Cell Collective11298000ModelsMultiomicsTomas Helikarhttps://cellcollective.org/#3512/oxidative-stress-pathway31.03171SBML1Cell Collectivehttps://cellcollective.org/#3512:1/oxidative-stress-pathway<h4>Background</h4>Oxidative stress is a consequence of normal and abnormal cellular metabolism and is linked to the development of human diseases. The effective functioning of the pathway responding to oxidative stress protects the cellular DNA against oxidative damage; conversely the failure of the oxidative stress response mechanism can induce aberrant cellular behavior leading to diseases such as neurodegenerative disorders and cancer. Thus, understanding the normal signaling present in oxidative stress response pathways and determining possible signaling alterations leading to disease could provide us with useful pointers for therapeutic purposes. Using knowledge of oxidative stress response pathways from the literature, we developed a Boolean network model whose simulated behavior is consistent with earlier experimental observations from the literature. Concatenating the oxidative stress response pathways with the PI3-Kinase-Akt pathway, the oxidative stress is linked to the phenotype of apoptosis, once again through a Boolean network model. Furthermore, we present an approach for pinpointing possible fault locations by using temporal variations in the oxidative stress input and observing the resulting deviations in the apoptotic signature from the normally predicted pathway. Such an approach could potentially form the basis for designing more effective combination therapies against complex diseases such as cancer.<h4>Results</h4>In this paper, we have developed a Boolean network model for the oxidative stress response. This model was developed based on pathway information from the current literature pertaining to oxidative stress. Where applicable, the behaviour predicted by the model is in agreement with experimental observations from the published literature. We have also linked the oxidative stress response to the phenomenon of apoptosis via the PI3k/Akt pathway.<h4>Conclusions</h4>It is our hope that some of the additional predictions here, such as those pertaining to the oscillatory behaviour of certain genes in the presence of oxidative stress, will be experimentally validated in the near future. Of course, it should be pointed out that the theoretical procedure presented here for pinpointing fault locations in a biological network with feedback will need to be further simplified before it can be even considered for practical biological validation.Boolean modeling and fault diagnosis in oxidative stress response.Sridharan Sriram S, Layek Ritwik R, Datta Aniruddha A, Venkatraj Jijayanagaram JDNA Oxidative, Forms, Wap3, PRKBA, Akt/PKB, Materials, CG5373, dP60, single-organism developmental process, Vps34, ATVPS34, DAKT1/PKB, postnatal development, Wfdc14, Nitrative Stress, PI3K, BcDNA:LD15217, Dp110, growth and development, Tumor, AKT1, type I programmed cell death, VPS34, Damage, 11621, temporal, MAGE-E1 antigen, PI-3 kinase, p110-alpha, Readability, Techniques, PHOSPHATIDYLINOSITOL 3-KINASE, Oxidative DNA, diseases, Extrinsic Pathway Apoptoses, DmelCG2699, Oxidative, F8A5.4, Method, responsivity, Nitro-Oxidative Stress, diseases and disorders, p110alpha, Nitro-Oxidative Stresses, Kinase, phosphatidylinositol 3-kinase activity, Oxidative Injury, DNA Damage, average, Oxidative Injuries, human disease, thymus nucleic acid, Dp60, Man (Taxonomy), Pi3K92D, CG4141, PI3K_59F, catalyst activity, Oxidative Cleavage, Pi3k, PI3-kinase activity, Oxidative DNA Damages, PI[[3]]K, PKB|Akt, PI3Kgamma, Anti-oxidative, SURGICAL AND MEDICAL PROCEDURES, RacPK, MCAP, Intrinsic Pathway Apoptosis, Oxidative Stress Injuries, Oxidative Stresses, p55alpha, Methodological Studies, HCA1, malignant neoplasm, Classic, intermediary metabolism, Classical Apoptosis, PI3K 68D, Homo sapiens disease, Double-Stranded DNA, Malignancies, Pi3K, PI3k, deoxyribonucleic acids, DNAn, ATP Phosphotransferases, MCMTC, ATP, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, single organism signaling, single-organism behavior, Tumors, dVps34, PI3K68D, dakt, Papers, Caspase-Dependent Apoptosis, aberrant, functional failure, Process, P110DELTA, PtdIns-3-kinase activity, Modern, rea, p50alpha, Double-Stranded, l(3)89Bq, Procedure, CG2699, results, DmelCG5373, vacuolar protein sorting 34, Acceptance Processes, predicted, dPIK, 1-phosphatidylinositol 3-kinase activity, (Deoxyribonucleotide)n+m, Literatures, Acceptance Process, PKB/Akt, PKB/AKT, AKT/PKB, Benign, signaling (initiator) caspase activity, C530050K14, dAkt, dAKT, induction of apoptosis, Oxidative and Nitrosative Stress, Intrinsic Pathway, Extrinsic Pathway Apoptosis, DAMAGE, Hepatocellular carcinoma-associated protein 1, type-1 PI3K, Diseases, p-Akt, Genetic Materials, DNA Oxidative Damages, failure, Caspase-Dependent, desoxyribose nucleic acid, DAkt, Genetic Material, Hopes, l(3)04226, CG11621, Transphosphorylases, DPKB, Epistemology, pAkt, p85alpha, Benign Neoplasms, Methodological, PI3K 68_D, dAKT/dPKB, PKB/dAKT, Methodological Study, DmelCG4141, human, F8A5_4, Malignant Neoplasms, experimental procedures, Nitro-Oxidative, Intrinsic Pathway Apoptoses, APDS, Phenotypes, disease, p110D, Dakt, induction of apoptosis by p53, Material, dPKB, PI3KBETA, ds DNA, Skalp, Extrinsic Pathway, Oxidative Stress Injury, Cistron, DNA, p120-PI3K, mMage-e1, Classical, Apoptoses, droPIK57, Oxidative Damage, RAC-ALPHA, Hopefulness, DRAC-PK85, atypia, other disease, Oxidative Stress, DmelCG4006, human being, DNS, Procedures, (Deoxyribonucleotide)n, experimental, Antioxidative, Processes, Neoplasms, PI3K92E, caspase-dependent programmed cell death, Benign Neoplasm, number, Antioxidative Stress, Caspase Dependent Apoptosis, Pi3K_59F, Gene, disfunctional, type I phosphatidylinositol kinase activity, Malignant, Feedbacks., presence, activation of apoptosis, Deoxyribonucleic acids, phosphatidylinositol 3-kinase, Stresses, Human, Intervention or Procedure, Dpkb, PIK3, Oxidative Nitrative, dVps34/PI3K59F, Pi3Kp60, Homo sapiens, Deoxyribonucleic Acid, Stress Injury, p60, PI3K-dp110, Studies, Oxidative Cleavages, disease or disorder, dPI3K, PHOSPATIDYLINOSITOL 3-KINASE, atypical, anon-92Ed, Type I, Man, Pi3, Phosphotransferase, Technique, Oxidative Damages, Pi6, Dp110/PI3K, PI3K-68D/E, class I, reactivity, Injury, methods, Genetic, Malignancy, interventionDescription, experimental section, Double Stranded, Interventional, Deoxyribonucleic acid, PI3'K, AI847422, Serpina1c, Transphosphorylase, Pi3Kp110, apoptosis activator activity, non-neoplastic, P110BETA, Neoplasias, Study, PI3K-68D, PI3K21B, Anti oxidative Stress, Oxidative DNA Damage, AKT, Antioxidative Stresses, Akt, Classic Apoptosis, DRAC-PK, disorder, Spi1-6, (Deoxyribonucleotide)m, MCM, Spi1-3, Behaviors, incidence, Cancer, Apoptosis, Cpk, dP110, Intervention Strategies, Malignant Neoplasm, 6330412C24Rik, AA414921, akt, p120, class II, DNAn+1, type III phosphoinositide 3-kinase activity, Alpha-dystrobrevin-associated MAGE Protein, disorders, p110, DAkt1, Vps34p, defective, medical condition, DAKT1, Anti-oxidative Stresses, Cistrons, Phosphotransferases, PI(3)K, cpk, PI3K-92E/Dp110, development, Oxidative Nitrative Stress, PIK3C1, count in organism, PKB, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, MT, CWS6, vps34, CWS5, Oxidative Nitrative Stresses, Programmed Cell Death, PKB-ALPHA, Neoplasm, dp110, condition, D-Akt, CG4006, ds-DNA, PI3CG, Dakt1, PI-3-K, Intervention, apoptosis signaling, Acceptance, PI3K-59F, primary cancer, Anti-oxidative Stress, apoptosis, DNA Oxidative Damage, akt1, PI3K-Dp110, RGD1560259, dAkt1, Kinases, DRAC-PK66, postnatal growth, class III, Cancers, DmelCG11621, Understanding, Cleavage, p110gamma, malignant tumor, Classic Apoptoses, caPI3K, dAkt/PKB, dakt1, CLOVE, signalling process, DmVps34, IMD14, apoptotic program, PI3K_68D, Modern Man, PKBalpha, PI3K-92D, Stress, Desoxyribonukleinsaeure, commitment to apoptosis, dAKT1, Dmp110, RAC, Rac, response, cellular metabolism, Nitro Oxidative Stress, growth, NeoplasiaDNA Oxidative, Antemortem Diagnoses, screening, Oxidative Stress, Antemortem Diagnosis, findings, Antioxidative, Antioxidative Stress, Nitrative Stress, responsivity., Anti-oxidative Stresses, Diagnosis, Damage, Examination and Diagnoses, Diagnoses, Stresses, Oxidative Nitrative Stress, Postmortem, Screenings, Oxidative Nitrative, Oxidative DNA, Oxidative, Stress Injury, Mass Screenings, Oxidative and Nitrosative Stress, Oxidative Nitrative Stresses, Examinations and Diagnoses, Nitro-Oxidative Stress, Mass, symptoms, Screening, Oxidative Cleavages, DNA Oxidative Damages, Nitro-Oxidative Stresses, Antemortem, Postmortem Diagnosis, Oxidative Injury, DNA Damage, Oxidative Damages, Diagnoses and Examination, reactivity, Postmortem Diagnoses, Oxidative Injuries, Injury, Anti-oxidative Stress, DNA Oxidative Damage, Oxidative Cleavage, signs, Diagnoses and Examinations, Cleavage, Oxidative DNA Damages, Anti-oxidative, Nitro-Oxidative, Oxidative Stress Injuries, Oxidative Stresses, Anti oxidative Stress, Oxidative DNA Damage, Antioxidative Stresses, Stress, Oxidative Stress Injury, DNA, response, Nitro Oxidative Stress, Diagnose, Oxidative DamageDNA Oxidative, Oxidative Injuries, Oxidative Stress, Injury, Anti-oxidative Stress, DNA Oxidative Damage, Antioxidative, Oxidative Cleavage, Antioxidative Stress, Nitrative Stress, Cleavage, Oxidative DNA Damages, Anti-oxidative Stresses, Damage, Anti-oxidative, Nitro-Oxidative, Stresses, Oxidative Nitrative Stress, Oxidative Stress Injuries, Oxidative Stresses, Oxidative Nitrative, Anti oxidative Stress, Oxidative DNA, Oxidative, Oxidative DNA Damage, Stress Injury, Antioxidative Stresses, Oxidative and Nitrosative Stress, Oxidative Nitrative Stresses, Stress, Nitro-Oxidative Stress, Oxidative Cleavages, Oxidative Stress Injury, DNA Oxidative Damages, Nitro-Oxidative Stresses, DNA, Oxidative Injury, Nitro Oxidative Stress, Oxidative Damage., DNA Damage, Oxidative Damages, Oxidative DamageForms, PRKBA, Akt/PKB, Materials, dP60, Vps34, DAKT1/PKB, Wfdc14, Neurologic Diseases, BcDNA:LD15217, growth and development, Tumor, AKT1, VPS34, 11621, MAGE-E1 antigen, PI-3 kinase, p110-alpha, Oxidative DNA, Oxidative, Neurologic Disorders, Method, responsivity, 10.5, Nitro-Oxidative Stresses, DNA Damage, 10.9, average, thymus nucleic acid, Dp60, F, Degenerative Condition, PI3K_59F, Oxidative Cleavage, PI3-kinase activity, V, PI3Kgamma, SURGICAL AND MEDICAL PROCEDURES, RacPK, MCAP, Intrinsic Pathway Apoptosis, Oxidative Stresses, Degenerative Neurologic Disease, PI3K 68D, Homo sapiens disease, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, single organism signaling, Tumors, dVps34, functional failure, rea, p50alpha, Procedure, CG2699, DmelCG5373, Acceptance Processes, predicted, AKT/PKB, Benign, signaling (initiator) caspase activity, C530050K14, induction of apoptosis, DAMAGE, Hepatocellular carcinoma-associated protein 1, type-1 PI3K, p-Akt, DNA Oxidative Damages, Caspase-Dependent, desoxyribose nucleic acid, CG11621, Degenerative Diseases, Benign Neoplasms, Methodological, Neurologic Disease, dAKT/dPKB, PKB/dAKT, DmelCG4141, human, F8A5_4, Malignant Neoplasms, Nitro-Oxidative, Intrinsic Pathway Apoptoses, APDS, Phenotypes, Material, PI3KBETA, ds DNA, Skalp, Extrinsic Pathway, eve2, DNA, Feedbacks, Oxidative Damage, RAC-ALPHA, atypia, DmelCG4006, DNS, (Deoxyribonucleotide)n, Antioxidative, Processes, Neoplasms, number, Degenerative Neurologic Disorders, activation of apoptosis, Human, PIK3, dVps34/PI3K59F, Pi3Kp60, Deoxyribonucleic Acid, PI3K-dp110, disease or disorder, dPI3K, Projections and Predictions, atypical, anon-92Ed, even, Man, Pi3, Technique, Oxidative Damages, Pi6, class I, Injury, interventionDescription, Double Stranded, Deoxyribonucleic acid, AI847422, Serpina1c, Pi3Kp110, P110BETA, Neoplasias, Study, Neurologic, Neurologic Degenerative Diseases, PI3K21B, AKT, Antioxidative Stresses, Akt, Classic Apoptosis, Degenerative Neurologic Diseases, Spinal Cord, (Deoxyribonucleotide)m, MCM, Cancer, Apoptosis, Cpk, Neurologic Disorder, Malignant Neoplasm, AA414921, akt, class II, DNAn+1, type III phosphoinositide 3-kinase activity, disorders, DAkt1, defective, DAKT1, Anti-oxidative Stresses, PI(3)K, cpk, PI3K-92E/Dp110, PIK3C1, PKB, MT, CWS6, CWS5, Oxidative Nitrative Stresses, PKB-ALPHA, Neoplasm, condition, CG4006, Eve, EVE, background, Dakt1, Intervention, primary cancer, Anti-oxidative Stress, apoptosis, DNA Oxidative Damage, RGD1560259, postnatal growth, Neurologic Degenerative Conditions, Cancers, DmelCG11621, Understanding, malignant tumor, Classic Apoptoses, caPI3K, dAkt/PKB, CLOVE, signalling process, DmVps34, IMD14, apoptotic program, PI3K_68D, PI3K-92D, Stress, Desoxyribonukleinsaeure, commitment to apoptosis, Central Nervous System, Dmp110, cellular metabolism, Neoplasia, DNA Oxidative, Wap3, CG5373, single-organism developmental process, ATVPS34, postnatal development, Nitrative Stress, PI3K, Dp110, Neurologic Degenerative Condition, type I programmed cell death, Damage, temporal, Readability, Techniques, PHOSPHATIDYLINOSITOL 3-KINASE, diseases, Extrinsic Pathway Apoptoses, DmelCG2699, F8A5.4, Nitro-Oxidative Stress, diseases and disorders, p110alpha, phosphatidylinositol 3-kinase activity, Oxidative Injury, Nervous System Degenerative Diseases, Oxidative Injuries, human disease, Man (Taxonomy), DmelCG2328, Pi3K92D, CG4141, catalyst activity, Pi3k, Futurology, Oxidative DNA Damages, PI[[3]]K, Neurodegenerative Disorder, PKB|Akt, Anti-oxidative, Oxidative Stress Injuries, p55alpha, Methodological Studies, HCA1, malignant neoplasm, Classic, intermediary metabolism, Classical Apoptosis, Neurologic Degenerative Disease, Therapies, Double-Stranded DNA, Malignancies, Pi3K, PI3k, deoxyribonucleic acids, DNAn, MCMTC, single-organism behavior, Predictions and Projections, Therapy, PI3K68D, dakt, Papers, Caspase-Dependent Apoptosis, aberrant, Process, P110DELTA, PtdIns-3-kinase activity, Modern, Double-Stranded, l(3)89Bq, results, vacuolar protein sorting 34, dPIK, 1-phosphatidylinositol 3-kinase activity, (Deoxyribonucleotide)n+m, Literatures, CG2328., Acceptance Process, PKB/Akt, PKB/AKT, dAkt, dAKT, Oxidative and Nitrosative Stress, Intrinsic Pathway, Extrinsic Pathway Apoptosis, Diseases, Genetic Materials, VI, failure, DAkt, Genetic Material, Hopes, l(3)04226, DPKB, Epistemology, 20.35, pAkt, p85alpha, PI3K 68_D, Methodological Study, Treatments, disease, p110D, Dakt, induction of apoptosis by p53, Degenerative, dPKB, Oxidative Stress Injury, Cistron, p120-PI3K, mMage-e1, Classical, Apoptoses, droPIK57, 14.10, Hopefulness, DRAC-PK85, other disease, Oxidative Stress, human being, Procedures, PI3K92E, caspase-dependent programmed cell death, Benign Neoplasm, Antioxidative Stress, Caspase Dependent Apoptosis, Pi3K_59F, Gene, disfunctional, type I phosphatidylinositol kinase activity, Malignant, presence, cerebral degeneration disease, Deoxyribonucleic acids, phosphatidylinositol 3-kinase, Stresses, Intervention or Procedure, Dpkb, Oxidative Nitrative, Homo sapiens, Stress Injury, p60, Studies, Oxidative Cleavages, PHOSPATIDYLINOSITOL 3-KINASE, Type I, Dp110/PI3K, PI3K-68D/E, reactivity, Nervous System, Genetic, Malignancy, Interventional, PI3'K, apoptosis activator activity, Neurodegenerative Disorders, non-neoplastic, PI3K-68D, Anti oxidative Stress, Oxidative DNA Damage, DRAC-PK, disorder, Spi1-6, Spi1-3, Behaviors, incidence, dP110, Intervention Strategies, 6330412C24Rik, p120, Alpha-dystrobrevin-associated MAGE Protein, p110, Vps34p, medical condition, Cistrons, Degenerative Neurologic Disorder, development, Oxidative Nitrative Stress, count in organism, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, vps34, Programmed Cell Death, dp110, D-Akt, ds-DNA, PI3CG, PI-3-K, apoptosis signaling, Acceptance, Degenerative Conditions, PI3K-59F, akt1, PI3K-Dp110, dAkt1, DRAC-PK66, class III, l(2)46Ce, Cleavage, p110gamma, l(2)46Cg, introduction, l(2)46CFj, l(2)46CFh, dakt1, Therapeutic, l(2)46CFp, Modern Man, PKBalpha, Neurodegenerative Disease, Treatment, dAKT1, RAC, Rac, response, Nitro Oxidative Stress, Future, E(eve), growth, l(2)46CFg11298falseOxidative Stress PathwayOxidative stress is a consequence of normal and abnormal cellular metabolism and is linked to the development of human diseases. The effective functioning of the pathway responding to oxidative stress protects the cellular DNA against oxidative damage; conversely the failure of the oxidative stress response mechanism can induce aberrant cellular behavior leading to diseases such as neurodegenerative disorders and cancer. Thus, understanding the normal signaling present in oxidative stress response pathways and determining possible signaling alterations leading to disease could provide us with useful pointers for therapeutic purposes. Using knowledge of oxidative stress response pathways from the literature, we developed a Boolean network model whose simulated behavior is consistent with earlier experimental observations from the literature. Concatenating the oxidative stress response pathways with the PI3-Kinase-Akt pathway, the oxidative stress is linked to the phenotype of apoptosis, once again through a Boolean network model. Furthermore, we present an approach for pinpointing possible fault locations by using temporal variations in the oxidative stress input and observing the resulting deviations in the apoptotic signature from the normally predicted pathway. Such an approach could potentially form the basis for designing more effective combination therapies against complex diseases such as cancer. RESULTS: In this paper, we have developed a Boolean network model for the oxidative stress response. This model was developed based on pathway information from the current literature pertaining to oxidative stress. Where applicable, the behaviour predicted by the model is in agreement with experimental observations from the published literature. We have also linked the oxidative stress response to the phenomenon of apoptosis via the PI3k/Akt pathway. CONCLUSIONS: It is our hope that some of the additional predictions here, such as those pertaining to the oscillatory behaviour of certain genes in the presence of oxidative stress, will be experimentally validated in the near future. Of course, it should be pointed out that the theoretical procedure presented here for pinpointing fault locations in a biological network with feedback will need to be further simplified before it can be even considered for practical biological validation.2013-06-012017-07-142017-07-14351223134720