mortality and morbidity; however, no effective pharmacological therapy has been established. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, selectively binds to the transmembrane guanylyl cyclase (GC)-B receptor and exerts anti-inflammatory and anti-fibrotic effects in various organs through vascular endothelial cells and fibroblasts that have a cell-surface GC-B receptor. Given the pathophysiological importance of fibroblast activation in pulmonary fibrosis, we hypothesized that the anti-fibrotic and anti-inflammatory effects of exogenous CNP against bleomycin (BLM)-induced pulmonary fibrosis were exerted in part by the effect of CNP on pulmonary fibroblasts...
February 19, 2016: Respiratory Research
Ming-Hui Fan, Qiang Zhu, Hui-Hua Li, Hyun-Jeong Ra, Sonali Majumdar, Dexter L Gulick, Jacob A Jerome, Daniel H Madsen, Melpo Christofidou-Solomidou, David W Speicher, William W Bachovchin, Carol Feghali-Bostwick, Ellen Puré
Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury...
April 8, 2016: Journal of Biological Chemistry
J L Judge, K M Owens, S J Pollock, C F Woeller, T H Thatcher, J P Williams, R P Phipps, P J Sime, R M Kottmann
Pulmonary fibrosis is a common and dose-limiting side-effect of ionizing radiation used to treat cancers of the thoracic region. Few effective therapies are available for this disease. Pulmonary fibrosis is characterized by an accumulation of myofibroblasts and excess deposition of extracellular matrix proteins. Although prior studies have reported that ionizing radiation induces fibroblast to myofibroblast differentiation and collagen production, the mechanism remains unclear. Transforming growth factor-β (TGF-β) is a key profibrotic cytokine that drives myofibroblast differentiation and extracellular matrix production...
October 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
Nicole C Stoddard, Jerold Chun
Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models...
January 2015: Biomolecules & Therapeutics
Christian R Osadnik, Fernanda M M Rodrigues, Carlos A Camillo, Matthias Loeckx, Wim Janssens, Christophe Dooms, Thierry Troosters
Skeletal muscle dysfunction and physical inactivity are two clinically important features of a wide range of acute and chronic respiratory conditions. Optimisation of both of these features is important in order to improve physical function, prevent clinical deterioration and maximise community participation. One of the most potent and evidence-based interventions to address these physical deficits is pulmonary rehabilitation (PR). Whilst the majority of PR research has been conducted in patients with chronic obstructive pulmonary disease, there is widespread recognition that PR can benefit many other respiratory patient groups...
2015: Respiration; International Review of Thoracic Diseases
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