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Bruno P, Pala D, Micoli A, Corsi M, Accetta A, Carzaniga L, Ronchi P, Fiorelli C, Formica M, Pizzirani D, Mazzucato R, Guariento S, Bertolini S, Martucci C, Allen AD, Mileo V, Capacchi S, Gallo PM, Fioni A, Xanxo Fernandez S, Villetti G, Puccini P, Civelli M, Guala M, Retini M, Martinelli P, Visentini F, Pavoni V, Daldosso M, Fontana S, Biagetti M, Capelli AM. Discovery of CHF-6523, an Inhaled Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease. J Med Chem 2025; 68:2444-2465. [PMID: 39635891 DOI: 10.1021/acs.jmedchem.4c02062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a propeller-shape topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound 18. This novel inhaled selective PI3Kδ inhibitor displayed durable anti-inflammatory activity in a disease-relevant rat model of Th-2-driven acute lung inflammation and safe in vitro and in vivo preclinical profiles. Therefore, compound 18 showed the appropriate discovery profile and was progressed to clinical trials in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients as CHF-6523.
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Affiliation(s)
- Paolo Bruno
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Daniele Pala
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Alessandra Micoli
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Mauro Corsi
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Alessandro Accetta
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Laura Carzaniga
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Paolo Ronchi
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Claudio Fiorelli
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Michele Formica
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Daniela Pizzirani
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Roberta Mazzucato
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Sara Guariento
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Serena Bertolini
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Cataldo Martucci
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Andrew Dennis Allen
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Valentina Mileo
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Silvia Capacchi
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Paola Maria Gallo
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Alessandro Fioni
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | | | - Gino Villetti
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Paola Puccini
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Maurizio Civelli
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Matilde Guala
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Michele Retini
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Prisca Martinelli
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Filippo Visentini
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Valentina Pavoni
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Matteo Daldosso
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Stefano Fontana
- Aptuit, an Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy
| | - Matteo Biagetti
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Anna Maria Capelli
- Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
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Feng J, Dang H, Zhang X, Huang W, Ma C, Zhang A, Hao M, Xie L. A universal gene expression signature-based strategy for the high-throughput discovery of anti-inflammatory drugs. Inflamm Res 2025; 74:2. [PMID: 39762416 PMCID: PMC11703948 DOI: 10.1007/s00011-024-01968-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 09/16/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Traditional Chinese medicine (TCM) is a valuable resource for drug discovery and has demonstrated excellent efficacy in treating inflammatory diseases. This study aimed to develop a universal gene signature-based strategy for high-throughput discovery of anti-inflammatory drugs, especially Traditional Chinese medicine (TCM). METHODS The disease gene signature of liposaccharide-stimulated THP-1 cells and drug gene signatures of 655 drug candidates were established via sequencing. Anti-inflammatory drugs were screened based on similarities between drug gene signatures and the reversed disease gene signature. RESULTS Through screening, 83 potential anti-inflammatory drugs were identified. The efficacy of the TCM formula Biyun Powder, along with individual TCMs, Centipedea Herba, Kaempferiae Rhizoma, and Schizonepetae Spica Carbonisata, was verified in vitro or in vivo. Mechanistically, they exerted anti-inflammatory effects by inhibiting the nuclear factor-kappa B pathway. Kaempferol and luteolin were identified as bioactive IκB kinase-β inhibitors in Kaempferiae Rhizoma and Schizonepetae Spica Carbonisata, respectively. CONCLUSION We developed a universal gene signature-based approach for the high-throughput discovery of anti-inflammatory drugs that is applicable to compounds and to TCM herbs/formulae and established a workflow (screening, validation of efficacy, and identification of the mechanism of action and bioactive compounds) that can serve as a research template for high-throughput drug research.
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Affiliation(s)
- Juan Feng
- Medical Systems Biology Research Center, School of Medicine, Tsinghua University, Beijing, 100084, China
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, 518118, China
| | - Honglei Dang
- Beijing CapitalBio Pharma Co., Ltd, Beijing, 102206, China
| | - Xiaoling Zhang
- National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China
| | - Wenting Huang
- Medical Systems Biology Research Center, School of Medicine, Tsinghua University, Beijing, 100084, China
- National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China
| | - Chengmei Ma
- National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China
| | - Aixiang Zhang
- National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China
| | - Mimi Hao
- National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China
| | - Lan Xie
- Medical Systems Biology Research Center, School of Medicine, Tsinghua University, Beijing, 100084, China.
- National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China.
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Huang L, Zhang H, Zhuang R, Wen J. Copper Intake and Mortality Among Asthmatic Adults: A Cohort Study. Biol Trace Elem Res 2024:10.1007/s12011-024-04495-9. [PMID: 39710816 DOI: 10.1007/s12011-024-04495-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 12/16/2024] [Indexed: 12/24/2024]
Abstract
Previous studies have proved trace mineral disorders to be related to changes in oxidative stress, inflammatory state, and immune response in asthmatics. However, there is a scarcity of studies that examine the correlation between copper intake with mortality in asthmatic people. The aim of this research was to investigate the effect of copper intake on the asthmatic population's mortality. This investigation included 3175 individuals from the NHANES. Multiple statistical models were used in this investigation to discuss the correlation between copper intake and the asthmatic population's mortality. These models included Cox proportional hazards models, trend tests, restricted cubic splines (RCS), threshold effect model, and CoxBoost model. Three Cox hazard models showed an inverse relationship between copper intake and the risk of death in asthmatics. Statistical tests, such as trend tests, RCS models, and threshold effect models, proved an inverse and linear link between dietary copper and the risk of death. Through Kaplan-Meier analysis, asthmatic adults who had higher copper intake had a higher survival rate compared to asthmatics with lower copper intake. The CoxBoost model indicated that the intake of copper, selenium, and zinc had a protective effect on mortality, whereas iron was associated with an increased risk of death. The research proved an inverse and linear correlation between dietary copper intake and the risk of death among asthmatic people. Improving copper intake may have a positive impact on the long-term survival of individuals with asthma.
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Affiliation(s)
- Linlin Huang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Hegan Zhang
- Department of Gynecology, Quanzhou Women's and Children's Hospital, Quanzhou, Fujian, China
| | - Rongjuan Zhuang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Wen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Govoni M, Bassi M, Girardello L, Lucci G, Rony F, Charretier R, Galkin D, Faietti ML, Pioselli B, Modafferi G, Benfeitas R, Bonatti M, Miglietta D, Clark J, Pedersen F, Kirsten AM, Beeh KM, Kornmann O, Korn S, Ludwig-Sengpiel A, Watz H. CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD. Respir Res 2024; 25:380. [PMID: 39427187 PMCID: PMC11491004 DOI: 10.1186/s12931-024-02999-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 10/02/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition. Given patients with COPD continue to experience exacerbations despite the availability of effective therapies, anti-inflammatory treatments targeting novel pathways are needed. Kinases, notably the phosphoinositide 3-kinases (PI3K), are thought to be involved in chronic airway inflammation, with this pathway proposed as a critical regulator of inflammation and oxidative stress response in COPD. CHF6523 is an inhaled PI3Kδ inhibitor that has shown positive preclinical results. This manuscript reports the results of a study of CHF6523 in patients with stable COPD (chronic bronchitis phenotype), and who had evidence of type-2 inflammation. METHODS This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (N = 44) inhaled CHF6523 in one period, and placebo in the other, both twice daily. The primary objective was to assess the safety and tolerability of CHF6523; the secondary objective was to assess CHF6523 pharmacokinetics. Exploratory endpoints included target engagement (the relative reduction in phosphatidylinositol (3,4,5)-trisphosphate [PIP3]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics. RESULTS CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (Cmax), reached 15 and 10 min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios < 1.6 for Cmax and area under the curve from 0 to 12 h post-dose, and with steady state achieved on Day 20. Target engagement was confirmed by a significant 29.7% reduction from baseline in induced sputum PIP3 (29.5% reduction vs. placebo; adjusted ratio 0.705 [0.580, 0.856]; p = 0.001), but this did not translate into an anti-inflammatory pharmacodynamic effect, as assessed through measures including biomarkers and multi-omics. Additionally, although CHF6523 was generally well-tolerated, 95.2% of patients reported cough as an adverse event, most mild to moderate and resolving within one-hour post-dose. CONCLUSIONS These data, together with those from other PI3K inhibitors, suggest that PI3Kδ is not a suitable pathway for the management of COPD, as the achieved target engagement did not translate into any pharmacodynamic anti-inflammatory effect. TRIAL REGISTRATION ClinicalTrials.gov (NCT04032535); posted 23rd July 2019.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Martina Bonatti
- Chiesi Farmaceutici SpA, Parma, Italy
- Respiratory Medicine Unit, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | | | - Frauke Pedersen
- Velocity Clinical Research Grosshansdorf, Formerly Known as Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Anne-Marie Kirsten
- Velocity Clinical Research Grosshansdorf, Formerly Known as Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany
| | | | - Oliver Kornmann
- IKF Pneumologie Frankfurt, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany
| | - Stephanie Korn
- IKF Pneumologie Mainz, Mainz, Germany
- Thoraxklinik Heidelberg, Heidelberg, Germany
| | - Andrea Ludwig-Sengpiel
- Velocity Clinical Research Lübeck GmbH, Formerly Known as KLB Health Research, Lübeck, Germany
| | - Henrik Watz
- Velocity Clinical Research Grosshansdorf, Formerly Known as Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany
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Peng C, Xue L, Yue Y, Chen W, Wang W, Shen J. Duloxetine HCl Alleviates Asthma Symptoms by Regulating PI3K/AKT/mTOR and Nrf2/HO-1 Signaling Pathways. Inflammation 2023; 46:2449-2469. [PMID: 37644164 DOI: 10.1007/s10753-023-01892-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023]
Abstract
Asthma is an inflammatory disease characterized by airway hyperresponsiveness, airway remodeling, and airway inflammation. In recent years, the prevalence of asthma has been increasing steadily and the pathogenesis of asthma varies from person to person. Due to poor compliance or resistance, existing drugs cannot achieve the desired therapeutic effect. Therefore, developing or screening asthma therapeutic drugs with high curative effects, low toxicity, and strong specificity is very urgent. Duloxetine HCl (DUX) is a selective serotonin and norepinephrine reuptake inhibitor, and it was mainly used to treat depression, osteoarthritis, and neuropathic pain. It was also reported that DUX has potential anti-infection, anti-inflammation, analgesic, antioxidative, and other pharmacological effects. However, whether DUX has some effects on asthma remains unknown. In order to investigate it, a series of ex vivo and in vivo experiments, including biological tension tests, patch clamp, histopathological analysis, lung function detection, oxidative stress enzyme activity detection, and molecular biology experiments, were designed in this study. We found that DUX can not only relax high potassium or ACh precontracted tracheal smooth muscle by regulating L-type voltage-dependent Ca2+ channel (L-VDCC) and nonselective cation channel (NSCC) ion channels but also alleviate asthma symptoms through anti-inflammatory and antioxidative response regulated by PI3K/AKT/mTOR and Nrf2/HO-1 signaling pathways. Our data suggests that DUX is expected to become a potential new drug for relieving or treating asthma.
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Affiliation(s)
- Changsi Peng
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China
| | - Lu Xue
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China
| | - Yanling Yue
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China
| | - Weiwei Chen
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China
| | - Wenyi Wang
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China
| | - Jinhua Shen
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China.
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Al-Sha’er MA, Taha M, Alelaimat MA. Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening. Med Chem Res 2023; 32:1109-1121. [DOI: 10.1007/s00044-023-03057-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/27/2023] [Indexed: 07/10/2024]
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Zhang P, Jiang Y, Ye X, Zhang C, Tang Y. PDK1 inhibition reduces autophagy and cell senescence through the PI3K/AKT signalling pathway in a cigarette smoke mouse emphysema model. Exp Ther Med 2023; 25:223. [PMID: 37123206 PMCID: PMC10133799 DOI: 10.3892/etm.2023.11922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 11/03/2022] [Indexed: 04/03/2023] Open
Abstract
A number of previous studies have demonstrated the pivotal role of PI3K/AKT signalling in cigarette smoke (CS)-induced emphysema, where phosphoinositide dependent protein kinase 1 (PDK1) is a critical component of this pathway. Therefore, the present study aimed to investigate the effects of a PDK1 inhibitor (GSK-2334470) on the expression levels of PI3K, AKT, cyclin-dependent kinase inhibitor 2A (p16) and LC3B in a CS + CS extract (CSE)-induced mouse emphysema model. CS exposure and intraperitoneal injections of CSE were combined for 4 weeks to establish an emphysema model. Mice (n=35) were randomly divided into the normal control, emphysema (CS), PI3K inhibitor (CS3) and PDK1 inhibitor (CS1) groups. Immunohistochemistry staining of lung tissues was used to measure the expression of the PI3K, PDK1 and AKT proteins in airway epithelial tissues. Immunofluorescence staining was also used to measure the levels of p16 and LC3BII protein expression in the airway epithelial tissues. In addition, PI3K, PDK1, AKT, p16 and LC3B protein expression was semi-quantified using western blotting. The expression of PDK1, PI3K and AKT proteins in the airway epithelial tissues was significantly increased in the CS + CSE group compared with that in the control group. The expression levels of p16 and LC3B were also increased as well in the CS + CSE group compared with those in the control group. The expression levels of PI3K, PDK1, AKT, LC3B and p16 in the airway epithelial tissues of the CS3 group were lower compared with those in the CS + CSE group. A decrease in the expression levels of PDK1, AKT, p16 and LC3B in the airway epithelial tissues of the CS1 group compared with those in the CS + CSE group was also observed. However, there were no significant differences in the expression levels of PI3K between the CS1 and the CS groups. The present study concluded that the inhibition of PDK1 can potentially reduce autophagy and cell senescence by downregulating the expression of PI3K/AKT pathway related proteins in airway epithelial cells, thereby protecting against CS + CSE-induced emphysema in mice.
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Affiliation(s)
- Peibei Zhang
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Youjun Jiang
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Xianwei Ye
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Cheng Zhang
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Yiling Tang
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
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Hong JH, Lee YC. Anti-Inflammatory Effects of Cicadidae Periostracum Extract and Oleic Acid through Inhibiting Inflammatory Chemokines Using PCR Arrays in LPS-Induced Lung inflammation In Vitro. LIFE (BASEL, SWITZERLAND) 2022; 12:life12060857. [PMID: 35743888 PMCID: PMC9225349 DOI: 10.3390/life12060857] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 05/26/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022]
Abstract
In this study, we aimed to evaluate the anti-inflammatory effects and mechanisms of CP and OA treatments in LPS-stimulated lung epithelial cells on overall chemokines and their receptors using PCR arrays. In addition, we aimed to confirm those effects and mechanisms in LPS-stimulated lung macrophages on some chemokines and cytokines. In our study, CP treatments significantly inhibited the inflammatory mediators CCL2, CCL3, CCL4, CCL5, CCL6, CCL9, CCL11, CCL17, CCL20, CXCL1, CXCL2, CXCL3, CXCL5, CXCL7, CXCL10, TNF-α, and IL-6, while markedly suppressing NF-κB p65 nuclear translocation and the phosphorylations of PI3K p55, Akt, Erk1/2, p38, and NF-κB p65 in LPS-stimulated lung epithelial cells. CP treatments also significantly decreased the inflammatory mediators CCL2, CCL5, CCL17, CXCL1, and CXCL2, while markedly inhibiting phospho-PI3K p55 and iNOS expression in LPS-stimulated lung macrophages. Likewise, OA treatments significantly suppressed the inflammatory mediators CCL2, CCL3, CCL4, CCL5, CCL8, CCL11, CXCL1, CXCL3, CXCL5, CXCL7, CXCL10, CCRL2, TNF-α, and IL-6, while markedly reducing the phosphorylations of PI3K p85, PI3K p55, p38, JNK, and NF-κB p65 in LPS-stimulated lung epithelial cells. Finally, OA treatments significantly inhibited the inflammatory mediators CCL2, CCL5, CCL17, CXCL1, CXCL2, TNF-α, and IL-6, while markedly suppressing phospho-PI3K p55, iNOS, and Cox-2 in LPS-stimulated lung macrophages. These results prove that CP and OA treatments have anti-inflammatory effects on the inflammatory chemokines and cytokines by inhibiting pro-inflammatory mediators, including PI3K, Akt, MAPKs, NF-κB, iNOS, and Cox-2. These findings suggest that CP and OA are potential chemokine-based therapeutic substances for treating the lung and airway inflammation seen in allergic disorders.
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Affiliation(s)
| | - Young-Cheol Lee
- Correspondence: ; Tel.: +82-33-730-0672; Fax: +82-33-730-0653
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Zeng L, Sun S, Chen P, Ye Q, Lin X, Wan H, Cai Y, Chen X. Mechanism of Peitu Shengjin Formula Shenlingbaizhu Powder in Treating Bronchial Asthma and Allergic Colitis through Different Diseases with Simultaneous Treatment Based on Network Pharmacology and Molecular Docking. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:4687788. [PMID: 35586697 PMCID: PMC9110165 DOI: 10.1155/2022/4687788] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 03/08/2022] [Accepted: 03/26/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Shenlingbaizhu powder (SLBZP), one of the classic Earth-cultivating and gold-generating prescriptions of traditional Chinese medicine, is widely used to treat various diseases. However, the pharmacological mechanisms of SLBZP on bronchial asthma (BA) and allergic colitis (AC) remain to be elucidated. METHODS Network pharmacology and molecular docking technology were used to explore the potential mechanism of SLBZP in treating BA and AC with the simultaneous treatment of different diseases. The potential active compounds of SLBZP and their corresponding targets were obtained from BATMAN-TCM, ETCM, SymMap TCM@TAIWAN, and TCMSP databases. BA and AC disease targets were collected through DisGeNET, TTD, GeneCards, PharmGKB, OMIM, NCBI, The Human Phenotype Ontology, and DrugBank databases. Common targets for drugs and diseases were screened by using the bioinformatics and evolutionary genomics platform. The analyses and visualizations of Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of common targets were carried out by R software. The key targets were screened by using the plug-in "cytoHubba" of Cytoscape software, and the "active compound-key target" network was constructed. Molecular docking analysis was performed using AutoDock software. The miRTarBase database was used to predict microRNAs (miRNAs) targeting key targets, and the key target-miRNA network was constructed. RESULT Through screening, 246 active compounds and 281 corresponding targets were obtained. Common targets were mainly enriched in 2933 biological processes and 182 signal pathways to play the role of treating BA and AC. There were 131 active compounds related to key targets. The results of molecular docking showed that the important active compounds in SLBZP had good binding ability with the key targets. The key target-miRNA network showed that 94 miRNAs were predicted. CONCLUSION SLBZP has played the role of treating different diseases with the same treatment on BA and AC through the characteristics of multicompound, multitarget, and multipathway of traditional Chinese medicine, which provides a theoretical basis for explaining the mechanism and clinical application of SLBZP treating different diseases with the same treatment in BA and AC.
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Affiliation(s)
- Liying Zeng
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Shaodan Sun
- The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong, China
| | - Peiwen Chen
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Qina Ye
- Guangzhou Women and Children Medical Center, Guangzhou 510623, Guangdong, China
| | - Xiaoling Lin
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Hongjun Wan
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Yawen Cai
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Xiaogang Chen
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
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10
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Zhu J, Li K, Xu L, Cai Y, Chen Y, Zhao X, Li H, Huang G, Jin J. Discovery of novel selective PI3Kγ inhibitors through combining machine learning-based virtual screening with multiple protein structures and bio-evaluation. J Adv Res 2022; 36:1-13. [PMID: 35127160 PMCID: PMC8800018 DOI: 10.1016/j.jare.2021.04.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 04/09/2021] [Accepted: 04/16/2021] [Indexed: 01/10/2023] Open
Abstract
Introduction Phosphoinositide 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of various diseases, and the diverse physiological roles of class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. However, the high structural conservation among the PI3K family makes it a big challenge to develop selective PI3Kγ inhibitors. Objectives A novel machine learning-based virtual screening with multiple PI3Kγ protein structures was developed to discover novel PI3Kγ inhibitors. Methods A large chemical database was screened using the virtual screening model, the top-ranked compounds were then subjected to a series of bio-evaluations, which led to the discovery of JN-KI3. The selective inhibition mechanism of JN-KI3 against PI3Kγ was uncovered by a theoretical study. Results 49 hits were identified through virtual screening, and the cell-free enzymatic studies found that JN-KI3 selectively inhibited PI3Kγ at a concentration as low as 3,873 nM but had no inhibitory effect on Class IA PI3Ks, leading to the selective cytotoxicity on hematologic cancer cells. Meanwhile, JN-KI3 potently blocked the PI3K signaling, finally led to distinct apoptosis of hematologic cell lines at a low concentration. Lastly, the key residues of PI3Kγ and the structural characteristics of JN-KI3, which both would influence γ isoform-selective inhibition, were highlighted by systematic theoretical studies. Conclusion The developed virtual screening model strongly manifests the robustness to find novel PI3Kγ inhibitors. JN-KI3 displays a specific cytotoxicity on hematologic tumor cells, and significantly promotes apoptosis associated with the inhibition of the PI3K signaling, which depicts PI3Kγ as a potential target for the hematologic tumor therapy. The theoretical results reveal that those key residues interacting with JN-KI3 are less common compared to most of the reported PI3Kγ inhibitors, indicating that JN-KI3 has novel structural characteristics as a selective PIK3γ inhibitor.
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Key Words
- ADMET, absorption, distribution, metabolism, excretion, and toxicity
- AKT, protein kinase B
- AUC, area under receiver operations characteristic curve
- Badapple, bioactivity data associative promiscuity pattern learning engine
- CADD, computer-aided drug design
- CDRA, confirmatory dose–response assays
- DMEM, Dulbecco’s Modified Eagle Medium
- DS3.5, discovery studio 3.5
- FBS, fetal bovine serum
- GPCR, G protein-coupled receptors
- H-bond, hydrogen bond
- Hematologic malignancies
- IMDM, Iscove’s Modified Dulbecco’s Medium
- Ionic, ionic interactions
- JN-KI3
- MD, molecular dynamics
- MM/GBSA, molecular mechanics/generalized born surface area
- Molecular dynamics simulation
- NBC, naive Bayesian classifier
- PAGE, polyacrylamide gel electrophoresis
- PAINS, pan-assay interference compounds
- PARP, poly ADP-ribose polymerase
- PDB, protein data bank
- PI3K, Phosphoinositide 3-kinase
- PI3Kγ
- PSA, primary screening assays
- REOS, rapid elimination of swill
- RMSD, root-mean-squared-deviation
- RMSF, root-mean-squared-fluctuation
- ROC, receiver operations characteristic
- RTK, receptor tyrosine kinases
- SD, standard deviation
- SMILES, simplified molecular input line entry specification
- SP, standard precision
- Selective inhibitor
- VS, virtual screening
- Virtual screening
- Water Bridge, hydrogen bonds through water molecular bridge
- XP, extra precision
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Affiliation(s)
- Jingyu Zhu
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Kan Li
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Lei Xu
- Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, China
| | - Yanfei Cai
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yun Chen
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xinling Zhao
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Huazhong Li
- School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 21412 2, China
| | - Gang Huang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Jian Jin
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
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11
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Fagone E, Fruciano M, Gili E, Sambataro G, Vancheri C. Developing PI3K Inhibitors for Respiratory Diseases. Curr Top Microbiol Immunol 2022; 436:437-466. [DOI: 10.1007/978-3-031-06566-8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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12
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Mineral Micronutrients in Asthma. Nutrients 2021; 13:nu13114001. [PMID: 34836256 PMCID: PMC8625329 DOI: 10.3390/nu13114001] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 01/01/2023] Open
Abstract
Asthma represents one of the most common medical issues in the modern world. It is a chronic inflammatory disease characterized by persistent inflammation of the airways and disturbances in redox status, leading to hyperresponsiveness of bronchi and airway obstruction. Apart from classical risk factors such as air pollution, family history, allergies, or obesity, disturbances of the levels of micronutrients lead to impairments in the defense mechanisms of the affected organism against oxidative stress and proinflammatory stimuli. In the present review, the impact of micronutrients on the prevalence, severity, and possible risk factors of asthma is discussed. Although the influence of classical micronutrients such as selenium, copper, or zinc are well known, the effects of those such as iodine or manganese are only rarely mentioned. As a consequence, the aim of this paper is to demonstrate how disturbances in the levels of micronutrients and their supplementation might affect the course of asthma.
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13
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Oh K, Adnan M, Cho D. Uncovering Mechanisms of Zanthoxylum piperitum Fruits for the Alleviation of Rheumatoid Arthritis Based on Network Pharmacology. BIOLOGY 2021; 10:703. [PMID: 34439936 PMCID: PMC8389290 DOI: 10.3390/biology10080703] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/15/2021] [Accepted: 07/21/2021] [Indexed: 12/11/2022]
Abstract
Zanthoxylum piperitum fruits (ZPFs) have been demonstrated favorable clinical efficacy on rheumatoid arthritis (RA), but its compounds and mechanisms against RA have not been elucidated. This study was to investigate the compounds and mechanisms of ZPFs to alleviate RA via network pharmacology. The compounds from ZPFs were detected by gas chromatography-mass spectrometry (GC-MS) and screened to select drug-likeness compounds through SwissADME. Targets associated with bioactive compounds or RA were identified utilizing bioinformatics databases. The signaling pathways related to RA were constructed; interactions among targets; and signaling pathways-targets-compounds (STC) were analyzed by RPackage. Finally, a molecular docking test (MDT) was performed to validate affinity between targets and compounds on key signaling pathway(s). GC-MS detected a total of 85 compounds from ZPFs, and drug-likeness properties accepted all compounds. A total of 216 targets associated with compounds 3377 RA targets and 101 targets between them were finally identified. Then, a bubble chart exhibited that inactivation of MAPK (mitogen-activated protein kinase) and activation of PPAR (peroxisome proliferator-activated receptor) signaling pathway might be key pathways against RA. Overall, this work suggests that seven compounds from ZPFs and eight targets might be multiple targets on RA and provide integrated pharmacological evidence to support the clinical efficacy of ZPFs on RA.
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Affiliation(s)
| | | | - Dongha Cho
- Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea; (K.O.); (M.A.)
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14
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Michalak A, Lach T, Cichoż-Lach H. Oxidative Stress-A Key Player in the Course of Alcohol-Related Liver Disease. J Clin Med 2021; 10:3011. [PMID: 34300175 PMCID: PMC8303854 DOI: 10.3390/jcm10143011] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress is known to be an inseparable factor involved in the presentation of liver disorders. Free radicals interfere with DNA, proteins, and lipids, which are crucial in liver metabolism, changing their expression and biological functions. Additionally, oxidative stress modifies the function of micro-RNAs, impairing the metabolism of hepatocytes. Free radicals have also been proven to influence the function of certain transcriptional factors and to alter the cell cycle. The pathological appearance of alcohol-related liver disease (ALD) constitutes an ideal example of harmful effects due to the redox state. Finally, ethanol-induced toxicity and overproduction of free radicals provoke irreversible changes within liver parenchyma. Understanding the underlying mechanisms associated with the redox state in the course of ALD creates new possibilities of treatment for patients. The future of hepatology may become directly dependent on the effective action against reactive oxygen species. This review summarizes current data on the redox state in the natural history of ALD, highlighting the newest reports on this topic.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
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15
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Zhang F, Ma H, Wang ZL, Li WH, Liu H, Zhao YX. The PI3K/AKT/mTOR pathway regulates autophagy to induce apoptosis of alveolar epithelial cells in chronic obstructive pulmonary disease caused by PM2.5 particulate matter. J Int Med Res 2021; 48:300060520927919. [PMID: 32715876 PMCID: PMC7385846 DOI: 10.1177/0300060520927919] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective Many lung diseases are associated with changes in autophagic activity. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a key regulatory role in autophagy. Our aim was to explore the function of PI3K/AKT/mTOR pathway on autophagy in chronic obstructive pulmonary disease (COPD) caused by particulate matter with a diameter <2.5 µm (PM2.5). Methods Male C57BL/6 mice were randomly divided into sham, model, and PI3K inhibitor groups. Mice were exposed to PM2.5 for 4 weeks to establish an in vivo COPD model. Alveolar epithelial cells were stimulated with PM2.5 to establish an in vitro COPD model. Results In mice with COPD induced by PM2.5, the PI3K inhibitor PF-04979064 suppressed protein expression of PI3K, p-AKT, and p-mTOR to increase apoptosis of alveolar epithelial cells and reduce autophagy. Short interfering PI3K suppressed the PI3K/AKT/mTOR pathway to induce apoptosis and reduce autophagy of alveolar epithelial cells in an in vitro model of COPD. Activation of PI3K induced the PI3K/AKT/mTOR pathway to reduce apoptosis of alveolar epithelial cells in the in vitro model of COPD by promoting autophagy. Conclusions These data demonstrate that PI3K/AKT/mTOR pathway regulates autophagy to induce apoptosis of alveolar epithelial cells in COPD.
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Affiliation(s)
- Fang Zhang
- Department of Respiration, Gansu Province People Hospital, Lanzhou City, Gansu Province, China
| | - Hui Ma
- Department of Respiratory, Gansu Province People Hospital, Lanzhou City, Gansu Province, China
| | - Zhong Lan Wang
- Department of Respiratory Diseases, Gansu Province People Hospital, Lanzhou City, Gansu Province, China
| | - Wei Hua Li
- Department of Central Laboratory, Gansu Province People Hospital, Lanzhou City, Gansu Province, China
| | - Hua Liu
- Department of Respiration, Gansu Province People Hospital, Lanzhou City, Gansu Province, China
| | - Yan Xia Zhao
- Department of Respiration, Gansu Province People Hospital, Lanzhou City, Gansu Province, China
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16
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Govindammal M, Prasath M, Kamaraj S, Muthu S, Selvapandiyan M. Exploring the molecular structure, vibrational spectroscopic, quantum chemical calculation and molecular docking studies of curcumin: A potential PI3K/AKT uptake inhibitor. Heliyon 2021; 7:e06646. [PMID: 33898809 PMCID: PMC8056428 DOI: 10.1016/j.heliyon.2021.e06646] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/16/2021] [Accepted: 03/26/2021] [Indexed: 02/07/2023] Open
Abstract
The IUPAC name of curcumin is (1E, 6E)-1,7-Bis(4-hydroxy-3methoxyphenyl) hepta-1,6-e-3,5-dione (7B3M5D) and is characterized by spectroscopic profiling with FT-IR and FT-Raman spectra obtained both experimentally and theoretically. PED analysis was done for the confirmation of minimum energy obtained in the title compound. Optimized geometrical parameters are compared with experimental values obtained for 7B3M5D by utilizing B3LYP functional employing 6–311++G (d,p) level of theory. The HOMO-LUMO, MEP, and Fukui function analysis has been used to elucidate the information regarding charge transfer within the molecule. The stabilization energy and charge delocalization of the 7B3M5D were performed by NBO analysis. This article assesses that the title compound act as a potential inhibitor of the PI3K/AKT inhibitor through in silico studies, like molecular docking, molecular dynamics (MD), ADMET prediction and also this molecule obeys Lipinski's rule of five. 7B3M5D was docked effectively in the active site of PI3K/AKT inhibitor.
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Affiliation(s)
- M Govindammal
- Department of Physics, Periyar University PG Extension Centre, Dharmapuri, 636701, India
| | - M Prasath
- Department of Physics, Periyar University PG Extension Centre, Dharmapuri, 636701, India
| | - S Kamaraj
- Department of Biotechnology, Periyar University PG Extension Centre, Dharmapuri, India
| | - S Muthu
- Department of Physics, Arignar Anna Govt. Arts College, Cheyyar, 604407, Tamilnadu, India
| | - M Selvapandiyan
- Department of Physics, Periyar University PG Extension Centre, Dharmapuri, 636701, India
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17
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Adefemi F, Fruman DA, Marshall AJ. A Case for Phosphoinositide 3-Kinase-Targeted Therapy for Infectious Disease. THE JOURNAL OF IMMUNOLOGY 2021; 205:3237-3245. [PMID: 33288538 DOI: 10.4049/jimmunol.2000599] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 08/22/2020] [Indexed: 12/19/2022]
Abstract
PI3Ks activate critical signaling cascades and have multifaceted regulatory functions in the immune system. Loss-of-function and gain-of-function mutations in the PI3Kδ isoform have revealed that this enzyme can substantially impact immune responses to infectious agents and their products. Moreover, reports garnered from decades of infectious disease studies indicate that pharmacologic inhibition of the PI3K pathway could potentially be effective in limiting the growth of certain microbes via modulation of the immune system. In this review, we briefly highlight the development and applications of PI3K inhibitors and summarize data supporting the concept that PI3Kδ inhibitors initially developed for oncology have immune regulatory potential that could be exploited to improve the control of some infectious diseases. This repurposing of existing kinase inhibitors could lay the foundation for alternative infectious disease therapy using available therapeutic agents.
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Affiliation(s)
- Folayemi Adefemi
- Department of Immunology, Rady Faculty of Health Sciences, University of Manitoba, R3E-0T5 Winnipeg, Manitoba, Canada
| | - David A Fruman
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; and.,Institute for Immunology, University of California, Irvine, CA 92697
| | - Aaron J Marshall
- Department of Immunology, Rady Faculty of Health Sciences, University of Manitoba, R3E-0T5 Winnipeg, Manitoba, Canada;
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18
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Zhou W, Chen Z, Lu A, Liu Z. Systems Pharmacology-Based Strategy to Explore the Pharmacological Mechanisms of Citrus Peel (Chenpi) for Treating Complicated Diseases. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2021; 49:391-411. [PMID: 33622210 DOI: 10.1142/s0192415x2150018x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Citri Reticulatae Pericarpium (CRP), also known as Chenpi in Chinese, is the dry mature peel of Citrus reticulata Blanco or its cultivated varieties. CRP as the health-care food and dietary supplement has been widely used in various diseases. However, the potential pharmacological mechanisms of CRP to predict and treat various diseases have not yet been fully elucidated. A systems pharmacology-based approach is developed by integrating absorption, distribution, metabolism, and excretion screening, multiple target fishing, network pharmacology, as well as pathway analysis to comprehensively dissect the potential mechanism of CRP for therapy of various diseases. The results showed that 39 bioactive components and 121 potential protein targets were identified from CRP. The 121 targets are closely related to various diseases of the cardiovascular system, respiratory system, gastrointestinal system, etc. These targets are further mapped to compound-target, target-disease, and target-pathway networks to clarify the therapeutic mechanism of CRP at the system level. The current study sheds light on a promising way for promoting the discovery of new botanical drugs.
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Affiliation(s)
- Wei Zhou
- Department of Respirology & Allergy, Third Affiliated Hospital of Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, Shenzhen, P. R. China.,State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, Shenzhen, P. R. China
| | - Ziyi Chen
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, P. R. China
| | - Aiping Lu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong, P. R. China
| | - Zhigang Liu
- Department of Respirology & Allergy, Third Affiliated Hospital of Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, Shenzhen, P. R. China.,State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, Shenzhen, P. R. China
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19
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Zhu J, Li K, Yu L, Chen Y, Cai Y, Jin J, Hou T. Targeting phosphatidylinositol 3-kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors. Med Res Rev 2020; 41:1599-1621. [PMID: 33300614 DOI: 10.1002/med.21770] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 10/13/2020] [Accepted: 11/29/2020] [Indexed: 12/11/2022]
Abstract
Phosphatidylinositol 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of advanced solid tumors, leukemia, lymphoma, and inflammatory and autoimmune diseases. However, the high level of structural conservation among the members of the PI3K family and the diverse physiological roles of Class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. In this review, we provide an overview of the structural features of PI3Kγ that influence γ-isoform selectivity and discuss the structure-selectivity-activity relationship of existing clinical PI3Kγ inhibitors. Additionally, we summarize the experimental and computational techniques utilized to identify PI3Kγ inhibitors. The insights gained so far could be used to overcome the main challenges in development and accelerate the discovery of PI3Kγ-selective inhibitors.
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Affiliation(s)
- Jingyu Zhu
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Kan Li
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Li Yu
- School of Inspection and Testing Certification, Changzhou Vocational Institute of Engineering, Changzhou, Jiangsu, China
| | - Yun Chen
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Yanfei Cai
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Jian Jin
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Tingjun Hou
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
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20
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Oxidative stress in alcohol-related liver disease. World J Hepatol 2020. [DOI: 10.4254/wjh.v12.i7.333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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21
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Tan HK, Yates E, Lilly K, Dhanda AD. Oxidative stress in alcohol-related liver disease. World J Hepatol 2020; 12:332-349. [PMID: 32821333 PMCID: PMC7407918 DOI: 10.4254/wjh.v12.i7.332] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/06/2020] [Accepted: 05/17/2020] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption is one of the leading causes of the global burden of disease and results in high healthcare and economic costs. Heavy alcohol misuse leads to alcohol-related liver disease, which is responsible for a significant proportion of alcohol-attributable deaths globally. Other than reducing alcohol consumption, there are currently no effective treatments for alcohol-related liver disease. Oxidative stress refers to an imbalance in the production and elimination of reactive oxygen species and antioxidants. It plays important roles in several aspects of alcohol-related liver disease pathogenesis. Here, we review how chronic alcohol use results in oxidative stress through increased metabolism via the cytochrome P450 2E1 system producing reactive oxygen species, acetaldehyde and protein and DNA adducts. These trigger inflammatory signaling pathways within the liver leading to expression of pro-inflammatory mediators causing hepatocyte apoptosis and necrosis. Reactive oxygen species exposure also results in mitochondrial stress within hepatocytes causing structural and functional dysregulation of mitochondria and upregulating apoptotic signaling. There is also evidence that oxidative stress as well as the direct effect of alcohol influences epigenetic regulation. Increased global histone methylation and acetylation and specific histone acetylation inhibits antioxidant responses and promotes expression of key pro-inflammatory genes. This review highlights aspects of the role of oxidative stress in disease pathogenesis that warrant further study including mitochondrial stress and epigenetic regulation. Improved understanding of these processes may identify novel targets for therapy.
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Affiliation(s)
- Huey K Tan
- Hepatology Research Group, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, United Kingdom
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, United Kingdom
| | - Euan Yates
- Hepatology Research Group, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, United Kingdom
| | - Kristen Lilly
- Hepatology Research Group, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, United Kingdom
- Department of Clinical Immunology, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, United Kingdom
| | - Ashwin D Dhanda
- Hepatology Research Group, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, United Kingdom
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, United Kingdom
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Sun XJ, Li ZH, Zhang Y, Zhong XN, He ZY, Zhou JH, Chen SN, Feng Y. Theophylline and dexamethasone in combination reduce inflammation and prevent the decrease in HDAC2 expression seen in monocytes exposed to cigarette smoke extract. Exp Ther Med 2020; 19:3425-3431. [PMID: 32269608 PMCID: PMC7138918 DOI: 10.3892/etm.2020.8584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 09/20/2019] [Indexed: 12/12/2022] Open
Abstract
Lung and systemic inflammation are associated with impaired lung function and increased mortality in patients with chronic obstructive pulmonary disease (COPD). Theophylline and glucocorticoids have been shown to have an anti-inflammatory effect in some respiratory diseases. However, corticosteroid insensitivity is a major barrier to the anti-inflammatory management of COPD. This study aimed to explore whether a combined treatment of theophylline and dexamethasone (Dex) could decrease cigarette smoke extract (CSE)-induced inflammation via prevention of a reduction in histone deacetylase 2 (HDAC2) expression and through inhibition of the PI3K/Akt pathway, which may be related to corticosteroid sensitivity. The half-maximal inhibitory concentration (IC50) of Dex (IC50-Dex) was used to as a marker of corticosteroid sensitivity. IC50-Dex was determined through observation of Dex inhibition of tumor necrosis factor-α (TNF-α)-induced interleukin (IL)-8 release. Using reverse transcription quantitative PCR and western blotting, U937 cells treated with CSE were assessed for HDAC2 expression levels and phosphorylation levels of Akt. Theophylline and Dex pre-treatment was shown to significantly reduce the CSE-induced release of IL-8 and TNF-α. The combination of theophylline and Dex pretreatment also reversed corticosteroid insensitivity in CSE-induced U937 cells and inhibited the PI3K/AKT pathway to a greater extent than theophylline treatment alone. CSE-treated U937 cells showed a reduction in HDAC2 mRNA and protein expression compared with the control group. However, this effect was reduced after pre-incubation with the combined therapy or theophylline alone. In conclusion, pretreatment with theophylline and Dex decreased CSE-induced inflammation via inhibition of the PI3K/Akt pathway and increase in HDAC2 protein expression.
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Affiliation(s)
- Xue-Jiao Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
- Department of Respiratory and Critical Care Medicine, Liuzhou People's Hospital, Liuzhou, Guangxi 545006, P.R. China
| | - Zhan-Hua Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
- Department of Respiratory Medicine, Ruikang Hospital Affiliated to Guangxi Traditional Chinese Medicine University, Nanning, Guangxi 530021, P.R. China
| | - Yang Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiao-Ning Zhong
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Zhi-Yi He
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Ji-Hong Zhou
- Department of Respiratory Medicine, Ruikang Hospital Affiliated to Guangxi Traditional Chinese Medicine University, Nanning, Guangxi 530021, P.R. China
| | - Si-Ning Chen
- Department of Respiratory Medicine, Ruikang Hospital Affiliated to Guangxi Traditional Chinese Medicine University, Nanning, Guangxi 530021, P.R. China
| | - Yuan Feng
- Department of Respiratory Medicine, Ruikang Hospital Affiliated to Guangxi Traditional Chinese Medicine University, Nanning, Guangxi 530021, P.R. China
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Kim SR, Park HJ, Lee KB, Kim HJ, Jeong JS, Cho SH, Lee YC. Epithelial PI3K-δ Promotes House Dust Mite-Induced Allergic Asthma in NLRP3 Inflammasome-Dependent and -Independent Manners. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2020; 12:338-358. [PMID: 32009326 PMCID: PMC6997282 DOI: 10.4168/aair.2020.12.2.338] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/04/2019] [Accepted: 11/22/2019] [Indexed: 01/23/2023]
Abstract
PURPOSE Phosphoinositide 3-kinase (PI3K)-δ-dependent Akt activation is known to play critical roles in various immune responses of white blood cells in which PI3K-δ isoform is mostly expressed in contrast to the classes IA PI3Ks p110α and p110β. However, the immunological role of PI3K-δ isoform is still controversial in airway epithelium under house dust mite (HDM)-induced allergic response. This study aimed to evaluate the role of PI3K-δ isoform in HDM-induced allergic responses, focusing on NLRP3 inflammasome activation in airway epithelium. METHODS We used wild-type mice and PI3K-δ knock-out (KO) mice for HDM-induced asthma animal model and also performed in vitro experiments using primary cultured murine tracheal epithelial cells and human airway epithelial cells. RESULTS PI3K-δ activated HDM-induced NLRP3 inflammasome and epithelial cell-derived cytokines in the lung including airway epithelial cells. PI3K-δ KO mice or knock-down of PI3K-δ using siRNA exhibited the significant reduction in allergic asthmatic features and the suppression of NLRP3 inflammasome assembly as well as epithelial cell-derived cytokines. Interestingly, significantly increased expression of PI3K-δ isoform was observed in stimulated airway epithelial cells and the increases in epithelial cell-derived cytokines were markedly suppressed by blocking PI3K-δ, while these cytokine levels were independent of NLRP3 inflammasome activation. CONCLUSIONS The results of this study suggest that PI3K-δ-isoform can promote HDM-induced allergic airway inflammation via NLRP3 inflammasome-dependent response as well as via NLRP3 inflammasome-independent epithelial cell activation.
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Affiliation(s)
- So Ri Kim
- Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea.,Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Korea.
| | - Hae Jin Park
- Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea
| | - Kyung Bae Lee
- Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea
| | - Hee Jung Kim
- Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea
| | - Jae Seok Jeong
- Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea
| | - Seong Ho Cho
- Division of Allergy and Immunology, Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Yong Chul Lee
- Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea. .,Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Korea.
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24
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System level characterization of small molecule drugs and their affected long noncoding RNAs. Aging (Albany NY) 2019; 11:12428-12451. [PMID: 31852840 PMCID: PMC6949102 DOI: 10.18632/aging.102581] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 11/26/2019] [Indexed: 02/06/2023]
Abstract
Long noncoding RNAs (lncRNAs) have multiple regulatory roles and are involved in many human diseases. A potential therapeutic strategy based on targeting lncRNAs was recently developed. To gain insight into the global relationship between small molecule drugs and their affected lncRNAs, we constructed a small molecule lncRNA network consisting of 1206 nodes (1033 drugs and 173 lncRNAs) and 4770 drug-lncRNA associations using LNCmap, which reannotated the microarray data from the Connectivity Map (CMap) database. Based on network biology, we found that the connected drug pairs tended to share the same targets, indications, and side effects. In addition, the connected drug pairs tended to have a similar structure. By inferring the functions of lncRNAs through their co-expressing mRNAs, we found that lncRNA functions related to the modular interface were associated with the mode of action or side effects of the corresponding connected drugs, suggesting that lncRNAs may directly/indirectly participate in specific biological processes after drug administration. Finally, we investigated the tissue-specificity of drug-affected lncRNAs and found that some kinds of drugs tended to have a broader influence (e.g. antineoplastic and immunomodulating drugs), whereas some tissue-specific lncRNAs (nervous system) tended to be affected by multiple types of drugs.
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25
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Pirozzi F, Ren K, Murabito A, Ghigo A. PI3K Signaling in Chronic Obstructive Pulmonary Disease: Mechanisms, Targets, and Therapy. Curr Med Chem 2019; 26:2791-2800. [DOI: 10.2174/0929867325666180320120054] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 02/20/2018] [Accepted: 03/06/2018] [Indexed: 12/31/2022]
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder characterized by irreversible chronic inflammation and airflow obstruction. It affects more than 64 million patients worldwide and it is predicted to become the third cause of death in the industrialized world by 2030. Currently available therapies are not able to block disease progression and to reduce mortality, underlying the need for a better understanding of COPD pathophysiological mechanisms to identify new molecular therapeutic targets. Recent studies demonstrated that phosphoinositide 3-kinase (PI3K) signaling is prominently activated in COPD and correlates with an increased susceptibility of patients to lung infections. PI3Ks have thus emerged as promising alternative drug targets for COPD and a wide array of pan-isoform and isoform-selective inhibitors have been tested in preclinical models and are currently being evaluated in clinical studies. Here, we summarize the recent knowledge on the involvement of PI3K enzymes in the pathophysiology of COPD, and we discuss the most recent results arising from the preclinical as well as the clinical testing of PI3K inhibitors as novel therapeutics for COPD.
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Affiliation(s)
- Flora Pirozzi
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Kai Ren
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Alessandra Murabito
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Alessandra Ghigo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
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26
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Li K, Zhu J, Xu L, Jin J. Rational Design of Novel Phosphoinositide 3-Kinase Gamma (PI3Kγ) Selective Inhibitors: A Computational Investigation Integrating 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation. Chem Biodivers 2019; 16:e1900105. [PMID: 31111650 DOI: 10.1002/cbdv.201900105] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/20/2019] [Indexed: 11/08/2022]
Abstract
Phosphoinositide 3-kinase gamma (PI3Kγ) draws an increasing attention due to its link with deadly cancer, chronic inflammation and allergy. But the development of PI3Kγ selective inhibitors is still a challenging endeavor because of the high sequence homology with the other PI3K isoforms. In order to acquire valuable information about the interaction mechanism between potent inhibitors and PI3Kγ, a series of PI3Kγ isoform-selective inhibitors were analyzed by a systematic computational method, combining 3D-QSAR, molecular docking, molecular dynamic (MD) simulations, free energy calculations and decomposition. The general structure-activity relationships were revealed and some key residues relating to selectivity and high activity were highlighted. It provides precious guidance for rational virtual screening, modification and design of selective PI3Kγ inhibitors. Finally, ten novel inhibitors were optimized and P10 showed satisfactory predicted bioactivity, demonstrating the feasibility to develop potent PI3Kγ inhibitors through this computational modeling and optimization.
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Affiliation(s)
- Kan Li
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, P. R. China
| | - Jingyu Zhu
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, P. R. China
| | - Lei Xu
- Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, P. R. China
| | - Jian Jin
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, P. R. China
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Sullivan CR, Mielnik CA, O'Donovan SM, Funk AJ, Bentea E, DePasquale EA, Alganem K, Wen Z, Haroutunian V, Katsel P, Ramsey AJ, Meller J, McCullumsmith RE. Connectivity Analyses of Bioenergetic Changes in Schizophrenia: Identification of Novel Treatments. Mol Neurobiol 2019; 56:4492-4517. [PMID: 30338483 PMCID: PMC7584383 DOI: 10.1007/s12035-018-1390-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 10/11/2018] [Indexed: 01/21/2023]
Abstract
We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n = 16) and control (n = 16) and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of "reversing" the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens, may be employed to identify novel treatment strategies for schizophrenia and related diseases.
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Affiliation(s)
| | - Catharine A Mielnik
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | | | - Adam J Funk
- Department of Neuroscience, University of Toledo, Toledo, OH, USA
| | - Eduard Bentea
- Neurosciences TA Biology, UCB BioPharma SPRL, Braine-l'Alleud, Belgium
| | - Erica A DePasquale
- Department of Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Khaled Alganem
- Department of Neuroscience, University of Toledo, Toledo, OH, USA
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
| | - Vahram Haroutunian
- Department of Psychiatry and Neuroscience, The Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Pavel Katsel
- Department of Psychiatry and Neuroscience, The Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Amy J Ramsey
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Jarek Meller
- Department of Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Department of Electrical Engineering and Computer Science, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Department of Informatics, Nicolaus Copernicus University, Torun, Poland
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Al-Sha'er MA, Al-Aqtash RA, Taha MO. Discovery of New Phosphoinositide 3-kinase Delta (PI3Kδ) Inhibitors via Virtual Screening using Crystallography-derived Pharmacophore Modelling and QSAR Analysis. Med Chem 2019; 15:588-601. [PMID: 30799792 DOI: 10.2174/1573406415666190222125333] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/31/2019] [Accepted: 02/07/2019] [Indexed: 01/29/2023]
Abstract
BACKGROUND PI3Kδ is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3Kδ inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3Kδ binding. METHODS Seventeen PI3Kδ crystallographic complexes were used to extract 94 pharmacophore models. QSAR modelling was subsequently used to select the superior pharmacophore(s) that best explain bioactivity variation within a list of 79 diverse inhibitors (i.e., upon combination with other physicochemical descriptors). RESULTS The best QSAR model (r2 = 0.71, r2 LOO = 0.70, r2 press against external testing list of 15 compounds = 0.80) included a single crystallographic pharmacophore of optimal explanatory qualities. The resulting pharmacophore and QSAR model were used to screen the National Cancer Institute (NCI) database for new PI3Kδ inhibitors. Two hits showed low micromolar IC50 values. CONCLUSION Crystallography-based pharmacophores were successfully combined with QSAR analysis for the identification of novel PI3Kδ inhibitors.
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Affiliation(s)
- Mahmoud A Al-Sha'er
- Faculty of Pharmacy, Zarqa University, P.O. Box 132222, Zarqa, 13132, Jordan
| | - Rua'a A Al-Aqtash
- Faculty of Pharmacy, Zarqa University, P.O. Box 132222, Zarqa, 13132, Jordan
| | - Mutasem O Taha
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, Jordan
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29
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Mao S, Wu L, Shi W. Association between trace elements levels and asthma susceptibility. Respir Med 2018; 145:110-119. [PMID: 30509699 DOI: 10.1016/j.rmed.2018.10.028] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 10/22/2018] [Accepted: 10/24/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND It is well-documented that the dysregulation of trace elements may be involved in the pathogenesis of asthma. However, the precise changes of trace elements levels in asthma cases remain elusive. We established whether trace elements levels were associated with asthma susceptibility by pooling case-control studies. METHODS 34 studies were included. We extracted the standard mean differences (SMDs) and corresponding 95% confidence intervals (CIs). A pooled-analysis was performed. RESULTS No marked difference (95% CI: -1.437-0.218, p = 0.149) of Se level between asthma and controls. Significant difference (95% CI: 0.112-1.032, p = 0.015; 95% CI: 0.376-1.331, p < 10-4) of Cu level between asthma and controls was noted among overall populations and Asians. No marked difference of Zn level between asthma and controls was observed among overall populations, Asians, Caucasians and Africans. Significant difference (95% CI: -0.567 to -0.238, p < 10-4) of Mg level between asthma and controls was noted among Asians. Marked difference (95% CI: 0.258-2.864, p = 0.019; 95% CI: 0.270-3.282, p = 0.021) of Fe level between asthma and controls was noted among overall populations and Asians. Age had no impact on the pooled SMDs of Se, Cu, Zn, Mg and Fe between asthma and controls. Sensitivity analyses did not change the overall results. No publication bias was noted for overall populations. CONCLUSIONS Alterations of Cu, Mg and Fe levels may be a biomarker of asthma risk among specific populations. Further studies should be performed to clarify the strength of these elements in asthma.
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Affiliation(s)
- Song Mao
- Department of Pediatrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
| | - Liangxia Wu
- Department of Pediatrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
| | - Wenjing Shi
- Department of Pediatrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
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30
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Ino H, Wilson R, Terao T, Ogura H, Igarashi H, Cahn A, Numachi Y. Evaluation of the Safety, Tolerability, and Pharmacokinetics of GSK2269557 (Nemiralisib) Administered Via Dry Powder Inhaler to Healthy Japanese Subjects. Clin Pharmacol Drug Dev 2018; 8:78-86. [DOI: 10.1002/cpdd.614] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 08/02/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Hiroko Ino
- Medicines Development (Clinical Pharmacology Office); Japan Development Division; GlaxoSmithKline K.K.; Tokyo Japan
| | - Robert Wilson
- Clinical Pharmacology Modelling and Simulation; Medicine's Research Centre; GlaxoSmithKline; Stevenage Hertfordshire UK
| | - Takumi Terao
- Biomedical Data Sciences Department; Japan Development Division; GlaxoSmithKline K.K.; Tokyo Japan
| | - Hirofumi Ogura
- Medicines Development (Clinical Pharmacology Office); Japan Development Division; GlaxoSmithKline K.K.; Tokyo Japan
| | - Harue Igarashi
- Pre-Clinical Development; Japan Development Division; GlaxoSmithKline K.K.; Tokyo Japan
| | - Anthony Cahn
- Pharma Research & Development; Respiratory TAU; GlaxoSmithKline; Stevenage UK
| | - Yotaro Numachi
- Medicines Development; Japan Development Division; GlaxoSmithKline K.K.; Tokyo Japan
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31
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Sui X, Yu J, Wu J, Guo L, Shi X. Network and Pathway-Based Prioritization and Analyses of Genes Related to Chronic Obstructive Pulmonary Disease. CYTOLOGIA 2018. [DOI: 10.1508/cytologia.83.251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Xiaojun Sui
- Department of Respiration, Weihai Central Hospital
| | - Junfang Yu
- Department of Respiration, Weihai Central Hospital
| | - Jingbo Wu
- Department of Respiration, Weihai Central Hospital
| | - Lijuan Guo
- Department of Respiration, Weihai Central Hospital
| | - Xinjie Shi
- Department of Respiration, Weihai Central Hospital
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Galeone C, Scelfo C, Bertolini F, Caminati M, Ruggiero P, Facciolongo N, Menzella F. Precision Medicine in Targeted Therapies for Severe Asthma: Is There Any Place for "Omics" Technology? BIOMED RESEARCH INTERNATIONAL 2018; 2018:4617565. [PMID: 29992143 PMCID: PMC6016214 DOI: 10.1155/2018/4617565] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/23/2018] [Accepted: 05/17/2018] [Indexed: 12/28/2022]
Abstract
According to the current guidelines, severe asthma still represents a controversial topic in terms of definition and management. The introduction of novel biological therapies as a treatment option for severe asthmatic patients paved the way to a personalized approach, which aims at matching the appropriate therapy with the different asthma phenotypes. Traditional asthma phenotypes have been decomposing by an increasing number of asthma subclasses based on functional and physiopathological mechanisms. This is possible thanks to the development and application of different omics technologies. The new asthma classification patterns, particularly concerning severe asthma, include an increasing number of endotypes that have been identified using new omics technologies. The identification of endotypes provides new opportunities for the management of asthma symptoms, but this implies that biological therapies which target inflammatory mediators in the frame of specific patterns of inflammation should be developed. However, the pathway leading to a precision approach in asthma treatment is still at its beginning. The aim of this review is providing a synthetic overview of the current asthma management, with a particular focus on severe asthma, in the light of phenotype and endotype approach, and summarizing the current knowledge about "omics" science and their therapeutic relevance in the field of bronchial asthma.
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Affiliation(s)
- Carla Galeone
- Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia-IRCCS, Viale Amendola 2, 42122 Reggio Emilia, Italy
| | - Chiara Scelfo
- Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia-IRCCS, Viale Amendola 2, 42122 Reggio Emilia, Italy
| | - Francesca Bertolini
- Department of Bio and Health Informatics, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
| | - Marco Caminati
- Asthma Center and Allergy Unit, Verona University Hospital, Piazzale L.A. Scuro, 37134 Verona, Italy
| | - Patrizia Ruggiero
- Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia-IRCCS, Viale Amendola 2, 42122 Reggio Emilia, Italy
| | - Nicola Facciolongo
- Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia-IRCCS, Viale Amendola 2, 42122 Reggio Emilia, Italy
| | - Francesco Menzella
- Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia-IRCCS, Viale Amendola 2, 42122 Reggio Emilia, Italy
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Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors. Eur J Med Chem 2018; 151:9-17. [DOI: 10.1016/j.ejmech.2018.03.068] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/22/2018] [Accepted: 03/22/2018] [Indexed: 01/09/2023]
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Yanagisawa S, Baker JR, Vuppusetty C, Koga T, Colley T, Fenwick P, Donnelly LE, Barnes PJ, Ito K. The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure. PLoS One 2018; 13:e0193921. [PMID: 29509781 PMCID: PMC5839577 DOI: 10.1371/journal.pone.0193921] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 02/21/2018] [Indexed: 12/18/2022] Open
Abstract
SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.
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Affiliation(s)
- Satoru Yanagisawa
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Jonathan R. Baker
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Chaitanya Vuppusetty
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Takeshi Koga
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Thomas Colley
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Peter Fenwick
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Louise E. Donnelly
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Peter J. Barnes
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Kazuhiro Ito
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
- * E-mail:
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Chiang PC, Sutherlin D, Pang J, Salphati L. Investigation of Dose-Dependent Factors Limiting Oral Bioavailability: Case Study With the PI3K-δ Inhibitor. J Pharm Sci 2017; 105:1802-1809. [PMID: 27238480 DOI: 10.1016/j.xphs.2016.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 03/31/2016] [Accepted: 04/01/2016] [Indexed: 11/20/2022]
Abstract
It is understood that a potential issue for drugs with poor aqueous solubility is low oral absorption. If oral exposure issues arise when working with a low solubility drug candidate, the common action is to rely on enabling formulations to solve the issue. However, this approach becomes troublesome in the pre-clinical setting where compound absorption, distribution, metabolism, excretion properties are suboptimal and more factors limiting bioavailability may be at play. A narrow focus on solubility enhancement without a full understanding of compound absorption, distribution, metabolism, excretion properties can produce data that cloak the actual phenomena driving exposure. Compound 1 is a potent and selective PI3Kdelta inhibitor with poor aqueous solubility. In a pharmacokinetic study on dogs, exposure was found to be less than dose-linear. Besides the solubility, further investigations were conducted to identify other factors limiting oral exposure. It was observed that these limiting factors are dose dependent. Results from modeling pharmacokinetic under low-dose conditions suggest that exposure is significantly limited by metabolism and no exposure improvements should be expected from enabled formulations. Furthermore, enabling formulations are expected to exert a beneficial influence at higher doses. An in vivo test was conducted in dogs to verify this phenomenon.
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Affiliation(s)
- Po-Chang Chiang
- Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, California 94080.
| | - Daniel Sutherlin
- Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, California 94080
| | - Jodie Pang
- Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, California 94080
| | - Laurent Salphati
- Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, California 94080
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Zhou LF, Chen QZ, Yang CT, Fu ZD, Zhao ST, Chen Y, Li SN, Liao L, Zhou YB, Huang JR, Li JH. TRPC6 contributes to LPS-induced inflammation through ERK1/2 and p38 pathways in bronchial epithelial cells. Am J Physiol Cell Physiol 2017; 314:C278-C288. [PMID: 29141922 DOI: 10.1152/ajpcell.00117.2017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
receptor potential canonical (TRPC) channels are presently an emerging target for airway disorders. Recent evidence has indicated that TRPC6 as a member of the TRPC family plays an important role in airway inflammation, but its precise function in bronchial epithelial cells remains unclear. The aim of this study was to investigate the role of TRPC6 in Toll-like receptor 4 (TLR4)-mediated inflammation in human bronchial epithelial cells stimulated by endotoxin [lipopolysaccharide (LPS)]. Hyp9 is a simplified phloroglucinol derivative of hyperforin that highly selectively activates TRPC6 channels. The results show that the activation of TRPC6 by Hyp9 induced the production of interleukin (IL)-8 and IL-6. LPS was also able to induce the release of IL-8 and IL-6, which was significantly aggravated by Hyp9 and reduced by knockdown of TRPC6. Treatment with LPS not only chronically induced the expression of TRPC6 mRNA and protein in a TLR4-dependent manner but also acutely increased Ca2+ influx through TRPC6 channels. In addition, LPS-induced overexpression of TRPC6 and Ca2+ influx were associated with the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt. Importantly, TRPC6 was required for the activation of ERK1/2, p38, and NF-κB. In conclusion, these data reveal that LPS induced the overexpression of TRPC6 and TRPC6-dependent Ca2+ influx via the TLR4/PI3K/Akt pathway resulting in Ca2+ mobilization, which subsequently promoted the activation of ERK1/2, p38, and NF-κB and the inflammatory response in bronchial epithelial cells.
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Affiliation(s)
- Li-Fen Zhou
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Qing-Zi Chen
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Chun-Tao Yang
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Zhao-Di Fu
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Shen-Ting Zhao
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Yan Chen
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Shu-Ni Li
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Li Liao
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Yu-Bo Zhou
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
| | - Jian-Rong Huang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University , Guangzhou , China
| | - Jian-Hua Li
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital and Institute, Guangzhou Medical University , Guangzhou , China
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Sawa K, Koh Y, Kawaguchi T, Kambayashi S, Asai K, Mitsuoka S, Kimura T, Yoshimura N, Yoshimoto N, Kubo A, Saka H, Matsumura A, Wanibuchi H, Yamamoto N, Nishiyama N, Hirata K. PIK3CA mutation as a distinctive genetic feature of non-small cell lung cancer with chronic obstructive pulmonary disease: A comprehensive mutational analysis from a multi-institutional cohort. Lung Cancer 2017; 112:96-101. [PMID: 29191607 DOI: 10.1016/j.lungcan.2017.07.039] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/28/2017] [Accepted: 07/31/2017] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) have been proposed to have a mutual developmental mechanism, but their association has not been fully understood. We aimed to examine the association of the mutational landscape of NSCLC with co-morbid COPD. MATERIALS AND METHODS A total of 197 surgical specimens of early stage NSCLC were retrospectively collected from two independent sources, namely, the Japan Molecular Epidemiology for Lung Cancer Study and the Osaka City University Hospital cohort from 2010 to 2013. COPD and its severity were defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines and grading system. For molecular profiling of NSCLC patients with COPD, the extracted DNAs were deep-sequenced using next generation sequence technologies for somatic mutations in a maximum 72 cancer-associated genes. Logistic regression analysis was performed to evaluate the impact of COPD on the somatic mutations. RESULTS The COPD group (n=77), including 56 GOLD 1 and 21 GOLD 2 or 3 patients, had 58 squamous cell lung carcinoma (SCC) cases and 19 adenocarcinoma cases. The non-COPD group (n=120) had 53 SCC cases, 64 adenocarcinoma cases, and three cases with other histology. The frequency of PIK3CA mutation was significantly higher in the COPD group than in the non-COPD group (10.4% vs. 1.7%, p=0.015). Meanwhile, NFE2L2 mutation was observed only in SCC cases, with no difference in the frequency between the two groups (17.2% vs. 17.0%). In the multivariate logistic regression model with consideration for COPD status, age, smoking dose, pathological stage, and histology, significantly more PIK3CA mutation was observed in the presence of COPD (odds ratio=5.31, 95% CI: 1.03-27.29, p=0.046). CONCLUSIONS PIK3CA mutation is a distinctive genetic feature of NSCLC with COPD, regardless of age, smoking dose, pathological stage, and histology.
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Affiliation(s)
- Kenji Sawa
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Yasuhiro Koh
- Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Tomoya Kawaguchi
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.
| | - Satoshi Kambayashi
- Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kazuhisa Asai
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Shigeki Mitsuoka
- Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Tatsuo Kimura
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Naruo Yoshimura
- Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Naoki Yoshimoto
- Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Akihito Kubo
- Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi, Japan
| | - Hideo Saka
- Department of Respiratory Medicine and Medical Oncology, Japanese National Hospital Organization, Nagoya Medical Center, Nagoya, Japan
| | - Akihide Matsumura
- Department of Surgery, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Japan
| | - Hideki Wanibuchi
- Department of Molecular Pathology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Nobuyuki Yamamoto
- Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Noritoshi Nishiyama
- Department of Thoracic Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Kazuto Hirata
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
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38
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Yeo SCM, Fenwick PS, Barnes PJ, Lin HS, Donnelly LE. Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid-independent mechanism. Br J Pharmacol 2017; 174:2043-2059. [PMID: 28369685 PMCID: PMC5466528 DOI: 10.1111/bph.13803] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 03/10/2017] [Accepted: 03/14/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE Chronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol exhibits anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo. EXPERIMENTAL APPROACH Primary human airway epithelial cells derived from healthy and COPD subjects, and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Effects of isorhapontigenin and resveratrol on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8), and the activation of NF-κB, activator protein-1 (AP-1), MAPKs and PI3K/Akt/FoxO3A pathways were determined and compared with those of dexamethasone. The pharmacokinetic profiles of isorhapontigenin, after i.v. or oral administration, were assessed in Sprague-Dawley rats. KEY RESULTS Isorhapontigenin concentration-dependently inhibited IL-6 and CXCL8 release, with IC50 values at least twofold lower than those of resveratrol. These were associated with reduced activation of NF-κB and AP-1 and, notably, the PI3K/Akt/FoxO3A pathway, that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma levels after oral dosing. Its oral bioavailability was approximately 50% higher than resveratrol. CONCLUSIONS AND IMPLICATIONS Isorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared with resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD.
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Affiliation(s)
- Samuel Chao Ming Yeo
- Airway Disease, National Heart and Lung InstituteImperial College LondonLondonUK
- Department of Pharmacy, Faculty of ScienceNational University of SingaporeSingapore
| | - Peter S Fenwick
- Airway Disease, National Heart and Lung InstituteImperial College LondonLondonUK
| | - Peter J Barnes
- Airway Disease, National Heart and Lung InstituteImperial College LondonLondonUK
| | - Hai Shu Lin
- Department of Pharmacy, Faculty of ScienceNational University of SingaporeSingapore
| | - Louise E Donnelly
- Airway Disease, National Heart and Lung InstituteImperial College LondonLondonUK
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39
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Marcoux D, Qin LY, Ruan Z, Shi Q, Ruan Q, Weigelt C, Qiu H, Schieven G, Hynes J, Bhide R, Poss M, Tino J. Identification of highly potent and selective PI3Kδ inhibitors. Bioorg Med Chem Lett 2017; 27:2849-2853. [DOI: 10.1016/j.bmcl.2017.01.077] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 01/23/2017] [Accepted: 01/25/2017] [Indexed: 01/22/2023]
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40
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Chiang PC, Pang J, Liu J, Salphati L. An Investigation of Oral Exposure Variability and Formulation Strategy: A Case Study of PI3Kδ Inhibitor and Physiologically Based Pharmacokinetic Modeling in Beagle Dogs. J Pharm Sci 2017; 107:466-475. [PMID: 28652157 DOI: 10.1016/j.xphs.2017.06.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 05/25/2017] [Accepted: 06/08/2017] [Indexed: 10/19/2022]
Abstract
It is well acknowledged that drugs with poor aqueous solubility are often associated with poor oral absorption. Fortunately, drugs with a basic pKa can take advantage of solubilization in the stomach under the acidic environment to improve exposure. Consequently, high in vivo variability is often observed when stomach pH is altered. When issue encountered, enabling formulations are often used to solve the problem. However, each enabling formulation has its limitations and the situation can be further complicated by other absorption distribution metabolism elimination parameters. Therefore, formulation strategies need to consider various scenarios in order to be effective. Compound 1 is a potent phosphoinositide 3-kinase delta inhibitor with poor intrinsic solubility and 2 basic pKas. It was dosed as a suspension in dogs and found to have mediocre oral bioavailability with high variability. It was hypothesized that this variability was caused by their stomach pH variability. Pharmacokinetic modeling suggested that the issue could be improved with particle size reduction. Meanwhile, it was found that although the Madin-Darby canine kidney permeability was reasonable, Madin-Darby canine kidney transfected with human MDR1 gene (MDCK-MDR1) suggested that Compound 1 is an efflux transporter substrate. Findings were integrated into the design for in vivo studies in dogs. Data obtained from those studies allowed us to quickly narrow down the formulation approaches.
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Affiliation(s)
- Po-Chang Chiang
- Department of SMPS, Genentech, 1 DNA Way, South San Francisco, California 94080.
| | - Jodie Pang
- Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, California 94080
| | - Jia Liu
- Department of SMPS, Genentech, 1 DNA Way, South San Francisco, California 94080
| | - Laurent Salphati
- Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, California 94080
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41
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Liu Q, Shi Q, Marcoux D, Batt DG, Cornelius L, Qin LY, Ruan Z, Neels J, Beaudoin-Bertrand M, Srivastava AS, Li L, Cherney RJ, Gong H, Watterson SH, Weigelt C, Gillooly KM, McIntyre KW, Xie JH, Obermeier MT, Fura A, Sleczka B, Stefanski K, Fancher RM, Padmanabhan S, Rp T, Kundu I, Rajareddy K, Smith R, Hennan JK, Xing D, Fan J, Levesque PC, Ruan Q, Pitt S, Zhang R, Pedicord D, Pan J, Yarde M, Lu H, Lippy J, Goldstine C, Skala S, Rampulla RA, Mathur A, Gupta A, Arunachalam PN, Sack JS, Muckelbauer JK, Cvijic ME, Salter-Cid LM, Bhide RS, Poss MA, Hynes J, Carter PH, Macor JE, Ruepp S, Schieven GL, Tino JA. Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders. J Med Chem 2017; 60:5193-5208. [PMID: 28541707 DOI: 10.1021/acs.jmedchem.7b00618] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
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Affiliation(s)
- Qingjie Liu
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Qing Shi
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - David Marcoux
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Douglas G Batt
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Lyndon Cornelius
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Lan-Ying Qin
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Zheming Ruan
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - James Neels
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Myra Beaudoin-Bertrand
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Anurag S Srivastava
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Ling Li
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Robert J Cherney
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Hua Gong
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Scott H Watterson
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Carolyn Weigelt
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Kathleen M Gillooly
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Kim W McIntyre
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Jenny H Xie
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Mary T Obermeier
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Aberra Fura
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Bogdan Sleczka
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Kevin Stefanski
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - R M Fancher
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Shweta Padmanabhan
- Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
| | - Thatipamula Rp
- Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
| | - Ipsit Kundu
- Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
| | | | - Rodney Smith
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - James K Hennan
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Dezhi Xing
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Jingsong Fan
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Paul C Levesque
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Qian Ruan
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Sidney Pitt
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Rosemary Zhang
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Donna Pedicord
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Jie Pan
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Melissa Yarde
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Hao Lu
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Jonathan Lippy
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Christine Goldstine
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Stacey Skala
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Richard A Rampulla
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Arvind Mathur
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Anuradha Gupta
- Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
| | - Pirama Nayagam Arunachalam
- Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
| | - John S Sack
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Jodi K Muckelbauer
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Mary Ellen Cvijic
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Luisa M Salter-Cid
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Rajeev S Bhide
- Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
| | - Michael A Poss
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - John Hynes
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Percy H Carter
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | | | - Stefan Ruepp
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Gary L Schieven
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
| | - Joseph A Tino
- Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
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Yanagisawa S, Baker JR, Vuppusetty C, Fenwick P, Donnelly LE, Ito K, Barnes PJ. Decreased phosphatase PTEN amplifies PI3K signaling and enhances proinflammatory cytokine release in COPD. Am J Physiol Lung Cell Mol Physiol 2017; 313:L230-L239. [PMID: 28522564 PMCID: PMC5582930 DOI: 10.1152/ajplung.00382.2016] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 05/05/2017] [Accepted: 05/05/2017] [Indexed: 12/31/2022] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. The aim of this study was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN protein expression was measured in the peripheral lung of COPD patients compared with smoking and nonsmoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of l-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knockdown by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared with the subjects without COPD (P < 0.001) and positively correlated with the severity of airflow obstruction (forced expiratory volume in 1-s percent predicted; r = 0.50; P = 0.0012). Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r = -0.41; P = 0.0042). In both primary bronchial epithelial cells and BEAS-2B cells, CSE decreased PTEN protein, which was reversed by N-acetyl cysteine treatment. PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory cytokines, such as IL-6, CXCL8, CCL2, and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.
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Affiliation(s)
- Satoru Yanagisawa
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Jonathan R Baker
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Chaitanya Vuppusetty
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Peter Fenwick
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Louise E Donnelly
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Kazuhiro Ito
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Peter J Barnes
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
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43
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Schwehm C, Kellam B, Garces AE, Hill SJ, Kindon ND, Bradshaw TD, Li J, Macdonald SJF, Rowedder JE, Stoddart LA, Stocks MJ. Design and Elaboration of a Tractable Tricyclic Scaffold To Synthesize Druglike Inhibitors of Dipeptidyl Peptidase-4 (DPP-4), Antagonists of the C-C Chemokine Receptor Type 5 (CCR5), and Highly Potent and Selective Phosphoinositol-3 Kinase δ (PI3Kδ) Inhibitors. J Med Chem 2017; 60:1534-1554. [PMID: 28128944 DOI: 10.1021/acs.jmedchem.6b01801] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.
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Affiliation(s)
- Carolin Schwehm
- School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K
| | - Barrie Kellam
- School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K
| | - Aimie E Garces
- School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K
| | - Stephen J Hill
- Institute of Cell Signalling, Medical School, University of Nottingham , Nottingham, NG7 2UH, U.K
| | - Nicholas D Kindon
- School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K
| | - Tracey D Bradshaw
- School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K
| | - Jin Li
- Hitgen Ltd. , F7-10, Building B3, Tianfu Life Science Park, 88 South Kayuan Road, Chengdu, Sichuan, China 610041
| | - Simon J F Macdonald
- GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K
| | - James E Rowedder
- GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K
| | - Leigh A Stoddart
- Institute of Cell Signalling, Medical School, University of Nottingham , Nottingham, NG7 2UH, U.K
| | - Michael J Stocks
- School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K
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44
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Gallelli L, Falcone D, Cannataro R, Perri M, Serra R, Pelaia G, Maselli R, Savino R, Spaziano G, D’Agostino B. Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: a therapeutic rationale approach. Drug Des Devel Ther 2017; 11:265-272. [PMID: 28176948 PMCID: PMC5271379 DOI: 10.2147/dddt.s118485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug.
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Affiliation(s)
- Luca Gallelli
- Department of Health Science, University of Catanzaro, Catanzaro
| | - Daniela Falcone
- Department of Health Science, University of Catanzaro, Catanzaro
| | - Roberto Cannataro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende
| | - Mariarita Perri
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro
| | - Girolamo Pelaia
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro
| | - Rosario Maselli
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro
| | - Rocco Savino
- Department of Health Science, University of Catanzaro, Catanzaro
| | - Giuseppe Spaziano
- Department of Experimental Medicine, School of Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - Bruno D’Agostino
- Department of Experimental Medicine, School of Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
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New Anti-inflammatory Drugs for COPD: Is There a Possibility of Developing Drugs That Can Fundamentally Suppress Inflammation? RESPIRATORY DISEASE SERIES: DIAGNOSTIC TOOLS AND DISEASE MANAGEMENTS 2017. [DOI: 10.1007/978-981-10-0839-9_14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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46
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Baker JR, Vuppusetty C, Colley T, Papaioannou AI, Fenwick P, Donnelly L, Ito K, Barnes PJ. Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells. Sci Rep 2016; 6:35871. [PMID: 27767101 PMCID: PMC5073335 DOI: 10.1038/srep35871] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 10/07/2016] [Indexed: 12/18/2022] Open
Abstract
Sirtuin-1 (SIRT1) and SIRT6, NAD+-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H2O2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases.
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Affiliation(s)
- J R Baker
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K
| | - C Vuppusetty
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K
| | - T Colley
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K
| | | | - P Fenwick
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K
| | - Louise Donnelly
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K
| | - K Ito
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K
| | - P J Barnes
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K
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Singh J, Shah R, Singh D. Inundation of asthma target research: Untangling asthma riddles. Pulm Pharmacol Ther 2016; 41:60-85. [PMID: 27667568 DOI: 10.1016/j.pupt.2016.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/11/2016] [Accepted: 09/20/2016] [Indexed: 12/31/2022]
Abstract
Asthma is an inveterate inflammatory disorder, delineated by the airway inflammation, bronchial hyperresponsiveness (BHR) and airway wall remodeling. Although, asthma is a vague term, and is recognized as heterogenous entity encompassing different phenotypes. Targeting single mediator or receptor did not prove much clinical significant, as asthma is complex disease involving myriad inflammatory mediators. Asthma may probably involve a large number of different types of molecular and cellular components interacting through complex pathophysiological pathways. This review covers the past, present, and future therapeutic approaches and pathophysiological mechanisms of asthma. Furthermore, review describe importance of targeting several mediators/modulators and receptor antagonists involved in the physiopathology of asthma. Novel targets for asthma research include Galectins, Immunological targets, K + Channels, Kinases and Transcription Factors, Toll-like receptors, Selectins and Transient receptor potential channels. But recent developments in asthma research are very promising, these include Bitter taste receptors (TAS2R) abated airway obstruction in mouse model of asthma and Calcium-sensing receptor obliterate inflammation and in bronchial hyperresponsiveness allergic asthma. All these progresses in asthma targets, and asthma phenotypes exploration are auspicious in untangling of asthma riddles.
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Affiliation(s)
- Jatinder Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India
| | - Ramanpreet Shah
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India
| | - Dhandeep Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India.
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48
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Henry CO, Dalloneau E, Pérez-Berezo MT, Plata C, Wu Y, Guillon A, Morello E, Aimar RF, Potier-Cartereau M, Esnard F, Coraux C, Börnchen C, Kiefmann R, Vandier C, Touqui L, Valverde MA, Cenac N, Si-Tahar M. In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 2016; 311:L664-75. [PMID: 27496898 DOI: 10.1152/ajplung.00442.2015] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 07/26/2016] [Indexed: 12/22/2022] Open
Abstract
Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of "transient receptor potential vanilloid-4" (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF-κB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF.
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Affiliation(s)
- Clémence O Henry
- Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France
| | - Emilie Dalloneau
- Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France
| | - Maria-Teresa Pérez-Berezo
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Cristina Plata
- Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Yongzheng Wu
- Unité de Défense Innée et Inflammation, Inserm U874, Institut Pasteur, Paris, France
| | - Antoine Guillon
- Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France; Service de Réanimation Polyvalente, Centre Hospitalier Régional Universitaire de Tours, Tours, France
| | - Eric Morello
- Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France
| | - Rose-France Aimar
- Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France
| | - Marie Potier-Cartereau
- Université François Rabelais, Tours, France; Inserm UMR1069, Nutrition, Croissance et Cancer, Tours, France; Ion Channels and Cancer network-Canceropole Grand Ouest, Tours, France
| | - Frédéric Esnard
- Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France
| | - Christelle Coraux
- Inserm UMR-S 903, SFR CAP-SANTE (FED 4231), Université de Champagne-Ardenne, Reims, France
| | - Christian Börnchen
- Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Department of Anaesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rainer Kiefmann
- Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Department of Anaesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christophe Vandier
- Université François Rabelais, Tours, France; Inserm UMR1069, Nutrition, Croissance et Cancer, Tours, France; Ion Channels and Cancer network-Canceropole Grand Ouest, Tours, France
| | - Lhousseine Touqui
- Unité de Défense Innée et Inflammation, Inserm U874, Institut Pasteur, Paris, France
| | - Miguel A Valverde
- Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Nicolas Cenac
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Mustapha Si-Tahar
- Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France;
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49
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Barnes PJ. Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease. Pharmacol Rev 2016; 68:788-815. [PMID: 27363440 DOI: 10.1124/pr.116.012518] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Multiple kinases play a critical role in orchestrating the chronic inflammation and structural changes in the respiratory tract of patients with asthma and chronic obstructive pulmonary disease (COPD). Kinases activate signaling pathways that lead to contraction of airway smooth muscle and release of inflammatory mediators (such as cytokines, chemokines, growth factors) as well as cell migration, activation, and proliferation. For this reason there has been great interest in the development of kinase inhibitors as anti-inflammatory therapies, particular where corticosteroids are less effective, as in severe asthma and COPD. However, it has proven difficult to develop selective kinase inhibitors that are both effective and safe after oral administration and this has led to a search for inhaled kinase inhibitors, which would reduce systemic exposure. Although many kinases have been implicated in inflammation and remodeling of airway disease, very few classes of drug have reached the stage of clinical studies in these diseases. The most promising drugs are p38 MAP kinases, isoenzyme-selective PI3-kinases, Janus-activated kinases, and Syk-kinases, and inhaled formulations of these drugs are now in development. There has also been interest in developing inhibitors that block more than one kinase, because these drugs may be more effective and with less risk of losing efficacy with time. No kinase inhibitors are yet on the market for the treatment of airway diseases, but as kinase inhibitors are improved from other therapeutic areas there is hope that these drugs may eventually prove useful in treating refractory asthma and COPD.
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Affiliation(s)
- Peter J Barnes
- National Heart and Lung Institute, Imperial College, London, United Kingdom
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50
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Abstract
Noneosinophilic airway inflammation occurs in approximately 50% of patients with asthma. It is subdivided into neutrophilic or paucigranulocytic inflammation, although the proportion of each subtype is uncertain because of variable cut-off points used to define neutrophilia. This article reviews the evidence for noneosinophilic inflammation being a target for therapy in asthma and assesses clinical trials of licensed drugs, novel small molecules and biologics agents in noneosinophilic inflammation. Current symptoms, rate of exacerbations and decline in lung function are generally less in noneosinophilic asthma than eosinophilic asthma. Noneosinophilic inflammation is associated with corticosteroid insensitivity. Neutrophil activation in the airways and systemic inflammation is reported in neutrophilic asthma. Neutrophilia in asthma may be due to corticosteroids, associated chronic pulmonary infection, altered airway microbiome or delayed neutrophil apoptosis. The cause of poorly controlled noneosinophilic asthma may differ between patients and involve several mechanism including neutrophilic inflammation, T helper 2 (Th2)-low or other subtypes of airway inflammation or corticosteroid insensitivity as well as noninflammatory pathways such as airway hyperreactivity and remodelling. Smoking cessation in asthmatic smokers and removal from exposure to some occupational agents reduces neutrophilic inflammation. Preliminary studies of 'off-label' use of licensed drugs suggest that macrolides show efficacy in nonsmokers with noneosinophilic severe asthma and statins, low-dose theophylline and peroxisome proliferator-activated receptor gamma (PPARγ) agonists may benefit asthmatic smokers with noneosinophilic inflammation. Novel small molecules targeting neutrophilic inflammation, such as chemokine (CXC) receptor 2 (CXCR2) antagonists reduce neutrophils, but do not improve clinical outcomes in studies to date. Inhaled phosphodiesterase (PDE)4 inhibitors, dual PDE3 and PDE4 inhibitors, p38MAPK (mitogen-activated protein kinase) inhibitors, tyrosine kinase inhibitors and PI (phosphoinositide) 3kinase inhibitors are under development and these compounds may be of benefit in noneosinophilic inflammation. The results of clinical trials of biological agents targeting mediators associated with noneosinophilic inflammation, such as interleukin (IL)-17 and tumor necrosis factor (TNF)-α are disappointing. Greater understanding of the mechanisms of noneosinophilic inflammation in asthma should lead to improved therapies.
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Affiliation(s)
- Neil C Thomson
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 0YN, UK
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