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1
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Lyu Z, Yang J, Xu Z, Wang W, Cheng W, Tsui KL, Zhang Q. Predicting the risk of ischemic stroke in patients with atrial fibrillation using heterogeneous drug-protein-disease network-based deep learning. APL Bioeng 2025; 9:026104. [PMID: 40191603 PMCID: PMC11970939 DOI: 10.1063/5.0242570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/11/2025] [Indexed: 04/09/2025] Open
Abstract
Current risk assessment models for predicting ischemic stroke (IS) in patients with atrial fibrillation (AF) often fail to account for the effects of medications and the complex interactions between drugs, proteins, and diseases. We developed an interpretable deep learning model, the AF-Biological-IS-Path (ABioSPath), to predict one-year IS risk in AF patients by integrating drug-protein-disease pathways with real-world clinical data. Using a heterogeneous multilayer network, ABioSPath identifies mechanisms of drug actions and the propagation of comorbid diseases. By combining mechanistic pathways with patient-specific characteristics, the model provides individualized IS risk assessments and identifies potential molecular pathways involved. We utilized the electronic health record data from 7859 AF patients, collected between January 2008 and December 2009 across 43 hospitals in Hong Kong. ABioSPath outperformed baseline models in all evaluation metrics, achieving an AUROC of 0.7815 (95% CI: 0.7346-0.8283), a positive predictive value of 0.430, a negative predictive value of 0.870, a sensitivity of 0.500, a specificity of 0.885, an average precision of 0.409, and a Brier score of 0.195. Cohort-level analysis identified key proteins, such as CRP, REN, and PTGS2, within the most common pathways. Individual-level analysis further highlighted the importance of PIK3/Akt and cytokine and chemokine signaling pathways and identified IS risks associated with less-studied drugs like prochlorperazine maleate. ABioSPath offers a robust, data-driven approach for IS risk prediction, requiring only routinely collected clinical data without the need for costly biomarkers. Beyond IS, the model has potential applications in screening risks for other diseases, enhancing patient care, and providing insights for drug development.
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Affiliation(s)
| | - Jiannan Yang
- Musketeers Foundation Institute of Data Science, The University of Hong Kong, Hong Kong SAR, China
| | - Zhongzhi Xu
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Weilan Wang
- Centre for Healthy Longevity, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Kwok-Leung Tsui
- Department of Manufacturing, Systems, and Industrial Engineering, University of Texas, Arlington, Texas 76019, USA
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2
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Breen AK, Thomas S, Beckett D, Agsalud M, Gingras G, Williams J, Wasko BM. An mTOR inhibitor discovery system using drug-sensitized yeast. GeroScience 2025:10.1007/s11357-025-01534-8. [PMID: 39885115 DOI: 10.1007/s11357-025-01534-8] [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: 10/02/2024] [Accepted: 01/17/2025] [Indexed: 02/01/2025] Open
Abstract
Inhibition of the target of rapamycin (TOR/mTOR) protein kinase by the drug rapamycin extends lifespan and health span across diverse species. However, rapamycin has potential off-target and side effects that warrant the discovery of additional TOR inhibitors. TOR was initially discovered in Saccharomyces cerevisiae (yeast) which contains two TOR paralogs, TOR1 and TOR2. Yeast lacking functional Tor1 are viable but are hypersensitive to growth inhibition by TORC1 inhibitors, which is a property of yeast that can be exploited to identify TOR inhibitors. Additionally, yeast lacking FK506-sensitive proline rotamase (FPR1) or containing a tor1-1 allele (a mutation in the Fpr1-rapamycin binding domain of Tor1) are robustly and selectively resistant to rapamycin and analogs that allosterically inhibit TOR activity via an FPR1-dependent mechanism. To facilitate the identification of TOR inhibitors, we generated a panel of yeast strains with mutations in TOR pathway genes combined with the removal of 12 additional genes involved in drug efflux. This creates a drug-sensitive strain background that can sensitively and effectively identify TOR inhibitors. In a wild-type yeast strain background, 25 µM of Torin1 and 100 µM of GSK2126458 (omipalisib) are necessary to observe TOR1-dependent growth inhibition by these known TOR inhibitors. In contrast, 100 nM Torin1 and 500 nM GSK2126458 (omipalisib) are sufficient to identify TOR1-dependent growth inhibition in the drug-sensitized background. This represents a 200-fold and 250-fold increase in detection sensitivity for Torin1 and GSK2126458, respectively. Additionally, for the TOR inhibitor AZD8055, the drug-sensitive system resolves that the compound results in TOR1-dependent growth sensitivity at 100 µM, whereas no growth inhibition is observed in a wild-type yeast strain background. Our platform also identifies the caffeine analog aminophylline as a TOR1-dependent growth inhibitor via selective tor1 growth sensitivity. We also tested nebivolol, isoliquiritigenin, canagliflozin, withaferin A, ganoderic acid A, and taurine and found no evidence for TOR inhibition using our yeast growth-based model. Our results demonstrate that this system is highly effective at identifying compounds that inhibit the TOR pathway. It offers a rapid, cost-efficient, and sensitive tool for drug discovery, with the potential to expedite the identification of new TOR inhibitors that could serve as geroprotective and/or anti-cancer agents.
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Affiliation(s)
- Anna K Breen
- Department of Biomedical Sciences, Western University of Health Sciences, Lebanon, OR, 97355, USA
| | - Sarah Thomas
- Department of Biomedical Sciences, Western University of Health Sciences, Lebanon, OR, 97355, USA
| | - David Beckett
- Department of Biomedical Sciences, Western University of Health Sciences, Lebanon, OR, 97355, USA
| | - Matthew Agsalud
- Department of Biomedical Sciences, Western University of Health Sciences, Lebanon, OR, 97355, USA
| | - Graham Gingras
- Department of Biomedical Sciences, Western University of Health Sciences, Lebanon, OR, 97355, USA
| | - Judd Williams
- Department of Biomedical Sciences, Western University of Health Sciences, Lebanon, OR, 97355, USA
| | - Brian M Wasko
- Department of Biomedical Sciences, Western University of Health Sciences, Lebanon, OR, 97355, USA.
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Shi Q, Wang J, Malik H, Li X, Streeter J, Sharafuddin J, Weatherford E, Stein D, Itan Y, Chen B, Hall D, Song LS, Abel ED. IRS2 Signaling Protects Against Stress-Induced Arrhythmia by Maintaining Ca 2+ Homeostasis. Circulation 2024; 150:1966-1983. [PMID: 39253856 PMCID: PMC11631690 DOI: 10.1161/circulationaha.123.065048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 08/13/2024] [Indexed: 09/11/2024]
Abstract
BACKGROUND The docking protein IRS2 (insulin receptor substrate protein-2) is an important mediator of insulin signaling and may also regulate other signaling pathways. Murine hearts with cardiomyocyte-restricted deletion of Irs2 (cIRS2-KO) are more susceptible to pressure overload-induced cardiac dysfunction, implying a critical protective role of IRS2 in cardiac adaptation to stress through mechanisms that are not fully understood. There is limited evidence regarding the function of IRS2 beyond metabolic homeostasis regulation, particularly in the context of cardiac disease. METHODS A retrospective analysis of an electronic medical record database was conducted to identify patients with IRS2 variants and assess their risk of cardiac arrhythmias. Arrhythmia susceptibility was examined in cIRS2-KO mice. The underlying mechanisms were investigated using confocal calcium imaging of ex vivo whole hearts and isolated cardiomyocytes to assess calcium handling, Western blotting to analyze the involved signaling pathways, and pharmacological and genetic interventions to rescue arrhythmias in cIRS2-KO mice. RESULTS The retrospective analysis identified patients with IRS2 variants of uncertain significance with a potential association to an increased risk of cardiac arrhythmias compared with matched controls. cIRS2-KO hearts were found to be prone to catecholamine-sensitive ventricular tachycardia and reperfusion ventricular tachycardia. Confocal calcium imaging of ex vivo whole hearts and single isolated cardiomyocytes from cIRS2-KO hearts revealed decreased Ca²⁺ transient amplitudes, increased spontaneous Ca²⁺ sparks, and reduced sarcoplasmic reticulum Ca²⁺ content during sympathetic stress, indicating sarcoplasmic reticulum dysfunction. We identified that overactivation of the AKT1/NOS3 (nitric oxide synthase 3)/CaMKII (Ca²⁺/calmodulin-dependent protein kinase II)/RyR2 (type 2 ryanodine receptor) signaling pathway led to calcium mishandling and catecholamine-sensitive ventricular tachycardia in cIRS2-KO hearts. Pharmacological AKT inhibition or genetic stabilization of RyR2 rescued catecholamine-sensitive ventricular tachycardia in cIRS2-KO mice. CONCLUSIONS Cardiac IRS2 inhibits sympathetic stress-induced AKT/NOS3/CaMKII/RyR2 overactivation and calcium-dependent arrhythmogenesis. This novel IRS2 signaling axis, essential for maintaining cardiac calcium homeostasis under stress, presents a promising target for developing new antiarrhythmic therapies.
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Affiliation(s)
- Qian Shi
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Jinxi Wang
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Hamza Malik
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Xuguang Li
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Jennifer Streeter
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Jacob Sharafuddin
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Eric Weatherford
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
- Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - David Stein
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Yuval Itan
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Biyi Chen
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Duane Hall
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
- Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Long-Sheng Song
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
- Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA
- Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - E. Dale Abel
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
- Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA
- Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA
- Current address, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA
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Sheida A, Farshadi M, Mirzaei A, Najjar Khalilabad S, Zarepour F, Taghavi SP, Hosseini Khabr MS, Ravaei F, Rafiei S, Mosadeghi K, Yazdani MS, Fakhraie A, Ghattan A, Zamani Fard MM, Shahyan M, Rafiei M, Rahimian N, Talaei Zavareh SA, Mirzaei H. Potential of Natural Products in the Treatment of Glioma: Focus on Molecular Mechanisms. Cell Biochem Biophys 2024; 82:3157-3208. [PMID: 39150676 DOI: 10.1007/s12013-024-01447-x] [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] [Accepted: 07/17/2024] [Indexed: 08/17/2024]
Abstract
Despite the waning of traditional treatments for glioma due to possible long-term issues, the healing possibilities of substances derived from nature have been reignited in the scientific community. These natural substances, commonly found in fruits and vegetables, are considered potential alternatives to pharmaceuticals, as they have been shown in prior research to impact pathways surrounding cancer progression, metastases, invasion, and resistance. This review will explore the supposed molecular mechanisms of different natural components, such as berberine, curcumin, coffee, resveratrol, epigallocatechin-3-gallate, quercetin, tanshinone, silymarin, coumarin, and lycopene, concerning glioma treatment. While the benefits of a balanced diet containing these compounds are widely recognized, there is considerable scope for investigating the efficacy of these natural products in treating glioma.
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Affiliation(s)
- Amirhossein Sheida
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Amirhossein Mirzaei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shakiba Najjar Khalilabad
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Zarepour
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Pouya Taghavi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Sadat Hosseini Khabr
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Ravaei
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Sara Rafiei
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Kimia Mosadeghi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Sepehr Yazdani
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Fakhraie
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Ghattan
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Masoud Zamani Fard
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Shahyan
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Moein Rafiei
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | | | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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5
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Song X, Kirtipal N, Lee S, Malý P, Bharadwaj S. Current therapeutic targets and multifaceted physiological impacts of caffeine. Phytother Res 2023; 37:5558-5598. [PMID: 37679309 DOI: 10.1002/ptr.8000] [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: 04/13/2023] [Revised: 08/04/2023] [Accepted: 08/17/2023] [Indexed: 09/09/2023]
Abstract
Caffeine, which shares consubstantial structural similarity with purine adenosine, has been demonstrated as a nonselective adenosine receptor antagonist for eliciting most of the biological functions at physiologically relevant dosages. Accumulating evidence supports caffeine's beneficial effects against different disorders, such as total cardiovascular diseases and type 2 diabetes. Conversely, paradoxical effects are also linked to caffeine ingestion in humans including hypertension-hypotension and tachycardia-bradycardia. These observations suggest the association of caffeine action with its ingested concentration and/or concurrent interaction with preferential molecular targets to direct explicit events in the human body. Thus, a coherent analysis of the functional targets of caffeine, relevant to normal physiology, and disease pathophysiology, is required to understand the pharmacology of caffeine. This review provides a broad overview of the experimentally validated targets of caffeine, particularly those of therapeutic interest, and the impacts of caffeine on organ-specific physiology and pathophysiology. Overall, the available empirical and epidemiological evidence supports the dose-dependent functional activities of caffeine and advocates for further studies to get insights into the caffeine-induced changes under specific conditions, such as asthma, DNA repair, and cancer, in view of its therapeutic applications.
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Affiliation(s)
- Xinjie Song
- Zhejiang Provincial Key Lab for Chemical and Biological Processing Technology of Farm Product, School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, China
| | - Nikhil Kirtipal
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea
| | - Sunjae Lee
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea
| | - Petr Malý
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences v.v.i, BIOCEV Research Center, Vestec, Czech Republic
| | - Shiv Bharadwaj
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences v.v.i, BIOCEV Research Center, Vestec, Czech Republic
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Fenne KT, Clauss M, Schäfer Olstad D, Johansen EI, Jensen J. An Acute Bout of Endurance Exercise Does Not Prevent the Inhibitory Effect of Caffeine on Glucose Tolerance the following Morning. Nutrients 2023; 15:nu15081941. [PMID: 37111160 PMCID: PMC10143402 DOI: 10.3390/nu15081941] [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: 03/17/2023] [Revised: 03/29/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Caffeine reduces glucose tolerance, whereas exercise training improves glucose homeostasis. The aim of the present study was to investigate the effect of caffeine on glucose tolerance the morning after an acute bout of aerobic exercise. Methods: The study had a 2 × 2 factorial design. Oral glucose tolerance tests (OGTT) were performed after overnight fasting with/without caffeine and with/without exercise the evening before. Eight healthy young active males were included (Age 25.5 ± 1.5 years; 83.9 ± 9.0 kg; VO2max: 54.3 ± 7.0 mL·kg-1·min-1). The exercise session consisted of 30 min cycling at 71% of VO2max followed by four 5 min intervals at 84% with 3 min of cycling at 40% of VO2max between intervals. The exercise was performed at 17:00 h. Energy expenditure at each session was ~976 kcal. Lactate increased to ~8 mM during the exercise sessions. Participants arrived at the laboratory the following morning at 7.00 AM after an overnight fast. Resting blood samples were taken before blood pressure and heart rate variability (HRV) were measured. Caffeine (3 mg/kg bodyweight) or placebo (similar taste/flavor) was ingested, and blood samples, blood pressure and HRV were measured after 30 min. Next, the OGTTs were initiated (75 g glucose dissolved in 3 dL water) and blood was sampled. Blood pressure and HRV were measured during the OGTT. Caffeine increased the area under curve (AUC) for glucose independently of whether exercise was done the evening before (p = 0.03; Two-way ANOVA; Interaction: p = 0.835). Caffeine did not significantly increase AUC for C-peptides compared to placebo (p = 0.096), and C-peptide response was not influenced by exercise. The acute bout of exercise did not significantly improve glucose tolerance the following morning. Diastolic blood pressure during the OGTT was slightly higher after intake of caffeine, independent of whether exercise was performed the evening before or not. Neither caffeine nor exercise the evening before significantly influenced HRV. In conclusion, caffeine reduced glucose tolerance independently of whether endurance exercise was performed the evening before. The low dose of caffeine did not influence heart rate variability but increased diastolic blood pressure slightly.
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Affiliation(s)
- Karoline T Fenne
- Department of Physical Performance, Norwegian School of Sport Sciences, P.O. Box 4014, Ullevål Stadion, 0806 Oslo, Norway
| | - Matthieu Clauss
- Department of Physical Performance, Norwegian School of Sport Sciences, P.O. Box 4014, Ullevål Stadion, 0806 Oslo, Norway
| | | | - Egil I Johansen
- Department of Physical Performance, Norwegian School of Sport Sciences, P.O. Box 4014, Ullevål Stadion, 0806 Oslo, Norway
| | - Jørgen Jensen
- Department of Physical Performance, Norwegian School of Sport Sciences, P.O. Box 4014, Ullevål Stadion, 0806 Oslo, Norway
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Manivasakam P, Ravi A, Ramesh J, Bhuvarahamurthy D, Kasirajan K, Vijayapoopathi S, Venugopal B, Fliri AF. Autophagy: An Emerging Target for Developing Effective Analgesics. ACS OMEGA 2023; 8:9445-9453. [PMID: 36936313 PMCID: PMC10018516 DOI: 10.1021/acsomega.2c06949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/20/2023] [Indexed: 06/18/2023]
Abstract
Inadequate treatment of acute and chronic pain causes depression, anxiety, sleep disturbances, and increased mortality. Abuse and overdose of opioids and the side effects associated with chronic use of NSAID illustrate the need for development of safer and effective pain medication. Working toward this end, an in silico tool based on an emergent intelligence analytical platform that examines interactions between protein networks was used to identify molecular mechanisms involved in regulating the body's response to painful stimuli and drug treatments. Examining interactions between protein networks associated with the expression of over 20 different pain types suggests that the regulation of autophagy plays a central role in modulation of pain symptoms (see Materials and Methods). Using the topology of this regulatory scheme as an in silico screening tool, we identified that combinations of functions targeted by cannabidiol, myo-inositol, and fish oils with varying ratios of eicosapentaenoic and docosahexaenoic acids are projected to produce superior analgesia. For validating this prediction, we administered combinations of cannabidiol, myo-inositol, and fish oils to rats that received formalin injections in hind paws, prior to substance administration, and showed that analgesic effects produced by these combinations were comparable or superior to known NSAID analgesics, which suggests that these combinations have potential in treatment of pain.
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Affiliation(s)
| | - Atchayaa Ravi
- Department
of Medical Biochemistry, Dr. A.L.M. Postgraduate
Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, Tamil
Nadu, India
| | - Janani Ramesh
- Department
of Medical Biochemistry, Dr. A.L.M. Postgraduate
Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, Tamil
Nadu, India
- Renal
Division, Brigham and Women’s Hospital,
BWH, Boston, Massachusetts 02115-6195, United
States
| | | | - Kalaiyarasi Kasirajan
- Department
of Medical Biochemistry, Dr. A.L.M. Postgraduate
Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, Tamil
Nadu, India
| | - Singaravel Vijayapoopathi
- Department
of Medical Biochemistry, Dr. A.L.M. Postgraduate
Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, Tamil
Nadu, India
| | - Bhuvarahamurthy Venugopal
- Department
of Medical Biochemistry, Dr. A.L.M. Postgraduate
Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, Tamil
Nadu, India
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Mirza Z, Karim S. Structure-Based Profiling of Potential Phytomolecules with AKT1 a Key Cancer Drug Target. Molecules 2023; 28:molecules28062597. [PMID: 36985568 PMCID: PMC10051420 DOI: 10.3390/molecules28062597] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023] Open
Abstract
Identifying cancer biomarkers is imperative, as upregulated genes offer a better microenvironment for the tumor; hence, targeted inhibition is preferred. The theme of our study is to predict molecular interactions between cancer biomarker proteins and selected natural compounds. We identified an overexpressed potential molecular target (AKT1) and computationally evaluated its inhibition by four dietary ligands (isoliquiritigenin, shogaol, tehranolide, and theophylline). The three-dimensional structures of protein and phytochemicals were retrieved from the RCSB PDB database (4EKL) and NCBI’s PubChem, respectively. Rational structure-based docking studies were performed using AutoDock. Results were analyzed based primarily on the estimated free binding energy (kcal/mol), hydrogen bonds, and inhibition constant, Ki, to identify the most effective anti-cancer phytomolecule. Toxicity and drug-likeliness prediction were performed using OSIRIS and SwissADME. Amongst the four phytocompounds, tehranolide has better potential to suppress the expression of AKT1 and could be used for anti-cancer drug development, as inhibition of AKT1 is directly associated with the inhibition of growth, progression, and metastasis of the tumor. Docking analyses reveal that tehranolide has the most efficiency in inhibiting AKT1 and has the potential to be used for the therapeutic management of cancer. Natural compounds targeting cancer biomarkers offer less rejection, minimal toxicity, and fewer side effects.
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Affiliation(s)
- Zeenat Mirza
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Correspondence: or
| | - Sajjad Karim
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Wang L, Yu S, Yang N, Wang B. Studies on the Synthesis and Biological Activities of Novel Dihydroquinazolinone-Containing Caffeine Derivatives. CHINESE J ORG CHEM 2023. [DOI: 10.6023/cjoc202206024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
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10
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Verma VA, Halu B, Saundane AR, Meti RS. Synthesis, Biological Validation, and Docking Studies of Novel Purine Derivatives Containing Pyridopyrimidine, Pyrazolopyridine, and Pyranonapthyridine Rings †. Polycycl Aromat Compd 2022. [DOI: 10.1080/10406638.2020.1871384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Vaijinath A. Verma
- Department of Chemistry, Shri Prabhu Arts, Science and J.M. Bohra Commerce, Degree College, Shorapur, India
| | - Bharathi Halu
- Departmet of Biology, Government Pre University College, Sedam, India
| | - Anand R. Saundane
- Department of P.G. Studies and Research in Chemistry, Gulbarga University, Kalaburagi, India
| | - Rajkumar S. Meti
- Department of Biochemistry, Mangalore University, P.G. Centre Chikka Aluvara, Mangalore, India
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11
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Jacobson KA, Gao ZG, Matricon P, Eddy MT, Carlsson J. Adenosine A 2A receptor antagonists: from caffeine to selective non-xanthines. Br J Pharmacol 2022; 179:3496-3511. [PMID: 32424811 PMCID: PMC9251831 DOI: 10.1111/bph.15103] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/30/2020] [Accepted: 05/03/2020] [Indexed: 12/12/2022] Open
Abstract
A long evolution of knowledge of the psychostimulant caffeine led in the 1960s to another purine natural product, adenosine and its A2A receptor. Adenosine is a short-lived autocrine/paracrine mediator that acts pharmacologically at four different adenosine receptors in a manner opposite to the pan-antagonist caffeine and serves as an endogenous allostatic regulator. Although detrimental in the developing brain, caffeine appears to be cerebroprotective in aging. Moderate caffeine consumption in adults, except in pregnancy, may also provide benefit in pain, diabetes, and kidney and liver disorders. Inhibition of A2A receptors is one of caffeine's principal effects and we now understand this interaction at the atomic level. The A2A receptor has become a prototypical example of utilizing high-resolution structures of GPCRs for the rational design of chemically diverse drug molecules. The previous focus on discovery of selective A2A receptor antagonists for neurodegenerative diseases has expanded to include immunotherapy for cancer, and clinical trials have ensued. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.
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Affiliation(s)
- Kenneth A. Jacobson
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Zhan-Guo Gao
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pierre Matricon
- Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Matthew T. Eddy
- Department of Chemistry, University of Florida, Gainesville, FL, USA
| | - Jens Carlsson
- Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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12
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Song T, Zhang X, Ding M, Rodriguez-Paton A, Wang S, Wang G. DeepFusion: A Deep Learning Based Multi-Scale Feature Fusion Method for Predicting Drug-Target Interactions. Methods 2022; 204:269-277. [DOI: 10.1016/j.ymeth.2022.02.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/28/2022] [Accepted: 02/20/2022] [Indexed: 12/15/2022] Open
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Stadheim HK, Stensrud T, Brage S, Jensen J. Caffeine Increases Exercise Performance, Maximal Oxygen Uptake, and Oxygen Deficit in Elite Male Endurance Athletes. Med Sci Sports Exerc 2021; 53:2264-2273. [PMID: 34033621 DOI: 10.1249/mss.0000000000002704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
PURPOSE The aims of the present study were to test the hypothesis that caffeine increases maximal oxygen uptake (V˙O2max) and to characterize the physiological mechanisms underpinning improved high-intensity endurance capacity. METHODS Twenty-three elite endurance-trained male athletes were tested twice with and twice without caffeine (four tests) in a randomized, double-blinded, and placebo-controlled study with crossover design. Caffeine (4.5 mg·kg-1) or placebo was consumed 45 min before standardized warm-up. Time to exhaustion during an incremental test (running 10.5° incline, start speed 10.0 km·h-1, and 0.5 km·h-1 increase in speed every 30 s) determined performance. Oxygen uptake was measured continuously to determine V˙O2max and O2 deficit was calculated. RESULTS Caffeine increased time to exhaustion from 355 ± 41 to 375 ± 41 s (Δ19.4 ± 16.5 s; P < 0.001). Importantly, caffeine increased V˙O2max from 75.8 ± 5.6 to 76.7 ± 6.0 mL·kg-1·min-1 (Δ 0.9 ± 1.7 mL·kg-1·min-1; P < 0.003). Caffeine increased maximal heart rate (HRpeak) and ventilation (VEpeak). Caffeine increased O2 deficit from 63.1 ± 18.2 to 69.5 ± 17.5 mL·kg-1 (P < 0.02) and blood lactate compared with placebo. The increase in time to exhaustion after caffeine ingestion was reduced to 11.7 s after adjustment for the increase in V˙O2max. Caffeine did not significantly increase V˙O2max after adjustment for VEpeak and HRpeak. Adjustment for O2 deficit and lactate explained 6.2 s of the caffeine-induced increase in time to exhaustion. The increase in V˙O2max, VE, HR, O2 deficit, and lactate explained 63% of the increased performance after caffeine intake. CONCLUSION Caffeine increased V˙O2max in elite athletes, which contributed to improvement in high-intensity endurance performance. Increases in O2 deficit and lactate also contributed to the caffeine-induced improvement in endurance performance.
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Affiliation(s)
- Hans Kristian Stadheim
- Department of Physical Performance, Norwegian School of Sport Sciences, Ullevål Stadion, NORWAY
| | - Trine Stensrud
- Department of Physical Performance, Norwegian School of Sport Sciences, Ullevål Stadion, NORWAY
| | - Søren Brage
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Sciences, Cambridge Biomedical Campus, England, UNITED KINGDOM
| | - Jørgen Jensen
- Department of Physical Performance, Norwegian School of Sport Sciences, Ullevål Stadion, NORWAY
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14
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Di Rocco M, Galosi S, Lanza E, Tosato F, Caprini D, Folli V, Friedman J, Bocchinfuso G, Martire A, Di Schiavi E, Leuzzi V, Martinelli S. Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia. Hum Mol Genet 2021; 31:929-941. [PMID: 34622282 PMCID: PMC8947233 DOI: 10.1093/hmg/ddab296] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 10/04/2021] [Accepted: 10/04/2021] [Indexed: 12/12/2022] Open
Abstract
Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas9, whereas a knock-in strain carrying the p.A221D variant was already available. Like null mutants, homozygous knock-in animals showed increased egg laying and were hypersensitive to aldicarb, an inhibitor of acetylcholinesterase, suggesting excessive neurotransmitter release by different classes of motor neurons. Automated analysis of C. elegans locomotion indicated that goa-1 mutants move faster than control animals, with more frequent body bends and a higher reversal rate and display uncoordinated locomotion. Phenotypic profiling of heterozygous animals revealed a strong hypomorphic effect of both variants, with a partial dominant-negative activity for the p.A221D allele. Finally, caffeine was shown to rescue aberrant motor function in C. elegans harboring the goa-1 variants; this effect is mainly exerted through adenosine receptor antagonism. Overall, our findings establish a suitable platform for drug discovery, which may assist in accelerating the development of new therapies for this devastating condition, and highlight the potential role of caffeine in controlling GNAO1-related dyskinesia.
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Affiliation(s)
- Martina Di Rocco
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.,Department of Human Neuroscience, "Sapienza" University of Rome, Rome 00185, Italy
| | - Serena Galosi
- Department of Human Neuroscience, "Sapienza" University of Rome, Rome 00185, Italy
| | - Enrico Lanza
- Center for Life Nano Science, Istituto Italiano di Tecnologia, Rome 00161, Italy
| | - Federica Tosato
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy
| | - Davide Caprini
- Center for Life Nano Science, Istituto Italiano di Tecnologia, Rome 00161, Italy
| | - Viola Folli
- Center for Life Nano Science, Istituto Italiano di Tecnologia, Rome 00161, Italy
| | - Jennifer Friedman
- UCSD Department of Neuroscience and Pediatrics, Rady Children's Hospital Division of Neurology; Rady Children's Institute for Genomic Medicine, San Diego, USA
| | - Gianfranco Bocchinfuso
- Department of Chemical Sciences and Technologies, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Alberto Martire
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome 00161, Italy
| | - Elia Di Schiavi
- Institute of Biosciences and BioResources, National Research Council, Naples 80131, Italy
| | - Vincenzo Leuzzi
- Department of Human Neuroscience, "Sapienza" University of Rome, Rome 00185, Italy
| | - Simone Martinelli
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy
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Liu H, Zhang S, Li H, Zhang Y, Li Z, Wang B. Synthesis and Biological Activities of Novel 8-((3,4,4-Trifluorobut-3-en-1-yl)thio)-substituted Methylxanthines and Their Derivatives. CHINESE J ORG CHEM 2021. [DOI: 10.6023/cjoc202012006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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16
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Diaz N, Juarez M, Cancrini C, Heeg M, Soler-Palacín P, Payne A, Johnston GI, Helmer E, Cain D, Mann J, Yuill D, Conti F, Di Cesare S, Ehl S, Garcia-Prat M, Maccari ME, Martín-Nalda A, Martínez-Gallo M, Moshous D, Santilli V, Semeraro M, Simonetti A, Suarez F, Cavazzana M, Kracker S. Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies. THE JOURNAL OF IMMUNOLOGY 2020; 205:2979-2987. [PMID: 33115853 DOI: 10.4049/jimmunol.2000326] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 09/22/2020] [Indexed: 12/11/2022]
Abstract
Mutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15-25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk-benefit profile was maintained for ≤96 wk.
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Affiliation(s)
| | | | - Caterina Cancrini
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.,Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Children's Hospital Bambino Gesù, 00165 Rome, Italy
| | - Maximilian Heeg
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, 79106 Freiburg, Germany.,Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Pere Soler-Palacín
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital, 08035 Barcelona, Catalonia, Spain
| | | | | | | | | | | | | | - Francesca Conti
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.,Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Children's Hospital Bambino Gesù, 00165 Rome, Italy
| | - Silvia Di Cesare
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.,Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Children's Hospital Bambino Gesù, 00165 Rome, Italy
| | - Stephan Ehl
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, 79106 Freiburg, Germany.,Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Marina Garcia-Prat
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital, 08035 Barcelona, Catalonia, Spain
| | - Maria Elena Maccari
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, 79106 Freiburg, Germany.,Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Andrea Martín-Nalda
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital, 08035 Barcelona, Catalonia, Spain
| | - Mónica Martínez-Gallo
- Immunology Division and Diagnostic Immunology Research Group, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, 08035 Barcelona, Catalonia, Spain
| | - Despina Moshous
- Pediatric Immunology, Haematology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Center - University of Paris, 75743 Paris, France.,Imagine Institute, INSERM UMR 1163, University of Paris, 75015 Paris, France
| | - Veronica Santilli
- Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Children's Hospital Bambino Gesù, 00165 Rome, Italy
| | - Michaela Semeraro
- Imagine Institute, INSERM UMR 1163 et CNRS ERL 8254, University of Paris, 75015 Paris, France.,Academic Department of Pediatrics, Clinical Trial Unit, Children's Hospital Bambino Gesù, 00165 Rome, Italy
| | - Alessandra Simonetti
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.,Academic Department of Pediatrics, Clinical Trial Unit, Children's Hospital Bambino Gesù, 00165 Rome, Italy
| | - Felipe Suarez
- Imagine Institute, INSERM UMR 1163 et CNRS ERL 8254, University of Paris, 75015 Paris, France.,Adult Haematology Department, Haematology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Center - University of Paris, 75743 Paris, France
| | - Marina Cavazzana
- Biotherapy Clinical Investigation Center, University Hospitals Paris West, Assistance Publique-Hôpitaux de Paris, INSERM, 75004 Paris, France.,Imagine Institute, University of Paris, 75015 Paris, France.,Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; and.,Biotherapy Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Center - University of Paris, 75015 Paris, France
| | - Sven Kracker
- Imagine Institute, University of Paris, 75015 Paris, France.,Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; and
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Khaliullin F, Shabalina Y. Thietanyl Protection in the Synthesis of 8-Substituted 1-Benzyl-3-methyl-3,7-dihydro- 1H-purine-2,6-diones. Curr Org Synth 2020; 17:535-539. [PMID: 32600234 DOI: 10.2174/1570179417666200628015511] [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: 03/19/2020] [Revised: 05/30/2020] [Accepted: 06/01/2020] [Indexed: 11/22/2022]
Abstract
AIM AND OBJECTIVE 1-Аlkyl-3,7-dihydro-1H-purine-2,6-diones containing no substituents in the N7 position can be synthesized only using protecting groups, for example, benzyl protection. However, in the case of synthesis of 1-benzyl-3,7-dihydro-1H-purine-2,6-diones, the use of benzyl protection may lead to simultaneous debenzylation of both N1 and N7 positions. Therefore, it is necessary to use other protective groups for the synthesis of 1-benzyl-3,7-dihydro-1H-purine-2,6-diones. MATERIALS AND METHODS 8-Bromo- and 8-amino-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6-diones unsubstituted in the N7 position were synthesized with the use of thietanyl protecting group. The thietane ring was introduced via the reaction of 8-bromo-3-methyl-3,7-dihydro-1H-purine-2,6-dione with 2-chloromethylthiirane, giving rise to 8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-purine-2,6-dione. The subsequent alkylation with benzyl chloride yielded 1-benzyl-8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-purine-2,6-dione, which was oxidized with hydrogen peroxide to be converted to 1-benzyl-8-bromo-3-methyl-7-(1,1-dioxothietan- 3-yl)-3,7-dihydro-1H-purine-2,6-dione. This product reacted with amines to give 8-amino-substituted 1-benzyl-3- methyl-7-(1,1-dioxothietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones. The reaction of 8-substituted 1-benzyl-3- methyl-7-(1,1-dioxothietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones with sodium isopropoxide resulted in the removal of the thietanyl protection and afforded target 8-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6- diones. The structures of the targets compounds have been deduced upon their elemental analysis and spectral data (IR, 1H NMR, 13C NMR and 15N NMR). RESULTS AND DISCUSSION A new 8-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6-diones unsubstituted in the N7 position were synthesized using thietanyl protecting group. CONCLUSION The present study described a new route to synthesize some new 1,8-disubstituted 3-methyl-3,7- dihydro-1H-purine-2,6-diones unsubstituted in the N7 position starting from available 8-bromo-3-methyl-3,7- dihydro-1H-purine-2,6-dione with use of thietanyl protecting group. The advantages of this protocol are the possibility of the synthesis of 1-benzyl-substituted 3,7-dihydro-1H-purine-2,6-diones, the stability of the thietanyl protecting group upon nucleophilic substitution by amines of the bromine atom in the position 8, as well as mild conditions, and simple execution of experiments.
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Affiliation(s)
- Ferkat Khaliullin
- Department of Pharmaceutical Chemistry, Bashkir State Medical University, Ufa, Russian Federation
| | - Yuliya Shabalina
- Department of Pharmaceutical Chemistry, Bashkir State Medical University, Ufa, Russian Federation
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18
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Cui WQ, Wang ST, Pan D, Chang B, Sang LX. Caffeine and its main targets of colorectal cancer. World J Gastrointest Oncol 2020; 12:149-172. [PMID: 32104547 PMCID: PMC7031145 DOI: 10.4251/wjgo.v12.i2.149] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/25/2019] [Accepted: 11/13/2019] [Indexed: 02/05/2023] Open
Abstract
Caffeine is a purine alkaloid and is widely consumed in coffee, soda, tea, chocolate and energy drinks. To date, a growing number of studies have indicated that caffeine is associated with many diseases including colorectal cancer. Caffeine exerts its biological activity through binding to adenosine receptors, inhibiting phosphodiesterases, sensitizing calcium channels, antagonizing gamma-aminobutyric acid receptors and stimulating adrenal hormones. Some studies have indicated that caffeine can interact with signaling pathways such as transforming growth factor β, phosphoinositide-3-kinase/AKT/mammalian target of rapamycin and mitogen-activated protein kinase pathways through which caffeine can play an important role in colorectal cancer pathogenesis, metastasis and prognosis. Moreover, caffeine can act as a general antioxidant that protects cells from oxidative stress and also as a regulatory factor of the cell cycle that modulates the DNA repair system. Additionally, as for intestinal homeostasis, through the interaction with receptors and cytokines, caffeine can modulate the immune system mediating its effects on T lymphocytes, B lymphocytes, natural killer cells and macrophages. Furthermore, caffeine can not only directly inhibit species in the gut microbiome, such as Escherichia coli and Candida albicans but also can indirectly exert inhibition by increasing the effects of other antimicrobial drugs. This review summarizes the association between colorectal cancer and caffeine that is being currently studied.
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Affiliation(s)
- Wen-Qi Cui
- Department of Neurology, Shengjing Hospital, Affiliated Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- China Medical University 101K class 87, Shenyang 110001, Liaoning Province, China
| | - Shi-Tong Wang
- Department of Cardiovascular Ultrasound, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- China Medical University 101K class 87, Shenyang 110001, Liaoning Province, China
| | - Dan Pan
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Singh N, Shreshtha AK, Thakur M, Patra S. Xanthine scaffold: scope and potential in drug development. Heliyon 2018; 4:e00829. [PMID: 30302410 PMCID: PMC6174542 DOI: 10.1016/j.heliyon.2018.e00829] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 09/25/2018] [Accepted: 09/25/2018] [Indexed: 02/07/2023] Open
Abstract
Medicinal plants have been the basis for discovery of various important marketed drugs. Xanthine is one such lead molecule. Xanthines in various forms (caffeine, theophylline, theobromine, etc) are abode in tea, coffee, cocoa, chocolate etc. giving them popular recognition. These compounds are best known for their diverse pharmaceutical applications as cyclic nucleotide phosphodiesterase inhibition, antagonization of adenosine receptor, anti-inflammatory, anti-microbial, anti-oxidant and anti-tumor activities. These properties incentivize to use xanthine as scaffold to develop new derivatives. Chemical synthesis contributes greater diversity in xanthine based derivatisation. With highlighting the existing challenges in chemical synthesis, the present review focuses the probable solution to fill existing lacuna. The review summarizes the available knowledge of xanthine based drugs development along with exploring new xanthine led chemical synthesis path for bringing diversification in xanthine based research. The main objective of this review is to explore the immense potential of xanthine as scaffold in drug development.
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Affiliation(s)
- Nivedita Singh
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | | | - M.S. Thakur
- Fermentation Technology and Bioengineering Department, Central Food Technological Research Institute, Mysore, India
| | - Sanjukta Patra
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
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Dumontet C, Beck G, Gardebien F, Haudecoeur R, Mathé D, Matera EL, Tourette A, Mattei E, Esmenjaud J, Boyère C, Nurisso A, Peuchmaur M, Pérès B, Bouchaud G, Magnan A, Monneret G, Boumendjel A. Piperidinyl-embeded chalcones possessing anti PI3Kδ inhibitory properties exhibit anti-atopic properties in preclinical models. Eur J Med Chem 2018; 158:405-413. [PMID: 30237123 DOI: 10.1016/j.ejmech.2018.09.033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 09/09/2018] [Accepted: 09/11/2018] [Indexed: 11/25/2022]
Abstract
Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development.
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Affiliation(s)
- Charles Dumontet
- INSERM 1052/CNRS 5286/University of Lyon, Cancer Research Center of Lyon, France; Hospices Civils de Lyon, France
| | - Guillaume Beck
- Biologie Intégrée Du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de La Réunion, Univ. des Antilles; Laboratoire D'Excellence GR-Ex, Faculté des Sciences et Technologies, Saint Denis Messag, F-97715, La Réunion, Paris, France
| | - Fabrice Gardebien
- Biologie Intégrée Du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de La Réunion, Univ. des Antilles; Laboratoire D'Excellence GR-Ex, Faculté des Sciences et Technologies, Saint Denis Messag, F-97715, La Réunion, Paris, France
| | | | - Doriane Mathé
- INSERM 1052/CNRS 5286/University of Lyon, Cancer Research Center of Lyon, France
| | - Eva-Laure Matera
- INSERM 1052/CNRS 5286/University of Lyon, Cancer Research Center of Lyon, France
| | - Anne Tourette
- INSERM 1052/CNRS 5286/University of Lyon, Cancer Research Center of Lyon, France
| | - Eve Mattei
- INSERM 1052/CNRS 5286/University of Lyon, Cancer Research Center of Lyon, France
| | - Justine Esmenjaud
- INSERM 1052/CNRS 5286/University of Lyon, Cancer Research Center of Lyon, France
| | - Cédric Boyère
- Univ. Grenoble Alpes, CNRS, DPM UMR 5063, F-38041, Grenoble, France
| | - Alessandra Nurisso
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, CH-1211, Geneva 4, Switzerland
| | - Marine Peuchmaur
- Univ. Grenoble Alpes, CNRS, DPM UMR 5063, F-38041, Grenoble, France
| | - Basile Pérès
- Univ. Grenoble Alpes, CNRS, DPM UMR 5063, F-38041, Grenoble, France
| | - Grégory Bouchaud
- INSERM, CNRS, UNIV Nantes, L'institut Du Thorax, CHU, Nantes, France; INRA, UR1268, BIA, Nantes, France
| | - Antoine Magnan
- INSERM, CNRS, UNIV Nantes, L'institut Du Thorax, CHU, Nantes, France; INRA, UR1268, BIA, Nantes, France
| | | | - Ahcène Boumendjel
- Univ. Grenoble Alpes, CNRS, DPM UMR 5063, F-38041, Grenoble, France.
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21
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Mechanistic considerations in chemotherapeutic activity of caffeine. Biomed Pharmacother 2018; 105:312-319. [DOI: 10.1016/j.biopha.2018.05.144] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/28/2018] [Accepted: 05/28/2018] [Indexed: 12/15/2022] Open
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22
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Du X, Guan Y, Huang Q, Lv M, He X, Yan L, Hayashi S, Fang C, Wang X, Sheng J. Low Concentrations of Caffeine and Its Analogs Extend the Lifespan of Caenorhabditis elegans by Modulating IGF-1-Like Pathway. Front Aging Neurosci 2018; 10:211. [PMID: 30061824 PMCID: PMC6054938 DOI: 10.3389/fnagi.2018.00211] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 06/22/2018] [Indexed: 01/08/2023] Open
Abstract
Caffeine has been reported to delay aging and protect aging-associated disorders in Caenorhabditis elegans. However, the effects of low concentration of caffeine and its analogs on lifespan are currently missing. Herein, we report that at much lower concentrations (as low as 10 μg/ml), caffeine extended the lifespan of C. elegans without affecting food intake and reproduction. The effect of caffeine was dependent on IGF-1-like pathway, although the insulin receptor homolog, daf-2 allele, e1371, was dispensable. Four caffeine analogs, 1-methylxanthine, 7-methylxanthine, 1,3-dimethylxanthine, and 1,7-dimethylxanthine, also extended lifespan, whereas 3-methylxanthine and 3,7-dimethylxanthine did not exhibit lifespan-extending activity.
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Affiliation(s)
- Xiaocui Du
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.,Tea Research Center of Yunnan, Yunnan Academy of Agricultural Sciences, Kunming, China.,College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Yun Guan
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.,Tea Research Center of Yunnan, Yunnan Academy of Agricultural Sciences, Kunming, China.,College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Qin Huang
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.,Tea Research Center of Yunnan, Yunnan Academy of Agricultural Sciences, Kunming, China.,College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Ming Lv
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.,Tea Research Center of Yunnan, Yunnan Academy of Agricultural Sciences, Kunming, China.,College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Xiaofang He
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.,Tea Research Center of Yunnan, Yunnan Academy of Agricultural Sciences, Kunming, China.,College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Liang Yan
- Pu'er Institute of Pu-erh Tea, Pu'er, China
| | - Shuhei Hayashi
- Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan.,China-Japan Joint Center for Bioresource Research and Development, Yunnan Agricultural University, Kunming, China
| | - Chongye Fang
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.,Tea Research Center of Yunnan, Yunnan Academy of Agricultural Sciences, Kunming, China.,China-Japan Joint Center for Bioresource Research and Development, Yunnan Agricultural University, Kunming, China.,College of Veterinary Medicine, Yunnan Agricultural University, Kunming, China.,State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming, China
| | - Xuanjun Wang
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.,Tea Research Center of Yunnan, Yunnan Academy of Agricultural Sciences, Kunming, China.,China-Japan Joint Center for Bioresource Research and Development, Yunnan Agricultural University, Kunming, China.,State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming, China.,College of Science, Yunnan Agricultural University, Kunming, China
| | - Jun Sheng
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.,Tea Research Center of Yunnan, Yunnan Academy of Agricultural Sciences, Kunming, China.,China-Japan Joint Center for Bioresource Research and Development, Yunnan Agricultural University, Kunming, China.,State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming, China
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23
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Valencic E, Grasso AG, Conversano E, Lucafò M, Piscianz E, Gregori M, Conti F, Cancrini C, Tommasini A. Theophylline as a precision therapy in a young girl with PIK3R1 immunodeficiency. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2018; 6:2165-2167. [PMID: 29510232 DOI: 10.1016/j.jaip.2018.02.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 02/19/2018] [Accepted: 02/21/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Erica Valencic
- Department of Pediatrics, Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Antonio Giacomo Grasso
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Ester Conversano
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
| | - Marianna Lucafò
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Elisa Piscianz
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Massimo Gregori
- Department of Pediatrics, Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Francesca Conti
- Department of Pediatrics, Children's Hospital Bambino Gesù, Rome, Italy
| | - Caterina Cancrini
- Department of Pediatrics, Children's Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, "University of Rome Tor Vergata", Rome, Italy
| | - Alberto Tommasini
- Department of Pediatrics, Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
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24
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Holy EW, Camici GG, Akhmedov A, Stämpfli SF, Stähli BE, von Rickenbach B, Breitenstein A, Greutert H, Yang Z, Lüscher TF, Gebhard C, Tanner FC. Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition. Thromb Haemost 2017; 107:884-94. [DOI: 10.1160/th11-09-0624] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2011] [Accepted: 01/16/2012] [Indexed: 11/05/2022]
Abstract
SummaryTissue factor (TF) is the key activator of coagulation and is involved in acute coronary syndromes. Caffeine is often reported to increase cardiovascular risk; however, its effect on cardiovascular morbidity and mortality is controversial. Hence, this study was designed to investigate the impact of caffeine on endothelial TF expression in vitro. Caffeine concentration-dependently enhanced TF protein expression and surface activity in human endothelial cells stimulated by tumour necrosis factor (TNF)-α or thrombin. Caffeine inhibited phosphatidylinositol 3-kinase (PI3K) activity and this effect was comparable to that of the known PI3K inhibitor LY294002. Consistently, treatment of endothelial cells with LY294002 enhanced TNF-α induced TF expression to a similar extent as caffeine, and adenoviral expression of the active PI3K mutant (p110) reversed the effect of both caffeine and LY294002 on TF expression. Caffeine and LY294002 increased DNA binding capacity of the transcription factor nuclear factor κB, whereas the activation pattern of mitogen-activated protein kinases (MAPK) remained unaltered. Luciferase reporter assay revealed a caffeine dependent activation of the TF promoter, and RT-PCR revealed a dose dependent increase in TF mRNA levels when stimulated with caffeine in the presence of TNF-α. In conclusion, caffeine enhances TNF-α-induced endothelial TF protein expression as well as surface activity by inhibition of PI3K signalling. Since the caffeine concentrations applied in the present study are within the plasma range measured in humans, our findings indicate that caffeine enhances the prothrombotic potential of endothelial cells and underscore the importance of PI3K in mediating these effects.
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Cruz FF, Leite CE, Kist LW, de Oliveira GM, Bogo MR, Bonan CD, Campos MM, Morrone FB. Effects of caffeine on behavioral and inflammatory changes elicited by copper in zebrafish larvae: Role of adenosine receptors. Comp Biochem Physiol C Toxicol Pharmacol 2017; 194:28-36. [PMID: 28163255 DOI: 10.1016/j.cbpc.2017.01.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 01/25/2017] [Accepted: 01/27/2017] [Indexed: 12/13/2022]
Abstract
This study investigated the effects of caffeine in the behavioral and inflammatory alterations caused by copper in zebrafish larvae, attempting to correlate these changes with the modulation of adenosine receptors. To perform a survival curve, 7dpf larvae were exposed to 10μM CuSO4, combined to different concentrations of caffeine (100μM, 500μM and 1mM) for up to 24h. The treatment with copper showed lower survival rates only when combined with 500μM and 1mM of caffeine. We selected 4 and 24h as treatment time-points. The behavior evaluation was done by analyzing the traveled distance, the number of entries in the center, and the length of permanence in the center and the periphery of the well. The exposure to 10μM CuSO4 plus 500μM caffeine at 4 and 24h changed the behavioral parameters. To study the inflammatory effects of caffeine, we assessed the PGE2 levels by using UHPLC-MS/MS, and TNF, COX-2, IL-6 and IL-10 gene expression by RT-qPCR. The expression of adenosine receptors was also evaluated with RT-qPCR. When combined to copper, caffeine altered inflammatory markers depending on the time of exposure. Adenosine receptors expression was significantly increased, especially after 4h exposure to copper and caffeine together or separately. Our results demonstrated that caffeine enhances the inflammation induced by copper by decreasing animal survival, altering inflammatory markers and promoting behavioral changes in zebrafish larvae. We also conclude that alterations in adenosine receptors are related to those effects.
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Affiliation(s)
- Fernanda Fernandes Cruz
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Avenida Ipiranga, 6690, 90619-900 Porto Alegre, RS, Brazil; Laboratório de Farmacologia Aplicada, PUCRS, Avenida Ipiranga, 6681, Partenon, 90619-900 Porto Alegre, RS, Brazil
| | - Carlos Eduardo Leite
- Instituto de Toxicologia e Farmacologia, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil
| | - Luiza Wilges Kist
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Avenida Ipiranga, 6690, 90619-900 Porto Alegre, RS, Brazil; Laboratório de Genômica e Biologia Molecular, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil
| | - Giovanna Medeiros de Oliveira
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Avenida Ipiranga, 6690, 90619-900 Porto Alegre, RS, Brazil; Laboratório de Genômica e Biologia Molecular, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil
| | - Maurício Reis Bogo
- Faculdade de Biociências, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil; Laboratório de Genômica e Biologia Molecular, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil
| | - Carla Denise Bonan
- Faculdade de Biociências, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil
| | - Maria Martha Campos
- Instituto de Toxicologia e Farmacologia, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil; Faculdade de Odontologia, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil
| | - Fernanda Bueno Morrone
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Avenida Ipiranga, 6690, 90619-900 Porto Alegre, RS, Brazil; Laboratório de Farmacologia Aplicada, PUCRS, Avenida Ipiranga, 6681, Partenon, 90619-900 Porto Alegre, RS, Brazil; Faculdade de Farmácia, PUCRS, Avenida Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil.
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26
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Hock BD, MacPherson SA, McKenzie JL. Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells. PLoS One 2017; 12:e0172858. [PMID: 28257435 PMCID: PMC5336221 DOI: 10.1371/journal.pone.0172858] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 02/12/2017] [Indexed: 12/16/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is associated with T cell dysfunction. Activated CLL cells are found within the lymphoid tumor micro-environment and overcoming immuno-suppression induced by these cells may improve anti-CLL immune responses. However, the mechanisms by which activated CLL cells inhibit T cell responses, and reagents targeting such mechanisms have not been identified. Here we demonstrate that the ability of in vitro activated CLL cells to suppress T cell proliferation is not reversed by the presence of ecto-nuclease inhibitors or blockade of IL-10, PD-1 and CTLA-4 pathways. Caffeine is both an adenosine receptor antagonist and a phosphatidylinositol-3-kinase, p110δ (PI3Kδ) inhibitor and, at physiologically relevant levels, significantly reversed suppression. Significant reversal of suppression was also observed with the PI3Kδ specific inhibitor Idelalisib but not with adenosine receptor specific antagonists. Furthermore, addition of caffeine or Idelalisib to activated CLL cells significantly inhibited phosphorylation of AKT, a downstream kinase of PI3K, but did not affect CLL viability. These results suggest that caffeine, in common with Idelalisib, reduces the immuno-suppressive activity of activated CLL cells by inhibiting PI3Kδ. These findings raise the possibility that these compounds may provide a useful therapeutic adjunct by reducing immuno-suppression within the tumor micro-environment of CLL.
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MESH Headings
- Caffeine/administration & dosage
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Humans
- Immunity, Cellular/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Phosphatidylinositol 3-Kinases/biosynthesis
- Phosphorylation/drug effects
- Protein Kinase Inhibitors/administration & dosage
- Purines/administration & dosage
- Quinazolinones/administration & dosage
- Signal Transduction/drug effects
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/pathology
- Tumor Microenvironment/drug effects
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Affiliation(s)
- Barry D. Hock
- Haematology Research Group, Christchurch Hospital, Christchurch, New Zealand
- Pathology Department, University of Otago, Christchurch, New Zealand
- * E-mail:
| | - Sean A. MacPherson
- Pathology Department, University of Otago, Christchurch, New Zealand
- Haematology Department, Christchurch Hospital, Christchurch, New Zealand
| | - Judith L. McKenzie
- Haematology Research Group, Christchurch Hospital, Christchurch, New Zealand
- Pathology Department, University of Otago, Christchurch, New Zealand
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27
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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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28
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Abstract
Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug-drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease. The molecular mechanism(s) of action of theophylline are not well understood, but several potential targets have been suggested including non-selective inhibition of phosphodiesterases (PDE), inhibition of phosphoinositide 3-kinase, adenosine receptor antagonism and increased activity of certain histone deacetylases. Although theophylline has a narrow therapeutic window, other xanthines are in clinical use that are claimed to have a better tolerability such as doxofylline and bamifylline. Nonetheless, xanthines still play an important role in the treatment of asthma and COPD as they can show clinical benefit in patients who are refractory to glucocorticosteroid therapy, and withdrawal of xanthines from patients causes worsening of disease, even in patients taking concomitant glucocorticosteroids.More recently the orally active selective PDE4 inhibitor, roflumilast, has been introduced into clinical practice for the treatment of severe COPD on top of gold standard treatment. This drug has been shown to improve lung function in patients with severe COPD and to reduce exacerbations, but is dose limited by a range side effect, particularly gastrointestinal side effects.
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Affiliation(s)
- D Spina
- The Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London, SE1 9NH, UK
| | - C P Page
- The Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London, SE1 9NH, UK.
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Zolea F, Biamonte F, Battaglia AM, Faniello MC, Cuda G, Costanzo F. Caffeine Positively Modulates Ferritin Heavy Chain Expression in H460 Cells: Effects on Cell Proliferation. PLoS One 2016; 11:e0163078. [PMID: 27657916 PMCID: PMC5033359 DOI: 10.1371/journal.pone.0163078] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 09/02/2016] [Indexed: 12/31/2022] Open
Abstract
Both the methylxanthine caffeine and the heavy subunit of ferritin molecule (FHC) are able to control the proliferation rate of several cancer cell lines. While caffeine acts exclusively as a negative modulator of cell proliferation, FHC might reduce or enhance cell viability depending upon the different cell type. In this work we have demonstrated that physiological concentrations of caffeine reduce the proliferation rate of H460 cells: along with the modulation of p53, pAKT and Cyclin D1, caffeine also determines a significant FHC up-regulation through the activation of its transcriptional efficiency. FHC plays a central role in the molecular pathways modulated by caffeine, ending in a reduced cell growth, since its specific silencing by siRNA almost completely abolishes caffeine effects on H460 cell proliferation. These results allow the inclusion of ferritin heavy subunits among the multiple molecular targets of caffeine and open the way for studying the relationship between caffeine and intracellular iron metabolism.
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Affiliation(s)
- Fabiana Zolea
- Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Viale Europa, 88100, Catanzaro, Italy
| | - Flavia Biamonte
- Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Viale Europa, 88100, Catanzaro, Italy
| | - Anna Martina Battaglia
- Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Viale Europa, 88100, Catanzaro, Italy
| | - Maria Concetta Faniello
- Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Viale Europa, 88100, Catanzaro, Italy
| | - Giovanni Cuda
- Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Viale Europa, 88100, Catanzaro, Italy
| | - Francesco Costanzo
- Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Viale Europa, 88100, Catanzaro, Italy
- * E-mail:
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30
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Balu D, Ouyang J, Parakhia RA, Pitake S, Ochs RS. Ca 2+ effects on glucose transport and fatty acid oxidation in L6 skeletal muscle cell cultures. Biochem Biophys Rep 2016; 5:365-373. [PMID: 28955844 PMCID: PMC5600334 DOI: 10.1016/j.bbrep.2016.01.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 12/17/2015] [Accepted: 01/11/2016] [Indexed: 12/03/2022] Open
Abstract
We examined the effect of Ca2+ on skeletal muscle glucose transport and fatty acid oxidation using L6 cell cultures. Ca2+ stimulation of glucose transport is controversial. We found that caffeine (a Ca2+ secretagogue) stimulation of glucose transport was only evident in a two-part incubation protocol ("post-incubation"). Caffeine was present in the first incubation, the media removed, and labeled glucose added for the second. Caffeine elicited a rise in Ca2+ in the first incubation that was dissipated by the second. This post-incubation procedure was insensitive to glucose concentrations in the first incubation. With a single, direct incubation system (all components present together) caffeine caused a slight inhibition of glucose transport. This was likely due to caffeine induced inhibition of phosphatidylinositol 3-kinase (PI3K), since nanomolar concentrations of wortmannin, a selective PI3K inhibitor, also inhibited glucose transport, and previous investigators have also found this action. We did find a Ca2+ stimulation (using either caffeine or ionomycin) of fatty acid oxidation. This was observed in the absence (but not the presence) of added glucose. We conclude that Ca2+ stimulates fatty acid oxidation at a mitochondrial site, secondary to malonyl CoA inhibition (represented by the presence of glucose in our experiments). In summary, the experiments resolve a controversy on Ca2+ stimulation of glucose transport by skeletal muscle, introduce an important experimental consideration for the measurement of glucose transport, and uncover a new site of action for Ca2+ stimulation of fatty acid oxidation.
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Affiliation(s)
- Darrick Balu
- Dept. Psychiatry, McLean Hospital, MRC I 114, 115 Mill St., Belmont, MA 02478, USA
| | - Jiangyong Ouyang
- Department of Pharmacology, New York University School of Medicine, 550 1st Ave, New York, NY 10016, USA
| | - Rahulkumar A. Parakhia
- Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07407, USA
| | - Saumitra Pitake
- Department of Pharmaceutical Sciences, School of Pharmacy, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA
| | - Raymond S. Ochs
- Department of Pharmaceutical Sciences, School of Pharmacy, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA
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31
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Dirks-Naylor AJ. The benefits of coffee on skeletal muscle. Life Sci 2015; 143:182-186. [PMID: 26546720 DOI: 10.1016/j.lfs.2015.11.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/06/2015] [Accepted: 11/04/2015] [Indexed: 12/22/2022]
Abstract
Coffee is consumed worldwide with greater than a billion cups of coffee ingested every day. Epidemiological studies have revealed an association of coffee consumption with reduced incidence of a variety of chronic diseases as well as all-cause mortality. Current research has primarily focused on the effects of coffee or its components on various organ systems such as the cardiovascular system, with relatively little attention on skeletal muscle. Summary of current literature suggests that coffee has beneficial effects on skeletal muscle. Coffee has been shown to induce autophagy, improve insulin sensitivity, stimulate glucose uptake, slow the progression of sarcopenia, and promote the regeneration of injured muscle. Much more research is needed to reveal the full scope of benefits that coffee consumption may exert on skeletal muscle structure and function.
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Affiliation(s)
- Amie J Dirks-Naylor
- School of Pharmacy, Wingate University, 515 N. Main Street, Wingate, NC 28174, United States.
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32
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Bonyanian Z, Rose'Meyer RB. Caffeine and its Potential Role in Attenuating Impaired Wound Healing in Diabetes. JOURNAL OF CAFFEINE RESEARCH 2015. [DOI: 10.1089/jcr.2015.0011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Zeinab Bonyanian
- School of Medical Sciences, Griffith University, Gold Coast, Australia
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Tsuda S, Egawa T, Kitani K, Oshima R, Ma X, Hayashi T. Caffeine and contraction synergistically stimulate 5'-AMP-activated protein kinase and insulin-independent glucose transport in rat skeletal muscle. Physiol Rep 2015; 3:3/10/e12592. [PMID: 26471759 PMCID: PMC4632959 DOI: 10.14814/phy2.12592] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
5′-Adenosine monophosphate-activated protein kinase (AMPK) has been identified as a key mediator of contraction-stimulated insulin-independent glucose transport in skeletal muscle. Caffeine acutely stimulates AMPK in resting skeletal muscle, but it is unknown whether caffeine affects AMPK in contracting muscle. Isolated rat epitrochlearis muscle was preincubated and then incubated in the absence or presence of 3 mmol/L caffeine for 30 or 120 min. Electrical stimulation (ES) was used to evoke tetanic contractions during the last 10 min of the incubation period. The combination of caffeine plus contraction had additive effects on AMPKα Thr172 phosphorylation, α-isoform-specific AMPK activity, and 3-O-methylglucose (3MG) transport. In contrast, caffeine inhibited basal and contraction-stimulated Akt Ser473 phosphorylation. Caffeine significantly delayed muscle fatigue during contraction, and the combination of caffeine and contraction additively decreased ATP and phosphocreatine contents. Caffeine did not affect resting tension. Next, rats were given an intraperitoneal injection of caffeine (60 mg/kg body weight) or saline, and the extensor digitorum longus muscle was dissected 15 min later. ES of the sciatic nerve was performed to evoke tetanic contractions for 5 min before dissection. Similar to the findings from isolated muscles incubated in vitro, the combination of caffeine plus contraction in vivo had additive effects on AMPK phosphorylation, AMPK activity, and 3MG transport. Caffeine also inhibited basal and contraction-stimulated Akt phosphorylation in vivo. These findings suggest that caffeine and contraction synergistically stimulate AMPK activity and insulin-independent glucose transport, at least in part by decreasing muscle fatigue and thereby promoting energy consumption during contraction.
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Affiliation(s)
- Satoshi Tsuda
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan
| | - Tatsuro Egawa
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Toyohashi, 440-0016, Japan
| | - Kazuto Kitani
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan
| | - Rieko Oshima
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan
| | - Xiao Ma
- Key Laboratory of Puer Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, Yunnan Province, China
| | - Tatsuya Hayashi
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan
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Okita R, Wolf D, Yasuda K, Maeda A, Yukawa T, Saisho S, Shimizu K, Yamaguchi Y, Oka M, Nakayama E, Lundqvist A, Kiessling R, Seliger B, Nakata M. Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells. PLoS One 2015; 10:e0139809. [PMID: 26439264 PMCID: PMC4595469 DOI: 10.1371/journal.pone.0139809] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 09/17/2015] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION Several cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown. METHODS This study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis. RESULTS We demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a. CONCLUSION In keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.
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Affiliation(s)
- Riki Okita
- Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan
- Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
- * E-mail:
| | - Diana Wolf
- Institute of Medical Immunology, Martin Luther University, Halle-Wittenberg, Halle, Germany
| | - Koichiro Yasuda
- Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan
| | - Ai Maeda
- Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan
| | - Takuro Yukawa
- Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan
| | - Shinsuke Saisho
- Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan
| | - Katsuhiko Shimizu
- Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan
| | | | - Mikio Oka
- Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Eiichi Nakayama
- Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Kurashiki, Japan
| | - Andreas Lundqvist
- Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
| | - Rolf Kiessling
- Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University, Halle-Wittenberg, Halle, Germany
| | - Masao Nakata
- Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan
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Pitaksalee R, Sanvarinda Y, Sinchai T, Sanvarinda P, Thampithak A, Jantaratnotai N, Jariyawat S, Tuchinda P, Govitrapong P, Sanvarinda P. Autophagy Inhibition by Caffeine Increases Toxicity of Methamphetamine in SH-SY5Y Neuroblastoma Cell Line. Neurotox Res 2015; 27:421-9. [DOI: 10.1007/s12640-014-9513-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 11/29/2014] [Accepted: 12/22/2014] [Indexed: 12/31/2022]
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MOON JIHONG, LEE JUHEE, PARK JINYOUNG, KIM SUNGWOOK, LEE YOUJIN, KANG SEOGJIN, SEOL JAEWON, AHN DONGCHOON, PARK SANGYOUEL. Caffeine prevents human prion protein-mediated neurotoxicity through the induction of autophagy. Int J Mol Med 2014; 34:553-8. [DOI: 10.3892/ijmm.2014.1814] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 06/16/2014] [Indexed: 11/05/2022] Open
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Markou T, Chambers DJ. Lung injury after simulated cardiopulmonary bypass in an isolated perfused rat lung preparation: Role of mitogen-activated protein kinase/Akt signaling and the effects of theophylline. J Thorac Cardiovasc Surg 2014; 148:2335-44. [PMID: 24841445 PMCID: PMC4226635 DOI: 10.1016/j.jtcvs.2014.04.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 04/14/2014] [Accepted: 04/17/2014] [Indexed: 12/25/2022]
Abstract
Objectives Lung deflation and inflation during cardiac surgery with cardiopulmonary bypass contributes to pulmonary dysfunction postoperatively. Theophylline treatment for lung diseases has traditionally been thought to act by phosphodiesterase inhibition; however, increasing evidence has suggested other plausible mechanisms. We investigated the effects of deflation and reinflation on signaling pathways (p38-mitogen-activated protein kinase [MAPK], extracellular signal-regulated kinase 1 and 2 [ERK1/2], and Akt) and whether theophylline influences the deflation-induced lung injury and associated signaling. Methods Isolated rat lungs were perfused (15 mL/min) with deoxygenated rat blood in bicarbonate buffer and ventilated. After 20 minutes' equilibration, the lungs were deflated (60 minutes, aerobic perfusion 1.5 mL/min), followed by reinflation (60 minutes, anaerobic reperfusion 15 mL/min). Compliance, vascular resistance, and kinase phosphorylation were assessed during deflation and reinflation. The effects of SB203580 (50 μM), a p38-MAPK inhibitor, and theophylline (0.083 mM [therapeutic] or 3 mM [supratherapeutic]) on physiology and signaling were studied. Results Deflation reduced compliance by 44% compared with continuously ventilated lungs. p38-MAPK and Akt phosphorylation increased (three to fivefold) during deflation and reinflation, and ERK1/2 phosphorylation increased (approximately twofold) during reinflation. SB203580 had no effect on lung physiology or ERK1/2 and Akt activation. Both theophylline doses increased cyclic adenosine monophosphate, but only 3 mM theophylline improved compliance. p38-MAPK phosphorylation was not affected by theophylline; 0.083 mM theophylline inhibited reinflation-induced ERK1/2 phosphorylation (72% ± 3%); and 3 mM theophylline inhibited Akt phosphorylation during deflation (75% ± 5%) and reinflation (87% ± 4%). Conclusions Lung deflation and reinflation stimulates differential p38-MAPK, ERK1/2, and Akt activation, suggesting a role in lung injury during cardiopulmonary bypass. However, p38-MAPK was not involved in the compromised compliance. A supratherapeutic theophylline dose protected lungs against deflation-induced injury and was associated with inhibition of phosphoinositide 3-kinase/Akt rather than phosphodiesterase.
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Affiliation(s)
- Thomais Markou
- Cardiac Surgical Research, Rayne Institute, King's College London, St Thomas' Hospital Campus, London, United Kingdom.
| | - David J Chambers
- Cardiac Surgical Research, Rayne Institute, King's College London, Guy's and St Thomas' National Health Service Foundation Trust, St Thomas' Hospital, London, United Kingdom
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Al-Ansari MM, Aboussekhra A. Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes. PLoS One 2014; 9:e90907. [PMID: 24595168 PMCID: PMC3940951 DOI: 10.1371/journal.pone.0090907] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 02/06/2014] [Indexed: 12/13/2022] Open
Abstract
Background Active cancer-associated fibroblasts (CAFs) or myofibroblasts play important roles not only in the development and progression of breast carcinomas, but also in their prognosis and treatment. Therefore, targeting these cells through suppressing their supportive procarcinogenic paracrine effects is mandatory for improving the current therapies that are mainly targeting tumor cells. To this end, we investigated the effect of the natural and pharmacologically safe molecule, caffeine, on CAF cells and their various procarcinogenic effects. Methodology/Principal Findings We have shown here that caffeine up-regulates the tumor suppressor proteins p16, p21, p53 and Cav-1, and reduces the expression/secretion of various cytokines (IL-6, TGF-β, SDF-1 and MMP-2), and down-regulates α-SMA. Furthermore, caffeine suppressed the migratory/invasiveness abilities of CAF cells through PTEN-dependent Akt/Erk1/2 inactivation. Moreover, caffeine reduced the paracrine pro-invasion/−migration effects of CAF cells on breast cancer cells. These results indicate that caffeine can inactivate breast stromal myofibroblasts. This has been confirmed by showing that caffeine also suppresses the paracrine pro-angiogenic effect of CAF cells through down-regulating HIF-1αand its downstream effector VEGF-A. Interestingly, these effects were sustained in absence of caffeine. Conclusion/Significance The present findings provide a proof of principle that breast cancer myofibroblasts can be inactivated, and thereby caffeine may provide a safe and effective prevention against breast tumor growth/recurrence through inhibition of the procarcinogenic effects of active stromal fibroblasts.
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Affiliation(s)
- Mysoon M. Al-Ansari
- Department of Microbiology, Faculty of Science and Medical Studies, King Saud University, Riyadh, Saudi Arabia
| | - Abdelilah Aboussekhra
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- * E-mail:
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Edling CE, Selvaggi F, Ghonaim R, Maffucci T, Falasca M. Caffeine and the analog CGS 15943 inhibit cancer cell growth by targeting the phosphoinositide 3-kinase/Akt pathway. Cancer Biol Ther 2014; 15:524-32. [PMID: 24521981 DOI: 10.4161/cbt.28018] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Caffeine is a naturally occurring methylxanthine that acts as a non-selective adenosine receptor antagonist. Epidemiological studies demonstrated habitual coffee drinking to be significantly associated with liver cancer survival. We aimed to investigate the effects of caffeine and its analog CGS 15943 on hepatocellular carcinoma (HCC) and pancreatic cancer adenocarcinoma (PDAC). We demonstrate that caffeine and CGS 15943 block proliferation in HCC and PDAC cell lines by inhibiting the PI3K/Akt pathway. Importantly a kinase profiling assay reveals that CGS 15943 targets specifically the catalytic subunit of the class IB PI3K isoform (p110γ). These data give mechanistic insight into the action of caffeine and its analogs and they identify these compounds as promising lead compounds to develop drugs that can specifically target this PI3K isoform whose key role in cancer progression is emerging.
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Affiliation(s)
- Charlotte E Edling
- Queen Mary University of London; Blizard Institute; Barts and The London School of Medicine and Dentistry; Inositide Signalling Group; London, UK
| | - Federico Selvaggi
- Queen Mary University of London; Blizard Institute; Barts and The London School of Medicine and Dentistry; Inositide Signalling Group; London, UK
| | - Ragheda Ghonaim
- Queen Mary University of London; Blizard Institute; Barts and The London School of Medicine and Dentistry; Inositide Signalling Group; London, UK
| | - Tania Maffucci
- Queen Mary University of London; Blizard Institute; Barts and The London School of Medicine and Dentistry; Inositide Signalling Group; London, UK
| | - Marco Falasca
- Queen Mary University of London; Blizard Institute; Barts and The London School of Medicine and Dentistry; Inositide Signalling Group; London, UK
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Buchanan CM, Dickson JMJ, Lee WJ, Guthridge MA, Kendall JD, Shepherd PR. Oncogenic mutations of p110α isoform of PI 3-kinase upregulate its protein kinase activity. PLoS One 2013; 8:e71337. [PMID: 23936502 PMCID: PMC3731339 DOI: 10.1371/journal.pone.0071337] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 07/03/2013] [Indexed: 12/31/2022] Open
Abstract
In addition to lipid kinase activity, the class-I PI 3-kinases also function as protein kinases targeting regulatory autophosphorylation sites and exogenous substrates. The latter include a recently identified regulatory phosphorylation of the GM-CSF/IL-3 βc receptor contributing to survival of acute myeloid leukaemia cells. Previous studies suggested differences in the protein kinase activity of the 4 isoforms of class-I PI 3-kinase so we compared the ability of all class-I PI 3-kinases and 2 common oncogenic mutants to autophosphorylate, and to phosphorylate an intracellular fragment of the GM-CSF/IL-3 βc receptor (βic). We find p110α, p110β and p110γ all phosphorylate βic but p110δ is much less effective. The two most common oncogenic mutants of p110α, H1047R and E545K have stronger protein kinase activity than wildtype p110α, both in terms of autophosphorylation and towards βic. Importantly, the lipid kinase activity of the oncogenic mutants is still inhibited by autophosphorylation to a similar extent as wildtype p110α. Previous evidence indicates the protein kinase activity of p110α is Mn(2+) dependent, casting doubt over its role in vivo. However, we show that the oncogenic mutants of p110α plus p110β and p110γ all display significant activity in the presence of Mg(2+). Furthermore we demonstrate that some small molecule inhibitors of p110α lipid kinase activity (PIK-75 and A66) are equally effective against the protein kinase activity, but other inhibitors (e.g. wortmannin and TGX221) show different patterns of inhibition against the lipid and protein kinases activities. These findings have implications for the function of PI 3-kinase, especially in tumours carrying p110α mutations.
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Affiliation(s)
- Christina M. Buchanan
- Department of Molecular Medicine, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - James M. J. Dickson
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Woo-Jeong Lee
- Department of Molecular Medicine, University of Auckland, Auckland, New Zealand
| | - Mark A. Guthridge
- Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia
| | - Jackie D. Kendall
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
| | - Peter R. Shepherd
- Department of Molecular Medicine, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
- * E-mail:
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Johnson IM, Prakash H, Prathiba J, Raghunathan R, Malathi R. Spectral analysis of naturally occurring methylxanthines (theophylline, theobromine and caffeine) binding with DNA. PLoS One 2012; 7:e50019. [PMID: 23236361 PMCID: PMC3517612 DOI: 10.1371/journal.pone.0050019] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 10/17/2012] [Indexed: 12/13/2022] Open
Abstract
Nucleic acids exist in a dynamic equilibrium with a number of molecules that constantly interact with them and regulate the cellular activities. The inherent nature of the structure and conformational integrity of these macromolecules can lead to altered biological activity through proper targeting of nucleic acids binding ligands or drug molecules. We studied the interaction of naturally occurring methylxanthines such as theophylline, theobromine and caffeine with DNA, using UV absorption and Fourier transform infrared (FTIR) spectroscopic methods, and especially monitored their binding affinity in the presence of Mg(2+) and during helix-coil transitions of DNA by temperature (T(m)) or pH melting profiles. The study indicates that all these molecules effectively bind to DNA in a dose dependent manner. The overall binding constants of DNA-theophylline = 3.5×10(3) M(-1), DNA-theobromine = 1.1×10(3) M(-1), and DNA-Caffeine = 3.8×10(3) M(-1). On the other hand T(m)/pH melting profiles showed 24-35% of enhanced binding activity of methylxanthines during helix-coil transitions of DNA rather than to its native double helical structure. The FTIR analysis divulged that theophylline, theobromine and caffeine interact with all the base pairs of DNA (A-T; G-C) and phosphate group through hydrogen bond (H-bond) interaction. In the presence of Mg(2+), methylxanthines altered the structure of DNA from B to A-family. However, the B-family structure of DNA remained unaltered in DNA-methylxanthines complexes or in the absence of Mg(2+). The spectral analyses indicated the order of binding affinity as "caffeine≥theophylline>theobromine" to the native double helical DNA, and "theophylline≥theobromine>caffeine to the denatured form of DNA and in the presence of divalent metal ions.
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Affiliation(s)
- Irudayam Maria Johnson
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- Department of Genetics, Taramani Campus, University of Madras, Chennai, India
- * E-mail: (IMJ); (RM)
| | - Halan Prakash
- National Centre for Ultrafast Processes, Taramani Campus, University of Madras, Chennai, India
| | - Jeyaguru Prathiba
- Department of Genetics, Taramani Campus, University of Madras, Chennai, India
| | | | - Raghunathan Malathi
- Department of Genetics, Taramani Campus, University of Madras, Chennai, India
- * E-mail: (IMJ); (RM)
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Grant I, Cartwright JE, Lumicisi B, Wallace AE, Whitley GS. Caffeine inhibits EGF-stimulated trophoblast cell motility through the inhibition of mTORC2 and Akt. Endocrinology 2012; 153:4502-10. [PMID: 22851680 DOI: 10.1210/en.2011-1930] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Impaired trophoblast invasion is associated with pregnancy disorders such as early pregnancy loss and preeclampsia. There is evidence to suggest that the consumption of caffeine during pregnancy may increase the risk of pregnancy loss; however, little is known about the direct effect of caffeine on normal trophoblast biology. Our objectives were to examine the effect of caffeine on trophoblast migration and motility after stimulation with epidermal growth factor (EGF) and to investigate the intracellular signaling pathways involved in this process. Primary first-trimester extravillous trophoblasts (EVT) and the EVT-derived cell line SGHPL-4 were used to study the effect of caffeine on EGF-stimulated cellular motility using time-lapse microscopy. SGHPL-4 cells were further used to study the effect of caffeine and cAMP on EGF-stimulated invasion of fibrin gels. The influence of caffeine and cAMP on EGF-stimulated intracellular signaling pathways leading to the activation of Akt were investigated by Western blot analysis. Caffeine inhibits both EGF-stimulated primary EVT and SGHPL-4 cell motility. EGF stimulation activates phosphatidylinositol 3-kinase, and Akt and caffeine inhibit this activation. Although cAMP inhibits both motility and invasion, it does not inhibit the activation of Akt, indicating that the effects of caffeine seen in this study are independent of cAMP. Further investigation indicated a role for mammalian target of rapamycin complex 2 (mTORC2) as a target for the inhibitory effect of caffeine. In conclusion, we demonstrate that caffeine inhibits EGF-stimulated trophoblast invasion and motility in vitro and so could adversely influence trophoblast biology in vivo.
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Affiliation(s)
- Isobelle Grant
- Biomedical Sciences, St. George's University of London, Cranmer Terrace, London SW17 0RE, United Kingdom
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Kawano Y, Nagata M, Kohno T, Ichimiya A, Iwakiri T, Okumura M, Arimori K. Caffeine increases the antitumor effect of Cisplatin in human hepatocellular carcinoma cells. Biol Pharm Bull 2012; 35:400-7. [PMID: 22382328 DOI: 10.1248/bpb.35.400] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Caffeine is thought to increase the antitumor effect of cisplatin or DNA-damaging agents because it is known that caffeine inhibits DNA repair. Caffeine-assisted chemotherapy has been used in the treatment of osteosarcomas. In addition, there are several reports about combination chemotherapy with caffeine for certain malignancies other than osteosarcomas. However, there are no reports that show the utility of combination chemotherapy with caffeine for hepatocellular carcinoma (HCC). We examined the combined effects of caffeine and cisplatin in human HCC cell lines, and screened for a more effective administration method of caffeine in vitro. Human HCC cell lines (HepG2, HLF, HuH-7, and Li-7) were exposed to caffeine (0-0.5 mM) and cisplatin (0-1.2 μg/mL) for 72 h, either alone or in combination. Cell numbers were measured by WST-8 assay, and cell apoptosis was determined by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) binding assay. As a result, caffeine increased the antitumor effect of cisplatin on cell proliferation and cell apoptosis in the HCC cell lines. Moreover, this effect was dependent on the amount of exposure to caffeine. These results suggest that caffeine-assisted chemotherapy is useful for HCC treatment.
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Affiliation(s)
- Yohei Kawano
- Department of Pharmacy, University of Miyazaki Hospital, Kiyotake-cho, Miyazaki, Japan
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Fujimaki S, Matsuda Y, Wakai T, Sanpei A, Kubota M, Takamura M, Yamagiwa S, Yano M, Ohkoshi S, Aoyagi Y. Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling. Cancer Lett 2012; 319:98-108. [PMID: 22265862 DOI: 10.1016/j.canlet.2011.12.043] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Revised: 12/21/2011] [Accepted: 12/22/2011] [Indexed: 12/21/2022]
Abstract
Sorafenib is a multi-kinase inhibitor applicable to hepatocellular carcinoma (HCC), but its limited therapeutic effects are a major problem to be solved. Here, we show that blockade of ataxia telangiectasia mutated (ATM) improves the antitumor effects of sorafenib. When hepatoma cell lines HepG2 and PLC/PRF/5 were treated with sorafenib plus ATM small inhibitory RNAs, ATM inhibitor KU55933 or caffeine, Akt signaling was suppressed and the cytotoxic effects were significantly potentiated. Moreover, ATM inhibition effectively suppressed the sorafenib-induced cell migration. Taken together, manipulation of ATM activity might be a useful strategy for improving sorafenib treatment of HCC.
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Affiliation(s)
- Shun Fujimaki
- Department of Medical Technology, Niigata University Graduate School of Health Sciences, Niigata, Japan
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Abstract
The G(2) checkpoint is an indispensable pathway for cancers lacking p53 function, for delaying cell cycle progression, and for completing DNA repair. Therefore, disruption of this pathway is expected to offer selective therapy for these highly prevalent cancers. The aim of this study was to identify an inhibitor of the G(2) checkpoint including the ataxia-telangiectasia-mutated and Rad3-related checkpoint kinase 1 pathway that selectively suppresses the growth of p53-deficient cells. To obtain molecules with a novel mechanism of action, we constructed a high-throughput screening system that detected abrogation of the G(2) checkpoint in X-irradiated HT-29 cells. The screening resulted in identification of a guanidine analog, CBP-93872 that dose dependently inhibited the G(2) checkpoint induced by DNA damage. Interestingly, CBP-93872 directly suppressed the growth of p53-mutated cancer cell lines with wild-type CDKN2A by eliciting G(1) arrest, but not CDKN2A-deleted and/or wild-type p53 lines. CBP-93872 decreased phospho-cdc2 Y15 by inhibiting phosphorylation of Chk1, but did not suppress phospho-Chk2 or the kinase activities of either Chk1 or Chk2 in cellular or cell-free assays. These results suggest that a checkpoint modulator through suppression of Chk1 phosphorylation provides synthetic lethality to p53-deficient cells.
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Melnik BC. Leucine signaling in the pathogenesis of type 2 diabetes and obesity. World J Diabetes 2012; 3:38-53. [PMID: 22442749 PMCID: PMC3310004 DOI: 10.4239/wjd.v3.i3.38] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2011] [Revised: 02/29/2012] [Accepted: 03/09/2012] [Indexed: 02/06/2023] Open
Abstract
Epidemiological evidence points to increased dairy and meat consumption, staples of the Western diet, as major risk factors for the development of type 2 diabetes (T2D). This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1). mTORC1, a pivotal nutrient-sensitive kinase, promotes growth and cell proliferation in response to glucose, energy, growth factors and amino acids. Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine, a primary and independent stimulator for mTORC1 activation. The downstream target of mTORC1, the kinase S6K1, induces insulin resistance by phosphorylation of insulin receptor substrate-1, thereby increasing the metabolic burden of β-cells. Moreover, leucine-mediated mTORC1-S6K1-signaling plays an important role in adipogenesis, thus increasing the risk of obesity-mediated insulin resistance. High consumption of leucine-rich proteins explains exaggerated mTORC1-dependent insulin secretion, increased β-cell growth and β-cell proliferation promoting an early onset of replicative β-cell senescence with subsequent β-cell apoptosis. Disturbances of β-cell mass regulation with increased β-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D, which are all associated with hyperactivation of mTORC1. In contrast, the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling. Plant-derived polyphenols and flavonoids are identified as natural inhibitors of mTORC1 and exert anti-diabetic and anti-obesity effects. Furthermore, bariatric surgery in obesity reduces increased plasma levels of leucine and other branched-chain amino acids. Attenuation of leucine-mediated mTORC1 signaling by defining appropriate upper limits of the daily intake of leucine-rich animal and dairy proteins may offer a great chance for the prevention of T2D and obesity, as well as other epidemic diseases of civilization with increased mTORC1 signaling, especially cancer and neurodegenerative diseases, which are frequently associated with T2D.
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Affiliation(s)
- Bodo C Melnik
- Bodo C Melnik, Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49090 Osnabrück, Germany
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KOBAYASHI M, MATSUDA Y, IWAI H, HIRAMITSU M, INOUE T, KATAGIRI T, YAMASHITA Y, ASHIDA H, MURAI A, HORIO F. Coffee Improves Insulin-Stimulated Akt Phosphorylation in Liver and Skeletal Muscle in Diabetic KK-Ay Mice. J Nutr Sci Vitaminol (Tokyo) 2012; 58:408-14. [DOI: 10.3177/jnsv.58.408] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Adaphostin promotes caffeine-evoked autocrine Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia cells. Biochem J 2011; 439:453-67. [DOI: 10.1042/bj20110725] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The present study was conducted to verify whether caffeine is beneficial for improving leukaemia therapy. Co-treatment with adaphostin (a Bcr/Abl inhibitor) was found to potentiate caffeine-induced Fas/FasL up-regulation. Although adaphostin did not elicit ASK1 (apoptosis signal-regulating kinase 1)-mediated phosphorylation of p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase), co-treatment with adaphostin notably increased p38 MAPK/JNK activation in caffeine-treated cells. Suppression of p38 MAPK and JNK abrogated Fas/FasL up-regulation in caffeine- and caffeine/adaphostin-treated cells. Compared with caffeine, adaphostin markedly suppressed Akt/ERK (extracellular-signal-regulated kinase)-mediated MKP-1 (MAPK phosphatase 1) protein expression in K562 cells. MKP-1 down-regulation eventually elucidated the enhanced effect of adaphostin on p38 MAPK/JNK activation and subsequent Fas/FasL up-regulation in caffeine-treated cells. Knockdown of p38α MAPK and JNK1, ATF-2 (activating transcription factor 2) and c-Jun by siRNA (small interfering RNA) proved that p38α MAPK/ATF-2 and JNK1/c-Jun pathways were responsible for caffeine-evoked Fas/FasL up-regulation. Moreover, Ca2+ and ROS (reactive oxygen species) were demonstrated to be responsible for ASK1 activation and Akt/ERK inactivation respectively in caffeine- and caffeine/adaphostin-treated cells. Likewise, adaphostin functionally enhanced caffeine-induced Fas/FasL up-regulation in leukaemia cells that expressed Bcr/Abl. Taken together, the results of the present study suggest a therapeutic strategy in improving the efficacy of adaphostin via Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia.
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Egawa T, Tsuda S, Ma X, Hamada T, Hayashi T. Caffeine modulates phosphorylation of insulin receptor substrate-1 and impairs insulin signal transduction in rat skeletal muscle. J Appl Physiol (1985) 2011; 111:1629-36. [PMID: 21940847 DOI: 10.1152/japplphysiol.00249.2011] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Caffeine decreases insulin sensitivity and insulin-stimulated glucose transport in skeletal muscle; however, the precise mechanism responsible for this deleterious effect is not understood fully. We investigated the effects of incubation with caffeine on insulin signaling in rat epitrochlearis muscle. Caffeine (≥1 mM, ≥15 min) suppressed insulin-stimulated insulin receptor substrate (IRS)-1 Tyr(612) phosphorylation in a dose- and time-dependent manner. These responses were associated with inhibition of the insulin-stimulated phosphorylation of phosphatidylinositol 3-kinase (PI3K) Tyr(458), Akt Ser(473), and glycogen synthase kinase-3β Ser(9) and with inhibition of insulin-stimulated 3-O-methyl-d-glucose (3MG) transport but not with inhibition of the phosphorylation of insulin receptor-β Tyr(1158/62/63). Furthermore, caffeine enhanced phosphorylation of IRS-1 Ser(307) and an IRS-1 Ser(307) kinase, inhibitor-κB kinase (IKK)-α/β Ser(176/180). Blockade of IKK/IRS-1 Ser(307) by caffeic acid ameliorated the caffeine-induced downregulation of IRS-1 Tyr(612) phosphorylation and 3MG transport. Caffeine also increased the phosphorylation of IRS-1 Ser(789) and an IRS-1 Ser(789) kinase, 5'-AMP-activated protein kinase (AMPK). However, inhibition of IRS-1 Ser(789) and AMPK phosphorylation by dantrolene did not rescue the caffeine-induced downregulation of IRS-1 Tyr(612) phosphorylation or 3MG transport. In addition, caffeine suppressed the phosphorylation of insulin-stimulated IRS-1 Ser(636/639) and upstream kinases, including the mammalian target of rapamycin and p70S6 kinase. Intravenous injection of caffeine at a physiological dose (5 mg/kg) in rats inhibited the phosphorylation of insulin-stimulated IRS-1 Tyr(612) and Akt Ser(473) in epitrochlearis muscle. Our results indicate that caffeine inhibits insulin signaling partly through the IKK/IRS-1 Ser(307) pathway, via a Ca(2+)- and AMPK-independent mechanism in skeletal muscle.
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Affiliation(s)
- Tatsuro Egawa
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan
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