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1
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Qiao L, Khalilimeybodi A, Linden-Santangeli NJ, Rangamani P. The Evolution of Systems Biology and Systems Medicine: From Mechanistic Models to Uncertainty Quantification. Annu Rev Biomed Eng 2025; 27:425-447. [PMID: 39971380 DOI: 10.1146/annurev-bioeng-102723-065309] [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] [Indexed: 02/21/2025]
Abstract
Understanding interaction mechanisms within cells, tissues, and organisms is crucial for driving developments across biology and medicine. Mathematical modeling is an essential tool for simulating such biological systems. Building on experiments, mechanistic models are widely used to describe small-scale intracellular networks. The development of sequencing techniques and computational tools has recently enabled multiscale models. Combining such larger scale network modeling with mechanistic modeling provides us with an opportunity to reveal previously unknown disease mechanisms and pharmacological interventions. Here, we review systems biology models from mechanistic models to multiscale models that integrate multiple layers of cellular networks and discuss how they can be used to shed light on disease states and even wellness-related states. Additionally, we introduce several methods that increase the certainty and accuracy of model predictions. Thus, combining mechanistic models with emerging mathematical and computational techniques can provide us with increasingly powerful tools to understand disease states and inspire drug discoveries.
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Affiliation(s)
- Lingxia Qiao
- Department of Pharmacology, University of California San Diego, La Jolla, California, USA;
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, California, USA
| | - Ali Khalilimeybodi
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, California, USA
| | | | - Padmini Rangamani
- Department of Pharmacology, University of California San Diego, La Jolla, California, USA;
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, California, USA
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2
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Puniya BL. Artificial-intelligence-driven Innovations in Mechanistic Computational Modeling and Digital Twins for Biomedical Applications. J Mol Biol 2025:169181. [PMID: 40316010 DOI: 10.1016/j.jmb.2025.169181] [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: 01/06/2025] [Revised: 04/09/2025] [Accepted: 04/27/2025] [Indexed: 05/04/2025]
Abstract
Understanding of complex biological systems remains a significant challenge due to their high dimensionality, nonlinearity, and context-specific behavior. Artificial intelligence (AI) and mechanistic modeling are becoming essential tools for studying such complex systems. Mechanistic modeling can facilitate the construction of simulatable models that are interpretable but often struggle with scalability and parameters estimation. AI can integrate multi-omics data to create predictive models, but it lacks interpretability. The gap between these two modeling methods limits our ability to develop comprehensive and predictive models for biomedical applications. This article reviews the most recent advancements in the integration of AI and mechanistic modeling to fill this gap. Recently, with omics availability, AI has led to new discoveries in mechanistic computational modeling. The mechanistic models can also help in getting insight into the mechanism for prediction made by AI models. This integration is helpful in modeling complex systems, estimating the parameters that are hard to capture in experiments, and creating surrogate models to reduce computational costs because of expensive mechanistic model simulations. This article focuses on advancements in mechanistic computational models and AI models and their integration for scientific discoveries in biology, pharmacology, drug discovery and diseases. The mechanistic models with AI integration can facilitate biological discoveries to advance our understanding of disease mechanisms, drug development, and personalized medicine. The article also highlights the role of AI and mechanistic model integration in the development of more advanced models in the biomedical domain, such as medical digital twins and virtual patients for pharmacological discoveries.
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Affiliation(s)
- Bhanwar Lal Puniya
- Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, United States.
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3
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Wang Z, Guo J, Dong T, Liang Y, Liu Z, Wang F, Zhang Y. Proteomic Profiling of Hu Sheep Placental Development Across Gestational Stages Reveals Stage-Specific Regulatory Networks. Int J Mol Sci 2025; 26:4236. [PMID: 40362472 PMCID: PMC12071506 DOI: 10.3390/ijms26094236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 04/16/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
Placental development plays a pivotal role in ensuring successful pregnancy outcomes, yet its molecular regulatory mechanisms in sheep remain poorly characterized. This study aimed to systematically investigate stage-specific proteomic dynamics and functional adaptations in ovine placental tissues across gestation to elucidate molecular drivers of placental maturation. Using data-independent acquisition proteomics, we identified 7774 proteins in Hu sheep placental tissues at gestational days 50, 80, and 120. Comparative analysis revealed 1450, 1026, and 1964 differentially expressed proteins (DEPs) in the 50 d vs. 80 d, 80 d vs. 120 d, and 50 d vs. 120 d comparisons, respectively. DEPs were functionally enriched in biological processes including cell proliferation, apoptosis, angiogenesis, nutrient transport, and steroid synthesis, with prominent involvement of the PI3K-Akt, MAPK, and estrogen signaling pathways. Protein interaction networks identified SRC, MAP3K1, KRAS, and TJP1 as central regulators exhibiting dynamic expression patterns across gestation. Temporal expression trends showed progressive upregulation of tight junction, immune response, and glucose metabolism proteins, contrasting with downregulation of endoplasmic reticulum protein processing and proteasome components. Validation experiments confirmed elevated proliferation/transport gene expression at 80 d versus 50 d, followed by increased apoptosis/transport genes and decreased proliferation markers at 120 d. This comprehensive proteomic profiling reveals stage-specific regulatory networks governing placental development in sheep, highlighting coordinated shifts in proliferative, metabolic, and structural remodeling processes. These findings advance our understanding of placental adaptation mechanisms and provide valuable insights for improving reproductive management in livestock species.
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Affiliation(s)
- Zhibo Wang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (Z.W.); (J.G.); (T.D.); (Y.L.); (Z.L.); (F.W.)
- Shanghai Animal Disease Prevention and Control Center, Shanghai 201103, China
| | - Jiahe Guo
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (Z.W.); (J.G.); (T.D.); (Y.L.); (Z.L.); (F.W.)
| | - Tianning Dong
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (Z.W.); (J.G.); (T.D.); (Y.L.); (Z.L.); (F.W.)
| | - Yaxu Liang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (Z.W.); (J.G.); (T.D.); (Y.L.); (Z.L.); (F.W.)
| | - Zhipeng Liu
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (Z.W.); (J.G.); (T.D.); (Y.L.); (Z.L.); (F.W.)
| | - Feng Wang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (Z.W.); (J.G.); (T.D.); (Y.L.); (Z.L.); (F.W.)
| | - Yanli Zhang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (Z.W.); (J.G.); (T.D.); (Y.L.); (Z.L.); (F.W.)
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Jeon S, Jeon Y, Lim JY, Kim Y, Cha B, Kim W. Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets. Signal Transduct Target Ther 2025; 10:4. [PMID: 39757214 DOI: 10.1038/s41392-024-02070-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/01/2024] [Accepted: 11/06/2024] [Indexed: 01/07/2025] Open
Abstract
Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed through the condensation of proteins, nucleic acids, and other molecules-in driving efficient and dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression and intracellular signal transduction, enabling rapid and finely tuned cellular responses. Their ability to regulate cellular signaling pathways is particularly significant, as it requires a careful balance between flexibility and precision. Disruption of this balance can lead to pathological conditions, including neurodegenerative diseases, cancer, and viral infections. Consequently, biomolecular condensates have emerged as promising therapeutic targets, with the potential to offer novel approaches to disease treatment. In this review, we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways, their roles in health and disease, and potential strategies for modulating condensate dynamics as a therapeutic approach. Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.
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Affiliation(s)
- Soyoung Jeon
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Yeram Jeon
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Ji-Youn Lim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea
| | - Yujeong Kim
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Boksik Cha
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea.
| | - Wantae Kim
- Department of Life Science, University of Seoul, Seoul, South Korea.
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Karamanolis NN, Kounatidis D, Vallianou NG, Dimitriou K, Tsaroucha E, Tsioulos G, Anastasiou IA, Mavrothalassitis E, Karampela I, Dalamaga M. Unraveling the Anti-Cancer Mechanisms of Antibiotics: Current Insights, Controversies, and Future Perspectives. Antibiotics (Basel) 2024; 14:9. [PMID: 39858295 PMCID: PMC11762948 DOI: 10.3390/antibiotics14010009] [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: 12/01/2024] [Revised: 12/18/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
Cancer persists as a significant global health challenge, claiming millions of lives annually despite remarkable strides in therapeutic innovation. Challenges such as drug resistance, toxicity, and suboptimal efficacy underscore the need for novel treatment paradigms. In this context, the repurposing of antibiotics as anti-cancer agents has emerged as an attractive prospect for investigation. Diverse classes of antibiotics have exhibited promising anti-cancer properties in both in vitro and in vivo studies. These mechanisms include the induction of apoptosis and cell cycle arrest, generation of reactive oxygen species, and inhibition of key regulators of cell proliferation and migration. Additional effects involve the disruption of angiogenesis and modulation of pivotal processes such as inflammation, immune response, mitochondrial dynamics, ferroptosis, and autophagy. Furthermore, antibiotics have demonstrated the potential to enhance the efficacy of conventional modalities like chemotherapy and radiotherapy, while alleviating treatment-induced toxicities. Nevertheless, the integration of antibiotics into oncological applications remains contentious, with concerns centered on their disruption of gut microbiota, interference with immunotherapeutic strategies, contribution to microbial resistance, and potential association with tumorigenesis. This narrative review explores the mechanisms of antibiotics' anti-cancer activity, addresses controversies about their dual role in cancer biology, and envisions future perspectives that include the development of novel derivatives and innovative frameworks for their incorporation into cancer treatment paradigms.
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Affiliation(s)
- Nikolaos Nektarios Karamanolis
- Second Department of Internal Medicine, Hippokratio General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.K.); (K.D.)
| | - Dimitris Kounatidis
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (I.A.A.)
| | - Natalia G. Vallianou
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (N.G.V.); (E.T.); (E.M.)
| | - Krystalia Dimitriou
- Second Department of Internal Medicine, Hippokratio General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.K.); (K.D.)
| | - Eleni Tsaroucha
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (N.G.V.); (E.T.); (E.M.)
| | - Georgios Tsioulos
- Fourth Department of Internal Medicine, Attikon General University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Ioanna A. Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (I.A.A.)
| | - Evangelos Mavrothalassitis
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (N.G.V.); (E.T.); (E.M.)
| | - Irene Karampela
- Second Department of Critical Care, Attikon General University Hospital, Medical School, National and Kapodistrian University of Athens, 12461 Athens, Greece;
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Suryavanshi A, Vandana, Shukla YK, Kumar V, Gupta P, Asati V, Mahapatra DK, Keservani RK, Jain SK, Bharti SK. MEK inhibitors in oncology: a patent review and update (2016 - present). Expert Opin Ther Pat 2024; 34:963-1007. [PMID: 39275922 DOI: 10.1080/13543776.2024.2403634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/12/2024] [Accepted: 08/22/2024] [Indexed: 09/16/2024]
Abstract
INTRODUCTION Mitogen-activated protein kinase (MEK) is one of the important components of Ras/Raf/MEK/ERK signaling pathway, transduces signal for cell growth, differentiation, and development. Deregulation of MEK leads to a wide variety of cancer; hence, MEK is considered as potential therapeutic targets for the treatment of cancer. The MEK1/2 inhibitors in combination with other inhibitors showed better therapeutic outcomes in various malignancies including resistant or relapsed or refractory cancer. AREAS COVERED A comprehensive patent literature from the year 2016 to May 2024 on MEK inhibitors in oncology, their combination products and structural insights have been reviewed through searching relevant information in PubMed, Scopus, Espacenet, Web of Science, World Intellectual Property Organization and Google Patent databases. EXPERT OPINION Overexpression and mutation of MEK have been reported to cause a wide variety of cancers especially resistant cancers. The MEK1/2 inhibitors in combination with other kinase (BRaf/KRas/PI3K) inhibitors showed significant anti-proliferative activity. Other combination of MEK inhibitor with PD-1, DYRK1, EGFR, BTK and/or VEGF inhibitors, etc. showed promising results in many cancers including colorectal, pancreatic, gastrointestinal, solid tumor, breast cancer, melanoma and multiple myeloma, etc. The dual or multi-targeted approaches of these combinations showed better and precise treatment of patients with resistant cancer.
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Affiliation(s)
- Anjali Suryavanshi
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Vandana
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Yugal Kishor Shukla
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Vipul Kumar
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Pragya Gupta
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Vivek Asati
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | - Debarshi Kar Mahapatra
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Raj K Keservani
- Faculty of B. Pharmacy, CSM Group of Institutions, Prayagraj, India
| | - Sanmati Kumar Jain
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Sanjay Kumar Bharti
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
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7
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Biddau G, Caviglia G, Piana M, Sommariva S. PCA-based synthetic sensitivity coefficients for chemical reaction network in cancer. Sci Rep 2024; 14:17706. [PMID: 39085332 PMCID: PMC11291660 DOI: 10.1038/s41598-024-67862-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 07/16/2024] [Indexed: 08/02/2024] Open
Abstract
Chemical reaction networks are powerful tools for modeling cell signaling and its disruptions in diseases like cancer. Realistic chemical reaction networks involve hundreds of proteins and reactions, resulting in a model depending on a consistently large number of kinetic parameters. Since finely calibrating all the parameters would require an unrealistic amount of data, proper sensitivity analysis is required to identify a subset of parameters for which fine tuning is needed and thus provide a fundamental tool for the qualitative analysis of the network. We present a multidisciplinary approach for computing a set of synthetic sensitivity indices. These indices rank the kinetic parameters, based on the impact that errors in their values would have on the protein concentration profile at equilibrium. Our tests on a chemical reaction network devised for colorectal cells demonstrate the effectiveness of the considered sensitivity indices in different scenarios including in-silico drug dosage and novel therapeutic target discovery. The Matlab code for computing the synthetic sensitivity indices and the data concerning the network for colorectal cells are available at https://github.com/theMIDAgroup/CRN_sensitivity.
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Affiliation(s)
- Giorgia Biddau
- MIDA, Dipartimento di Matematica, Dipartimento di Eccellenza 2023-2027, Università di Genova, Genova, Italy.
| | - Giacomo Caviglia
- MIDA, Dipartimento di Matematica, Dipartimento di Eccellenza 2023-2027, Università di Genova, Genova, Italy
| | - Michele Piana
- MIDA, Dipartimento di Matematica, Dipartimento di Eccellenza 2023-2027, Università di Genova, Genova, Italy
- IRCCS Ospedale Policlinico San Martino, LISCOMP, Genova, Italy
| | - Sara Sommariva
- MIDA, Dipartimento di Matematica, Dipartimento di Eccellenza 2023-2027, Università di Genova, Genova, Italy
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8
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De Carli A, Kapelyukh Y, Kursawe J, Chaplain MAJ, Wolf CR, Hamis S. Simulating BRAFV600E-MEK-ERK signalling dynamics in response to vertical inhibition treatment strategies. NPJ Syst Biol Appl 2024; 10:51. [PMID: 38750040 PMCID: PMC11096323 DOI: 10.1038/s41540-024-00379-9] [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: 12/13/2023] [Accepted: 04/29/2024] [Indexed: 05/18/2024] Open
Abstract
In vertical inhibition treatment strategies, multiple components of an intracellular pathway are simultaneously inhibited. Vertical inhibition of the BRAFV600E-MEK-ERK signalling pathway is a standard of care for treating BRAFV600E-mutated melanoma where two targeted cancer drugs, a BRAFV600E-inhibitor, and a MEK inhibitor, are administered in combination. Targeted therapies have been linked to early onsets of drug resistance, and thus treatment strategies of higher complexities and lower doses have been proposed as alternatives to current clinical strategies. However, finding optimal complex, low-dose treatment strategies is a challenge, as it is possible to design more treatment strategies than are feasibly testable in experimental settings. To quantitatively address this challenge, we develop a mathematical model of BRAFV600E-MEK-ERK signalling dynamics in response to combinations of the BRAFV600E-inhibitor dabrafenib (DBF), the MEK inhibitor trametinib (TMT), and the ERK-inhibitor SCH772984 (SCH). From a model of the BRAFV600E-MEK-ERK pathway, and a set of molecular-level drug-protein interactions, we extract a system of chemical reactions that is parameterised by in vitro data and converted to a system of ordinary differential equations (ODEs) using the law of mass action. The ODEs are solved numerically to produce simulations of how pathway-component concentrations change over time in response to different treatment strategies, i.e., inhibitor combinations and doses. The model can thus be used to limit the search space for effective treatment strategies that target the BRAFV600E-MEK-ERK pathway and warrant further experimental investigation. The results demonstrate that DBF and DBF-TMT-SCH therapies show marked sensitivity to BRAFV600E concentrations in silico, whilst TMT and SCH monotherapies do not.
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Affiliation(s)
- Alice De Carli
- School of Mathematics and Statistics, University of St Andrews, St Andrews, Scotland, UK
| | - Yury Kapelyukh
- School of Medicine, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK
| | - Jochen Kursawe
- School of Mathematics and Statistics, University of St Andrews, St Andrews, Scotland, UK
| | - Mark A J Chaplain
- School of Mathematics and Statistics, University of St Andrews, St Andrews, Scotland, UK
| | - C Roland Wolf
- School of Medicine, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK
| | - Sara Hamis
- School of Mathematics and Statistics, University of St Andrews, St Andrews, Scotland, UK.
- Tampere Institute for Advanced Study, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Department of Information Technology, Uppsala University, Uppsala, Sweden.
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9
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Sikiric P, Boban Blagaic A, Strbe S, Beketic Oreskovic L, Oreskovic I, Sikiric S, Staresinic M, Sever M, Kokot A, Jurjevic I, Matek D, Coric L, Krezic I, Tvrdeic A, Luetic K, Batelja Vuletic L, Pavic P, Mestrovic T, Sjekavica I, Skrtic A, Seiwerth S. The Stable Gastric Pentadecapeptide BPC 157 Pleiotropic Beneficial Activity and Its Possible Relations with Neurotransmitter Activity. Pharmaceuticals (Basel) 2024; 17:461. [PMID: 38675421 PMCID: PMC11053547 DOI: 10.3390/ph17040461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/24/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as a cytoprotection mediator holds a response specifically related to preventing or recovering damage as such) and its possible relations with neurotransmitter activity. We attempt to resolve the shortage of the pleiotropic beneficial effects of BPC 157, given the general standard neurotransmitter criteria, in classic terms. We substitute the lack of direct conclusive evidence (i.e., production within the neuron or present in it as a precursor molecule, released eliciting a response on the receptor on the target cells on neurons and being removed from the site of action once its signaling role is complete). This can be a network of interconnected evidence, previously envisaged in the implementation of the cytoprotection effects, consistent beneficial particular evidence that BPC 157 therapy counteracts dopamine, serotonin, glutamate, GABA, adrenalin/noradrenalin, acetylcholine, and NO-system disturbances. This specifically includes counteraction of those disturbances related to their receptors, both blockade and over-activity, destruction, depletion, tolerance, sensitization, and channel disturbances counteraction. Likewise, BPC 157 activates particular receptors (i.e., VGEF and growth hormone). Furthermore, close BPC 157/NO-system relations with the gasotransmitters crossing the cell membrane and acting directly on molecules inside the cell may envisage particular interactions with receptors on the plasma membrane of their target cells. Finally, there is nerve-muscle relation in various muscle disturbance counteractions, and nerve-nerve relation in various encephalopathies counteraction, which is also exemplified specifically by the BPC 157 therapy application.
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Lidija Beketic Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Ivana Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Mario Staresinic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Antonio Kokot
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Anatomy and Neuroscience, School of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Ivana Jurjevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Danijel Matek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Luka Coric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Ante Tvrdeic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Kresimir Luetic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Lovorka Batelja Vuletic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Predrag Pavic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Tomislav Mestrovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Anatomy and Neuroscience, School of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Ivica Sjekavica
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Diagnostic and Interventional Radiology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
| | - Anita Skrtic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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10
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Schmidt HN, Gaetjens TK, Leopin EE, Abel SM. Compartmental exchange regulates steady states and stochastic switching of a phosphorylation network. Biophys J 2024; 123:598-609. [PMID: 38317416 PMCID: PMC10938077 DOI: 10.1016/j.bpj.2024.01.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 01/24/2024] [Accepted: 01/31/2024] [Indexed: 02/07/2024] Open
Abstract
The phosphoregulation of proteins with multiple phosphorylation sites is governed by biochemical reaction networks that can exhibit multistable behavior. However, the behavior of such networks is typically studied in a single reaction volume, while cells are spatially organized into compartments that can exchange proteins. In this work, we use stochastic simulations to study the impact of compartmentalization on a two-site phosphorylation network. We characterize steady states and fluctuation-driven transitions between them as a function of the rate of protein exchange between two compartments. Surprisingly, the average time spent in a state before stochastically switching to another depends nonmonotonically on the protein exchange rate, with the most frequent switching occurring at intermediate exchange rates. At sufficiently small exchange rates, the state of the system and mean switching time are controlled largely by fluctuations in the balance of enzymes in each compartment. This leads to negatively correlated states in the compartments. For large exchange rates, the two compartments behave as a single effective compartment. However, when the compartmental volumes are unequal, the behavior differs from a single compartment with the same total volume. These results demonstrate that exchange of proteins between distinct compartments can regulate the emergent behavior of a common signaling motif.
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Affiliation(s)
- Hannah N Schmidt
- Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, Tennessee
| | - Thomas K Gaetjens
- Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, Tennessee
| | - Emily E Leopin
- Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, Tennessee
| | - Steven M Abel
- Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, Tennessee.
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11
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Wang C, Liu Y, Yang Y, Teng M, Wan X, Wu Z, Zhang Z. Splenic proteome profiling in response to Marek's disease virus strain GX0101 infection. BMC Vet Res 2024; 20:10. [PMID: 38183097 PMCID: PMC10768084 DOI: 10.1186/s12917-023-03852-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 12/13/2023] [Indexed: 01/07/2024] Open
Abstract
Marek's disease virus (MDV) strain GX0101 was the first reported field strain of recombinant gallid herpesvirus type 2 (GaHV-2). However, the splenic proteome of MDV-infected chickens remains unclear. In this study, a total of 28 1-day-old SPF chickens were intraperitoneally injected with chicken embryo fibroblast (CEF) containing 2000 PFU GX0101. Additionally, a control group, consisting of four one-day-old SPF chickens, received intraperitoneal equal doses of CEF. Blood and various tissue samples were collected at different intervals (7, 14, 21, 30, 45, 60, and 90 days post-infection; dpi) for histopathological, real-time PCR, and label-free quantitative analyses. The results showed that the serum expressions of MDV-related genes, meq and gB, peaked at 45 dpi. The heart, liver, and spleen were dissected at 30 and 45 dpi, and their hematoxylin-eosin staining indicated that virus infection compromised the normal organizational structure at 45 dpi. Particularly, the spleen structure was severely damaged, and the lymphocytes in the white medulla were significantly reduced. Furthermore, liquid chromatography-mass spectrometry (LC-MS) and label-free techniques were used to analyze the difference in splenic proteome profiles of the experimental and control groups at 30 and 45 dpi. Proteomic analysis identified 1660 and 1244 differentially expressed proteins (DEPs) at 30 and 40 dpi, respectively, compared with the uninfected spleen tissues. According to GO analysis, these DEPs were involved in processes such as organelle organization, cellular component biogenesis, cellular component assembly, anion binding, small molecule binding, metal ion binding, cation binding, cytosol, nuclear part, etc. Additionally, KEGG analysis indicated that the following pathways were linked to MDV-induced inflammation, apoptosis, and tumor: Wnt, Hippo, AMPK, cAMP, Notch, TGF-β, PI3K-Akt, Rap1, Ras, Calcium, NF-κB, PPAR, cGMP-PKG, Apoptosis, VEGF, mTOR, FoxO, TNF, JAK-STAT, MAPK, Prion disease, T cell receptor, and B cell receptor. We finally screened 674 DEPs that were linked to MDV infection in spleen tissue. This study improves our understanding of the MDV response mechanism in the spleen.
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Affiliation(s)
- Chuan Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, PR China.
| | - Yuanzi Liu
- Shaanxi Meili-OH Animal Health Co., Ltd, Xi'an, 712034, PR China
| | - Yuze Yang
- Beijing Animal Husbandry Station, Beijing, 100107, PR China
| | - Man Teng
- Key Laboratory of Animal Immunology of the Ministry of Agriculture, Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, 450002, PR China
| | - Xuerui Wan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, PR China
| | - Zixiang Wu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, PR China
| | - Zhao Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, PR China.
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12
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Ram A, Murphy D, DeCuzzi N, Patankar M, Hu J, Pargett M, Albeck JG. A guide to ERK dynamics, part 1: mechanisms and models. Biochem J 2023; 480:1887-1907. [PMID: 38038974 PMCID: PMC10754288 DOI: 10.1042/bcj20230276] [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: 07/09/2023] [Revised: 11/02/2023] [Accepted: 11/06/2023] [Indexed: 12/02/2023]
Abstract
Extracellular signal-regulated kinase (ERK) has long been studied as a key driver of both essential cellular processes and disease. A persistent question has been how this single pathway is able to direct multiple cell behaviors, including growth, proliferation, and death. Modern biosensor studies have revealed that the temporal pattern of ERK activity is highly variable and heterogeneous, and critically, that these dynamic differences modulate cell fate. This two-part review discusses the current understanding of dynamic activity in the ERK pathway, how it regulates cellular decisions, and how these cell fates lead to tissue regulation and pathology. In part 1, we cover the optogenetic and live-cell imaging technologies that first revealed the dynamic nature of ERK, as well as current challenges in biosensor data analysis. We also discuss advances in mathematical models for the mechanisms of ERK dynamics, including receptor-level regulation, negative feedback, cooperativity, and paracrine signaling. While hurdles still remain, it is clear that higher temporal and spatial resolution provide mechanistic insights into pathway circuitry. Exciting new algorithms and advanced computational tools enable quantitative measurements of single-cell ERK activation, which in turn inform better models of pathway behavior. However, the fact that current models still cannot fully recapitulate the diversity of ERK responses calls for a deeper understanding of network structure and signal transduction in general.
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Affiliation(s)
- Abhineet Ram
- Department of Molecular and Cellular Biology, University of California, Davis, U.S.A
| | - Devan Murphy
- Department of Molecular and Cellular Biology, University of California, Davis, U.S.A
| | - Nicholaus DeCuzzi
- Department of Molecular and Cellular Biology, University of California, Davis, U.S.A
| | - Madhura Patankar
- Department of Molecular and Cellular Biology, University of California, Davis, U.S.A
| | - Jason Hu
- Department of Molecular and Cellular Biology, University of California, Davis, U.S.A
| | - Michael Pargett
- Department of Molecular and Cellular Biology, University of California, Davis, U.S.A
| | - John G. Albeck
- Department of Molecular and Cellular Biology, University of California, Davis, U.S.A
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13
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Toader C, Eva L, Costea D, Corlatescu AD, Covache-Busuioc RA, Bratu BG, Glavan LA, Costin HP, Popa AA, Ciurea AV. Low-Grade Gliomas: Histological Subtypes, Molecular Mechanisms, and Treatment Strategies. Brain Sci 2023; 13:1700. [PMID: 38137148 PMCID: PMC10741942 DOI: 10.3390/brainsci13121700] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Low-Grade Gliomas (LGGs) represent a diverse group of brain tumors originating from glial cells, characterized by their unique histopathological and molecular features. This article offers a comprehensive exploration of LGGs, shedding light on their subtypes, histological and molecular aspects. By delving into the World Health Organization's grading system, 5th edition, various specificities were added due to an in-depth understanding of emerging laboratory techniques, especially genomic analysis. Moreover, treatment modalities are extensively discussed. The degree of surgical resection should always be considered according to postoperative quality of life and cognitive status. Adjuvant therapies focused on chemotherapy and radiotherapy depend on tumor grading and invasiveness. In the current literature, emerging targeted molecular therapies are well discussed due to their succinctly therapeutic effect; in our article, those therapies are summarized based on posttreatment results and possible adverse effects. This review serves as a valuable resource for clinicians, researchers, and medical professionals aiming to deepen their knowledge on LGGs and enhance patient care.
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Affiliation(s)
- Corneliu Toader
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (A.D.C.); (R.-A.C.-B.); (B.-G.B.); (L.A.G.); (H.P.C.); (A.A.P.); (A.V.C.)
- Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania
| | - Lucian Eva
- Department of Neurosurgery, Dunarea de Jos University, 800010 Galati, Romania
- Department of Neurosurgery, Clinical Emergency Hospital “Prof. Dr. Nicolae Oblu”, 700309 Iasi, Romania
| | - Daniel Costea
- Department of Neurosurgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Antonio Daniel Corlatescu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (A.D.C.); (R.-A.C.-B.); (B.-G.B.); (L.A.G.); (H.P.C.); (A.A.P.); (A.V.C.)
| | - Razvan-Adrian Covache-Busuioc
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (A.D.C.); (R.-A.C.-B.); (B.-G.B.); (L.A.G.); (H.P.C.); (A.A.P.); (A.V.C.)
| | - Bogdan-Gabriel Bratu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (A.D.C.); (R.-A.C.-B.); (B.-G.B.); (L.A.G.); (H.P.C.); (A.A.P.); (A.V.C.)
| | - Luca Andrei Glavan
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (A.D.C.); (R.-A.C.-B.); (B.-G.B.); (L.A.G.); (H.P.C.); (A.A.P.); (A.V.C.)
| | - Horia Petre Costin
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (A.D.C.); (R.-A.C.-B.); (B.-G.B.); (L.A.G.); (H.P.C.); (A.A.P.); (A.V.C.)
| | - Andrei Adrian Popa
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (A.D.C.); (R.-A.C.-B.); (B.-G.B.); (L.A.G.); (H.P.C.); (A.A.P.); (A.V.C.)
| | - Alexandru Vlad Ciurea
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (A.D.C.); (R.-A.C.-B.); (B.-G.B.); (L.A.G.); (H.P.C.); (A.A.P.); (A.V.C.)
- Neurosurgery Department, Sanador Clinical Hospital, 010991 Bucharest, Romania
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14
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Jurado M, Zorzano A, Castaño O. Cooperativity and oscillations: Regulatory mechanisms of K-Ras nanoclusters. Comput Biol Med 2023; 166:107455. [PMID: 37742420 DOI: 10.1016/j.compbiomed.2023.107455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 08/07/2023] [Accepted: 09/04/2023] [Indexed: 09/26/2023]
Abstract
K-Ras nanoclusters (NCs) concentrate all required molecules belonging to the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway in a small area where signaling events take place, increasing efficiency and specificity of signaling. Such nanostructures are characterized by controlled sizes and lifetimes distributions, but there is a poor understanding of the mechanisms involved in their dynamics of growth/decay. Here, a minimum computational model is presented to analyze the behavior of K-Ras NCs as cooperative dynamic structures that self-regulate their growth and decay according to their size. Indeed, the proposed model reveals that the growth and the local production of a K-Ras nanocluster depend positively on its actual size, whilst its lifetime is inversely proportional to the root of its size. The cooperative binding between the structural constituents of the NC (K-Ras proteins) induces oscillations in the size distributions of K-Ras NCs allowing them to range within controlled values, regulating the growth/decay dynamics of these NCs. Thereby, the size of a K-Ras NC is proposed as a key factor to regulate cell signaling, opening a range of possibilities to develop strategies for use in chronic diseases and cancer.
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Affiliation(s)
- Manuel Jurado
- Faculty of Pharmacy, University of Barcelona, Barcelona, Spain
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; CIBER of Diabetes and Associated Metabolic Diseases, Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.
| | - Oscar Castaño
- Electronics and Biomedical Engineering, Universitat de Barcelona (UB), Barcelona, Spain; Nanobioengineering and Biomaterials, Institute of Nanoscience and Nanotechnology of the University of Barcelona, Barcelona, Spain
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15
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Ram T, Singh AK, Kumar A, Singh H, Pathak P, Grishina M, Khalilullah H, Jaremko M, Emwas AH, Verma A, Kumar P. MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives. RSC Med Chem 2023; 14:1837-1857. [PMID: 37859720 PMCID: PMC10583825 DOI: 10.1039/d3md00145h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 07/12/2023] [Indexed: 10/21/2023] Open
Abstract
MEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the αC-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition.
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Affiliation(s)
- Teja Ram
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
| | - Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
| | - Harshwardhan Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
| | - Prateek Pathak
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University Chelyabinsk 454008 Russia
- Pharmaceutical Analysis and Quality Assurance and Pharmaceutical Chemistry, GITAM School of Pharmacy at "Hyderabad Campus", GITAM (Deemed to be University) India
| | - Maria Grishina
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University Chelyabinsk 454008 Russia
| | - Habibullah Khalilullah
- Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University Unayzah 51911 Saudi Arabia
| | - Mariusz Jaremko
- Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Abdul-Hamid Emwas
- Core Labs, King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Amita Verma
- Bioorganic and Med. Chem. Res., Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences Prayagraj 211007 India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
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16
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Almowallad S, Alqahtani LS, Mobashir M. NF-kB in Signaling Patterns and Its Temporal Dynamics Encode/Decode Human Diseases. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122012. [PMID: 36556376 PMCID: PMC9788026 DOI: 10.3390/life12122012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 11/30/2022] [Indexed: 12/05/2022]
Abstract
Defects in signaling pathways are the root cause of many disorders. These malformations come in a wide variety of types, and their causes are also very diverse. Some of these flaws can be brought on by pathogenic organisms and viruses, many of which can obstruct signaling processes. Other illnesses are linked to malfunctions in the way that cell signaling pathways work. When thinking about how errors in signaling pathways might cause disease, the idea of signalosome remodeling is helpful. The signalosome may be conveniently divided into two types of defects: phenotypic remodeling and genotypic remodeling. The majority of significant illnesses that affect people, including high blood pressure, heart disease, diabetes, and many types of mental illness, appear to be caused by minute phenotypic changes in signaling pathways. Such phenotypic remodeling modifies cell behavior and subverts normal cellular processes, resulting in illness. There has not been much progress in creating efficient therapies since it has been challenging to definitively confirm this connection between signalosome remodeling and illness. The considerable redundancy included into cell signaling systems presents several potential for developing novel treatments for various disease conditions. One of the most important pathways, NF-κB, controls several aspects of innate and adaptive immune responses, is a key modulator of inflammatory reactions, and has been widely studied both from experimental and theoretical perspectives. NF-κB contributes to the control of inflammasomes and stimulates the expression of a number of pro-inflammatory genes, including those that produce cytokines and chemokines. Additionally, NF-κB is essential for controlling innate immune cells and inflammatory T cells' survival, activation, and differentiation. As a result, aberrant NF-κB activation plays a role in the pathogenesis of several inflammatory illnesses. The activation and function of NF-κB in relation to inflammatory illnesses was covered here, and the advancement of treatment approaches based on NF-κB inhibition will be highlighted. This review presents the temporal behavior of NF-κB and its potential relevance in different human diseases which will be helpful not only for theoretical but also for experimental perspectives.
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Affiliation(s)
- Sanaa Almowallad
- Department of Biochemistry, Faculty of Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Leena S. Alqahtani
- Department of Biochemistry, College of Science, University of Jeddah, Jeddah 23445, Saudi Arabia
- Correspondence: (L.S.A.); (M.M.)
| | - Mohammad Mobashir
- SciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, P.O. Box 1031, S-17121 Stockholm, Sweden
- Department of Biosciences, Faculty of Natural Science, Jamia Millia Islamia, New Delhi 110025, India
- Special Infectious Agents Unit—BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi Arabia
- Correspondence: (L.S.A.); (M.M.)
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17
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Fabbri VP, Caporalini C, Asioli S, Buccoliero A. Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome. Pathologica 2022; 114:410-421. [PMID: 36534420 PMCID: PMC9763978 DOI: 10.32074/1591-951x-828] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 11/12/2022] [Indexed: 12/23/2022] Open
Abstract
The WHO 2021 classification of central nervous system cancers distinguishes diffuse gliomas that arise in adults (referred to as the "adult type") and those that arise in children (defined as "paediatric") based on clinical and molecular characteristics."). However, paediatric-type gliomas may occasionally be present in younger adults and occasionally adult-type gliomas may occur in children. Diffuse low-grade paediatric glioma includes diffuse astrocytoma altered by MYB or MYBL1, low-grade polymorphic juvenile neuroepithelial tumour, angiocentric glioma, and diffuse low-grade glioma with an altered MAPK pathway. Here, we examine these newly recognised entities according to WHO diagnostic criteria and propose an integrated diagnostic approach that can be used to separate these clinically and biologically distinct tumor groups.
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Affiliation(s)
- Viscardo Paolo Fabbri
- Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum University of Bologna, Bologna, Italy
- Azienda Ospedaliero Universitaria Policlinico Modena, Modena, Italy
| | | | - Sofia Asioli
- Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum University of Bologna, Bologna, Italy
- Programma Neurochirurgia Ipofisi- Pituitary Unit, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
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18
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Co-Expression of Adaptor Protein FAM159B with Different Markers for Neuroendocrine Cells: An Immunocytochemical and Immunohistochemical Study. Int J Mol Sci 2022; 23:ijms232113503. [DOI: 10.3390/ijms232113503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 10/23/2022] [Accepted: 11/03/2022] [Indexed: 11/06/2022] Open
Abstract
Little is known about the adaptor protein FAM159B. Recently, FAM159B was shown to be particularly expressed in neuroendocrine cells and tissues, such as pancreatic islets and neuroendocrine cells of the bronchopulmonary and gastrointestinal tracts, as well as in different types of neuroendocrine tumours. To gain insights into possible interactions of FAM159B with other proteins and/or receptors, we analysed the co-expression of FAM159B and various neuroendocrine-specific markers in the cancer cell lines BON-1, PC-3, NCI-h82, OH-1, and A431 and also in human pancreatic tissues and pancreatic neuroendocrine tumours. The markers included prominent markers of neuroendocrine differentiation, such as chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin (SYP), insulinoma-associated protein 1 (INSM1), neural cell adhesion molecule 1 (NCAM1), serotonin (5-HT), somatostatin-14/28 (SST), and several receptors that are typically expressed by neuroendocrine cells, such as dopamine receptor 2 (D2R), somatostatin receptor (SSTR) 1, 2, 3, 4 and 5, and regulator of G-protein signalling 9 (RGS9). FAM159B was expressed evenly throughout the cytosol in all five cancer cell lines. Immunocytochemical and immunohistochemical analyses revealed co-expression of FAM159B with SYP, INSM1, RGS9, D2R, SSTR2, SSTR3, SSTR4, and SSTR5 and strong overlapping co-localisation with NSE. Double-labelling and co-immunoprecipitation Western blot analyses confirmed a direct association between FAM159B and NSE. These results suggest the involvement of FAM159B in several intracellular signalling pathways and a direct or indirect influence on diverse membrane proteins and receptors.
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19
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Morella I, Pohořalá V, Calpe-López C, Brambilla R, Spanagel R, Bernardi RE. Nicotine self-administration and ERK signaling are altered in RasGRF2 knockout mice. Front Pharmacol 2022; 13:986566. [PMID: 36120353 PMCID: PMC9479000 DOI: 10.3389/fphar.2022.986566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/10/2022] [Indexed: 11/29/2022] Open
Abstract
Ras/Raf/MEK/ERK (Ras-ERK) signaling has been demonstrated to play a role in the effects of drugs of abuse such as cocaine and alcohol, but has not been extensively examined in nicotine-related reward behaviors. We examined the role of Ras Guanine Nucleotide Releasing Factor 2 (RasGRF2), an upstream mediator of the Ras-ERK signaling pathway, on nicotine self-administration (SA) in RasGRF2 KO and WT mice. We first demonstrated that acute nicotine exposure (0.4 mg/kg) resulted in an increase in phosphorylated ERK1/2 (pERK1/2) in the striatum, consistent with previous reports. We also demonstrated that increases in pERK1/2 resulting from acute (0.4 mg/kg) and repeated (0.4 mg/kg, 10 daily injections) exposure to nicotine in WT mice were not present in RasGRF2 KO mice, confirming that RasGRF2 at least partly regulates the activity of the Ras-ERK signaling pathway following nicotine exposure. We then performed intravenous nicotine SA (0.03 mg/kg/infusion for 10 days) in RasGRF2 KO and WT mice. Consistent with a previous report using cocaine SA, RasGRF2 KO mice demonstrated an increase in nicotine SA relative to WT controls. These findings suggest a role for RasGRF2 in the reinforcing effects of nicotine, and implicate the Ras-ERK signaling pathway as a common mediator of the response to drugs of abuse.
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Affiliation(s)
- Ilaria Morella
- Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, United Kingdom
- Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Veronika Pohořalá
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Claudia Calpe-López
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Riccardo Brambilla
- Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, United Kingdom
- Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Rainer Spanagel
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Rick E. Bernardi
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Shahidi N, Pan M, Tran K, Crampin EJ, Nickerson DP. A semantics, energy-based approach to automate biomodel composition. PLoS One 2022; 17:e0269497. [PMID: 35657966 PMCID: PMC9165793 DOI: 10.1371/journal.pone.0269497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 05/20/2022] [Indexed: 11/19/2022] Open
Abstract
Hierarchical modelling is essential to achieving complex, large-scale models. However, not all modelling schemes support hierarchical composition, and correctly mapping points of connection between models requires comprehensive knowledge of each model's components and assumptions. To address these challenges in integrating biosimulation models, we propose an approach to automatically and confidently compose biosimulation models. The approach uses bond graphs to combine aspects of physical and thermodynamics-based modelling with biological semantics. We improved on existing approaches by using semantic annotations to automate the recognition of common components. The approach is illustrated by coupling a model of the Ras-MAPK cascade to a model of the upstream activation of EGFR. Through this methodology, we aim to assist researchers and modellers in readily having access to more comprehensive biological systems models.
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Affiliation(s)
- Niloofar Shahidi
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Michael Pan
- Systems Biology Laboratory, School of Mathematics and Statistics, and Department of Biomedical Engineering, University of Melbourne, Melbourne, Victoria, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Faculty of Engineering and Information Technology, University of Melbourne, Melbourne, Victoria, Australia
- School of Mathematics and Statistics, Faculty of Science, University of Melbourne, Victoria, Australia
| | - Kenneth Tran
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Edmund J. Crampin
- Systems Biology Laboratory, School of Mathematics and Statistics, and Department of Biomedical Engineering, University of Melbourne, Melbourne, Victoria, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Faculty of Engineering and Information Technology, University of Melbourne, Melbourne, Victoria, Australia
- School of Mathematics and Statistics, Faculty of Science, University of Melbourne, Victoria, Australia
- School of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - David P. Nickerson
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
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21
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Extracellular vesicles in mammalian reproduction: a review. ZYGOTE 2022; 30:440-463. [PMID: 35652626 DOI: 10.1017/s0967199422000090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Over the last decades, extracellular vesicles (EVs) have been found to be implicated in a complex universal mechanism of communication between different cell types. EVs are nanostructures of lipid nature that have an exosomal or ectosomal biogenesis, responsible for the intercellular transport of proteins, lipids, carbohydrates, nucleic acids, ions, among other molecules. The content of EVs can vary due to various factors such as hormonal stimuli, non-physiological conditions, metabolic state, etc. Once EVs reach their target cell, they can modulate processes such as gene expression, metabolism, response to external factors, and can even be associated with the delivery of molecules involved in epigenetic inheritance processes in germ cells. In mammalian reproduction, EVs have been shown to play an important role, either in vivo or in vitro, modulating a variety of processes in sperm, oocytes and embryos, and in their respective environments. Moreover, EVs represent a biodegradable, harmless and specific vehicle, which makes them attractive allies to consider when improving assisted reproductive technologies (ARTs). Therefore, the present review aims to describe the content of the main EVs involved in mammalian reproduction and how they can vary due to different factors, as well as to detail how EVs modulate, directly or indirectly, different molecular processes in gametes and embryos. In addition, we will highlight the mechanisms that remain to be elucidated. We will also propose new perspectives according to the characteristics of each particular EV to improve the different ARTs.
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22
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Dessauges C, Mikelson J, Dobrzyński M, Jacques M, Frismantiene A, Gagliardi PA, Khammash M, Pertz O. Optogenetic actuator - ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics. Mol Syst Biol 2022; 18:e10670. [PMID: 35694820 PMCID: PMC9189677 DOI: 10.15252/msb.202110670] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 12/12/2022] Open
Abstract
Combining single-cell measurements of ERK activity dynamics with perturbations provides insights into the MAPK network topology. We built circuits consisting of an optogenetic actuator to activate MAPK signaling and an ERK biosensor to measure single-cell ERK dynamics. This allowed us to conduct RNAi screens to investigate the role of 50 MAPK proteins in ERK dynamics. We found that the MAPK network is robust against most node perturbations. We observed that the ERK-RAF and the ERK-RSK2-SOS negative feedback operate simultaneously to regulate ERK dynamics. Bypassing the RSK2-mediated feedback, either by direct optogenetic activation of RAS, or by RSK2 perturbation, sensitized ERK dynamics to further perturbations. Similarly, targeting this feedback in a human ErbB2-dependent oncogenic signaling model increased the efficiency of a MEK inhibitor. The RSK2-mediated feedback is thus important for the ability of the MAPK network to produce consistent ERK outputs, and its perturbation can enhance the efficiency of MAPK inhibitors.
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Affiliation(s)
| | - Jan Mikelson
- Department of Biosystems Science and EngineeringETH ZurichBaselSwitzerland
| | | | | | | | | | - Mustafa Khammash
- Department of Biosystems Science and EngineeringETH ZurichBaselSwitzerland
| | - Olivier Pertz
- Institute of Cell BiologyUniversity of BernBernSwitzerland
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23
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Oh D, Chen Z, Biswas KH, Bai F, Ong HT, Sheetz MP, Groves JT. Competition for shared downstream signaling molecules establishes indirect negative feedback between EGFR and EphA2. Biophys J 2022; 121:1897-1908. [DOI: 10.1016/j.bpj.2022.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 03/21/2022] [Accepted: 04/12/2022] [Indexed: 11/02/2022] Open
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Campos JF, Besson T, Berteina-Raboin S. Review on the Synthesis and Therapeutic Potential of Pyrido[2,3-d], [3,2-d], [3,4-d] and [4,3-d]pyrimidine Derivatives. Pharmaceuticals (Basel) 2022; 15:ph15030352. [PMID: 35337149 PMCID: PMC8949896 DOI: 10.3390/ph15030352] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/03/2022] [Accepted: 03/10/2022] [Indexed: 12/10/2022] Open
Abstract
The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review is organized into four sections, successively pyrido[2,3-d]pyrimidines, pyrido[3,4-d]pyrimidines, pyrido[4,3-d]pyrimidines and pyrido[3,2-d]pyrimidines. For each compound we present the biological activity and the synthetic route reported. To produce this manuscript, the bibliographic research was done using Reaxys and Scifinder for each kind of pyridopyrimidine.
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Affiliation(s)
- Joana F. Campos
- Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans CNRS, ICOA UMR 7311, BP 6759, Rue de Chartres, CEDEX 2, 45067 Orléans, France;
| | - Thierry Besson
- Université de Rouen-Normandie (UNIROUEN), INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France;
| | - Sabine Berteina-Raboin
- Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans CNRS, ICOA UMR 7311, BP 6759, Rue de Chartres, CEDEX 2, 45067 Orléans, France;
- Correspondence: ; Tel.: +33-238-494-856
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25
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Wang K, Zhang M, Zhao S, Xie Z, Zhang Y, Liu J, Zhang Y, Yang X, Wu N. Mutational spectrum of syndromic genes in sporadic brain arteriovenous malformation. Chin Neurosurg J 2022; 8:4. [PMID: 35209959 PMCID: PMC8867132 DOI: 10.1186/s41016-022-00270-8] [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: 01/12/2021] [Accepted: 01/13/2022] [Indexed: 11/22/2022] Open
Abstract
Background Brain arteriovenous malformations (BAVMs) are abnormal vessels that are apt to rupture, causing life-threatening intracranial hemorrhage (ICH). The estimated prevalence of BAVMs is 0.05% among otherwise healthy individuals. In this study, we aim to investigate the mutational spectrum of syndromic genes in sporadic BAVM. Methods We recruited a cohort of 150 patients with BAVM and performed whole-exome sequencing on their peripheral blood DNA. To explore the mutational spectrum of syndromic genes in sporadic brain arteriovenous malformation, we selected six genes according to the Online Mendelian Inheritance in Man (OMIM) and literature. All variants in the six candidate genes were extracted and underwent filtering for qualifying variants. Results There are a total of four patients with rare variants in hereditary hemorrhagic telangiectasia-related genes. In addition, we identified two patients have the variant of RASA1 gene in our database, which are also rare mutations that are absent from population databases. However, we did not find any patients with GNAQ mutations in our database. Conclusions In conclusion, we demonstrated that variants in syndromic vascular malformations play important roles in the etiology of sporadic BAVM.
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Affiliation(s)
- Kun Wang
- Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Mingqi Zhang
- Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Sen Zhao
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China
| | - Zhixin Xie
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China
| | - Yisen Zhang
- Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Jian Liu
- Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Ying Zhang
- Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Xinjian Yang
- Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
| | - Nan Wu
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China. .,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China. .,Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, 100730, China.
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26
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Live imaging approach of dynamic multicellular responses in ERK signaling during vertebrate tissue development. Biochem J 2022; 479:129-143. [PMID: 35050327 PMCID: PMC8883488 DOI: 10.1042/bcj20210557] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/28/2021] [Accepted: 01/05/2022] [Indexed: 11/17/2022]
Abstract
The chemical and mechanical responses of cells via the exchange of information during growth and development result in the formation of biological tissues. Information processing within the cells through the signaling pathways and networks inherent to the constituent cells has been well-studied. However, the cell signaling mechanisms responsible for generating dynamic multicellular responses in developing tissues remain unclear. Here, I review the dynamic multicellular response systems during the development and growth of vertebrate tissues based on the extracellular signal-regulated kinase (ERK) pathway. First, an overview of the function of the ERK signaling network in cells is provided, followed by descriptions of biosensors essential for live imaging of the quantification of ERK activity in tissues. Then adducing four examples, I highlight the contribution of live imaging techniques for studying the involvement of spatio-temporal patterns of ERK activity change in tissue development and growth. In addition, theoretical implications of ERK signaling are also discussed from the viewpoint of dynamic systems. This review might help in understanding ERK-mediated dynamic multicellular responses and tissue morphogenesis.
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Dahmardeh Ghalehno A, Boustan A, Abdi H, Aganj Z, Mosaffa F, Jamialahmadi K. The Potential for Natural Products to Overcome Cancer Drug Resistance by Modulation of Epithelial-Mesenchymal Transition. Nutr Cancer 2022; 74:2686-2712. [PMID: 34994266 DOI: 10.1080/01635581.2021.2022169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The acquisition of resistance and ultimately disease relapse after initial response to chemotherapy put obstacles in the way of cancer therapy. Epithelial-mesenchymal transition (EMT) is a biologic process that epithelial cells alter to mesenchymal cells and acquire fibroblast-like properties. EMT plays a significant role in cancer metastasis, motility, and survival. Recently, emerging evidence suggested that EMT pathways are very important in making drug-resistant involved in cancer. Natural products are gradually emerging as a valuable source of safe and effective anticancer compounds. Natural products could interfere with the different processes implicated in cancer drug resistance by reversing the EMT process. In this review, we illustrate the molecular mechanisms of EMT in the emergence of cancer metastasis. We then present the role of natural compounds in the suppression of EMT pathways in different cancers to overcome cancer cell drug resistance and improve tumor chemotherapy. HighlightsDrug-resistance is one of the obstacles to cancer treatment.EMT signaling pathways have been correlated to tumor invasion, metastasis, and drug-resistance.Various studies on the relationship between EMT and resistance to chemotherapy agents were reviewed.Different anticancer natural products with EMT inhibitory properties and drug resistance reversal effects were compared.
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Affiliation(s)
- Asefeh Dahmardeh Ghalehno
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arad Boustan
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hakimeh Abdi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Aganj
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Mosaffa
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khadijeh Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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28
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Membrane polarization in non-neuronal cells as a potential mechanism of metabolic disruption by depolarizing insecticides. Food Chem Toxicol 2022; 160:112804. [PMID: 34990786 DOI: 10.1016/j.fct.2021.112804] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/22/2021] [Accepted: 12/31/2021] [Indexed: 01/01/2023]
Abstract
A significant rise in the incidence of obesity and type 2 diabetes has occurred worldwide in the last two decades. Concurrently, a growing body of evidence suggests a connection between exposure to environmental pollutants, particularly insecticides, and the development of obesity and type 2 diabetes. This review summarizes key evidence of (1) the presence of different types of neuronal receptors - target sites for neurotoxic insecticides - in non-neuronal cells, (2) the activation of these receptors in non-neuronal cells by membrane-depolarizing insecticides, and (3) changes in metabolic functions, including lipid and glucose accumulation, associated with changes in membrane potential. Based on these findings, we propose that changes in membrane potential (Vmem) by certain insecticides serve as a novel regulator of lipid and glucose metabolism in non-excitable cells associated with obesity and type 2 diabetes.
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29
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Kamel NA, Ismail NSM, Yahia IS, Aboshanab KM. Potential Role of Colchicine in Combating COVID-19 Cytokine Storm and Its Ability to Inhibit Protease Enzyme of SARS-CoV-2 as Conferred by Molecular Docking Analysis. Medicina (B Aires) 2021; 58:medicina58010020. [PMID: 35056328 PMCID: PMC8781828 DOI: 10.3390/medicina58010020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/16/2021] [Accepted: 12/18/2021] [Indexed: 12/03/2022] Open
Abstract
Despite the advance in the management of Coronavirus disease 2019 (COVID-19), the global pandemic is still ongoing with a massive health crisis. COVID-19 manifestations may range from mild symptoms to severe life threatening ones. The hallmark of the disease severity is related to the overproduction of pro-inflammatory cytokines manifested as a cytokine storm. Based on its anti-inflammatory activity through interfering with several pro and anti-inflammatory pathways, colchicine had been proposed to reduce the cytokine storm and subsequently improve clinical outcomes. Molecular docking analysis of colchicine against RNA-dependent RNA polymerase (RdRp) and protease enzymes of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) revealed that colchicine provided a grid-based molecular docking method, C-DOCKER interaction energy 64.26 and 47.53 (Kcal/mol) with protease and RdRp, respectively. This finding indicated higher binding stability for colchicine–protease complexes than the colchicine–RdRp complex with the involvement of seven hydrogen bonds, six hydrogen acceptors with Asn142, Gly143, Ser144, and Glu166 and one hydrogen-bond donors with Cys145 of the protease enzyme. This is in addition to three hydrophobic interactions with His172, Glu166, and Arg188. A good alignment with the reference compound, Boceprevir, indicated high probability of binding to the protease enzyme of SARS-CoV-2. In conclusion, colchicine can ameliorate the destructive effect of the COVID-19 cytokine storm with a strong evidence of antiviral activity by inhibiting the protease enzyme of SARS-CoV-2.
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Affiliation(s)
- Noha A. Kamel
- Department of Microbiology, Faculty of Pharmacy, Misr International University (MIU), Cairo 19648, Egypt;
| | - Nasser S. M. Ismail
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo 11835, Egypt;
| | - Ibrahim S. Yahia
- Laboratory of Nano-Smart Materials for Science and Technology (LNSMST), Department of Physics, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia;
- Research Center for Advanced Materials Science (RCAMS), King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
- Nanoscience Laboratory for Environmental and Biomedical Applications (NLEBA), Semiconductor Laboratory, Department of Physics, Faculty of Education, Ain Shams University (ASU), Roxy, Cairo 11757, Egypt
| | - Khaled M. Aboshanab
- Department of Microbiology & Immunology, Faculty of Pharmacy, Ain Shams University (ASU), Abbassia, Cairo 11566, Egypt
- Correspondence: ; Tel.: +20-1-0075-82620; Fax: +20-2-2405110
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Gondal MN, Chaudhary SU. Navigating Multi-Scale Cancer Systems Biology Towards Model-Driven Clinical Oncology and Its Applications in Personalized Therapeutics. Front Oncol 2021; 11:712505. [PMID: 34900668 PMCID: PMC8652070 DOI: 10.3389/fonc.2021.712505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 10/26/2021] [Indexed: 12/19/2022] Open
Abstract
Rapid advancements in high-throughput omics technologies and experimental protocols have led to the generation of vast amounts of scale-specific biomolecular data on cancer that now populates several online databases and resources. Cancer systems biology models built using this data have the potential to provide specific insights into complex multifactorial aberrations underpinning tumor initiation, development, and metastasis. Furthermore, the annotation of these single- and multi-scale models with patient data can additionally assist in designing personalized therapeutic interventions as well as aid in clinical decision-making. Here, we have systematically reviewed the emergence and evolution of (i) repositories with scale-specific and multi-scale biomolecular cancer data, (ii) systems biology models developed using this data, (iii) associated simulation software for the development of personalized cancer therapeutics, and (iv) translational attempts to pipeline multi-scale panomics data for data-driven in silico clinical oncology. The review concludes that the absence of a generic, zero-code, panomics-based multi-scale modeling pipeline and associated software framework, impedes the development and seamless deployment of personalized in silico multi-scale models in clinical settings.
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Affiliation(s)
- Mahnoor Naseer Gondal
- Biomedical Informatics Research Laboratory, Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States
| | - Safee Ullah Chaudhary
- Biomedical Informatics Research Laboratory, Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan
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Quantifying ERK activity in response to inhibition of the BRAFV600E-MEK-ERK cascade using mathematical modelling. Br J Cancer 2021; 125:1552-1560. [PMID: 34621046 PMCID: PMC8608797 DOI: 10.1038/s41416-021-01565-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 09/06/2021] [Accepted: 09/21/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Simultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. However, the molecular mechanism of how vertical inhibition synergistically suppresses intracellular ERK activity, and consequently cell proliferation, are yet to be fully elucidated. METHODS We develop a mechanistic mathematical model that describes how the mutant BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, affect BRAFV600E-MEK-ERK signalling. The model is based on a system of chemical reactions that describes cascade signalling dynamics. Using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations that are parameterised by in vitro data and solved numerically to obtain the temporal evolution of cascade component concentrations. RESULTS The model provides a quantitative method to compute how dabrafenib and trametinib can be used in combination to synergistically inhibit ERK activity in BRAFV600E-mutant melanoma cells. The model elucidates molecular mechanisms of vertical inhibition of the BRAFV600E-MEK-ERK cascade and delineates how elevated BRAF concentrations generate drug resistance to dabrafenib and trametinib. The computational simulations further suggest that elevated ATP levels could be a factor in drug resistance to dabrafenib. CONCLUSIONS The model can be used to systematically motivate which dabrafenib-trametinib dose combinations, for treating BRAFV600E-mutated melanoma, warrant experimental investigation.
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He Y, Chen Y, Tong Y, Long W, Liu Q. Identification of a circRNA-miRNA-mRNA regulatory network for exploring novel therapeutic options for glioma. PeerJ 2021; 9:e11894. [PMID: 34434651 PMCID: PMC8351580 DOI: 10.7717/peerj.11894] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/12/2021] [Indexed: 12/19/2022] Open
Abstract
Background Glioma is the most common brain neoplasm with a poor prognosis. Circular RNA (circRNA) and their associated competing endogenous RNA (ceRNA) network play critical roles in the pathogenesis of glioma. However, the alteration of the circRNA-miRNA-mRNA regulatory network and its correlation with glioma therapy haven't been systematically analyzed. Methods With GEO, GEPIA2, circBank, CSCD, CircInteractome, mirWalk 2.0, and mirDIP 4.1, we constructed a circRNA-miRNA-mRNA network in glioma. LASSO regression and multivariate Cox regression analysis established a hub mRNA signature to assess the prognosis. GSVA was used to estimate the immune infiltration level. Potential anti-glioma drugs were forecasted using the cMap database and evaluated with GSEA using GEO data. Results A ceRNA network of seven circRNAs (hsa_circ_0030788/0034182/0000227/ 0018086/0000229/0036592/0002765), 15 miRNAs(hsa-miR-1200/1205/1248/ 1303/3925-5p/5693/581/586/599/607/640/647/6867-5p/767-3p/935), and 46 mRNAs (including 11 hub genes of ARHGAP11A, DRP2, HNRNPA3, IGFBP5, IP6K2, KLF10, KPNA4, NRP2, PAIP1, RCN1, and SEMA5A) was constructed. Functional enrichment showed they influenced majority of the hallmarks of tumors. Eleven hub genes were proven to be decent prognostic signatures for glioma in both TCGA and CGGA datasets. Forty-six LASSO regression significant genes were closely related to immune infiltration. Finally, five compounds (fulvestrant, tanespimycin, mifepristone, tretinoin, and harman) were predicted as potential treatments for glioma. Among them, mifepristone and tretinoin were proven to inhibit the cell cycle and DNA repair in glioma. Conclusion This study highlights the potential pathogenesis of the circRNA-miRNA-mRNA regulatory network and identifies novel therapeutic options for glioma.
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Affiliation(s)
- Yi He
- Neurosurgery Department, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Yihong Chen
- Neurosurgery Department, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Yuxin Tong
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Wenyong Long
- Neurosurgery Department, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Qing Liu
- Neurosurgery Department, Xiangya Hospital Central South University, Changsha, Hunan, China
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Lee J, Hong EM, Kim JH, Kim JH, Jung JH, Park SW, Koh DH, Jang HJ. Ursodeoxycholic acid shows antineoplastic effects in bile duct cancer cells via apoptosis induction; p53 activation; and EGFR-ERK, COX-2, and PI3K-AKT pathway inhibition. Mol Biol Rep 2021; 48:6231-6240. [PMID: 34392440 DOI: 10.1007/s11033-021-06331-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 03/31/2021] [Indexed: 11/24/2022]
Abstract
Unlike in normal cells, ursodeoxycholic acid (UDCA) causes apoptosis rather than protection in cancer cells. Aim of this study was to demonstrate whether UDCA actually inhibits proliferation and induces apoptosis in bile duct cancer cells; the effect of UDCA on the expression of COX-2, PI3K/AKT, ERK, and EGFR; how UDCA affects cancer cell invasiveness and metastasis, since these effects are not established in bile duct cancer cells. SNU-245 cells (human extrahepatic bile duct cancer cells) were cultured. MTT assays were performed to evaluate the effect of UDCA on the cell proliferation. A cell death detection enzyme-linked immunosorbent assay and a caspase-3 activity assay were used to determine apoptosis. Western blot analysis measured expression levels of various proteins. The invasiveness of the cancer cells was evaluated by invasion assay. In cultured bile duct cancer cells, UDCA suppressed cell proliferation in bile duct cancer cells by inducing apoptosis and p53 activation, blocking deoxycholic acid (DCA)-induced activated EGFR-ERK signaling and COX-2, inhibiting DCA-induced activated PI3K-AKT signaling, and suppressing the invasiveness of bile duct cancer cells. In addition, a MEK inhibitor impaired UDCA-induced apoptosis in bile duct cancer cells. UDCA has antineoplastic and apoptotic effects in bile duct cancer cells. Thus, UDCA could be a chemopreventive agent in patients with a high risk of cancer, and/or a therapeutic option that enhances other chemotherapeutics.
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Affiliation(s)
- Jin Lee
- Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Gangwon-Do, South Korea. .,Division of Gastroenterology, Hallym University Dongtan Sacred Heart Hospital, 7 Keunjaebong-Gil, Hwasung, Gyeonggi-Do, 18450, South Korea.
| | - Eun Mi Hong
- Division of Gastroenterology, Hallym University Dongtan Sacred Heart Hospital, 7 Keunjaebong-Gil, Hwasung, Gyeonggi-Do, 18450, South Korea
| | - Jung Han Kim
- Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Gangwon-Do, South Korea
| | - Jung Hee Kim
- Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Gangwon-Do, South Korea.,Division of Gastroenterology, Hallym University Dongtan Sacred Heart Hospital, 7 Keunjaebong-Gil, Hwasung, Gyeonggi-Do, 18450, South Korea
| | - Jang Han Jung
- Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Gangwon-Do, South Korea.,Division of Gastroenterology, Hallym University Dongtan Sacred Heart Hospital, 7 Keunjaebong-Gil, Hwasung, Gyeonggi-Do, 18450, South Korea
| | - Se Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Gangwon-Do, South Korea.,Division of Gastroenterology, Hallym University Dongtan Sacred Heart Hospital, 7 Keunjaebong-Gil, Hwasung, Gyeonggi-Do, 18450, South Korea
| | - Dong Hee Koh
- Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Gangwon-Do, South Korea.,Division of Gastroenterology, Hallym University Dongtan Sacred Heart Hospital, 7 Keunjaebong-Gil, Hwasung, Gyeonggi-Do, 18450, South Korea
| | - Hyun Joo Jang
- Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Gangwon-Do, South Korea.,Division of Gastroenterology, Hallym University Dongtan Sacred Heart Hospital, 7 Keunjaebong-Gil, Hwasung, Gyeonggi-Do, 18450, South Korea
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Kelly JB, Carlson DE, Low JS, Rice T, Thacker RW. The Relationship Between Microbiomes and Selective Regimes in the Sponge Genus Ircinia. Front Microbiol 2021; 12:607289. [PMID: 33776953 PMCID: PMC7990798 DOI: 10.3389/fmicb.2021.607289] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 02/18/2021] [Indexed: 01/17/2023] Open
Abstract
Sponges are often densely populated by microbes that benefit their hosts through nutrition and bioactive secondary metabolites; however, sponges must simultaneously contend with the toxicity of microbes and thwart microbial overgrowth. Despite these fundamental tenets of sponge biology, the patterns of selection in the host sponges' genomes that underlie tolerance and control of their microbiomes are still poorly understood. To elucidate these patterns of selection, we performed a population genetic analysis on multiple species of Ircinia from Belize, Florida, and Panama using an F ST -outlier approach on transcriptome-annotated RADseq loci. As part of the analysis, we delimited species boundaries among seven growth forms of Ircinia. Our analyses identified balancing selection in immunity genes that have implications for the hosts' tolerance of high densities of microbes. Additionally, our results support the hypothesis that each of the seven growth forms constitutes a distinct Ircinia species that is characterized by a unique microbiome. These results illuminate the evolutionary pathways that promote stable associations between host sponges and their microbiomes, and that potentially facilitate ecological divergence among Ircinia species.
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Affiliation(s)
- Joseph B. Kelly
- Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY, United States
- Limnological Institute University Konstanz, Aquatic Ecology and Evolution, Konstanz, Germany
| | - David E. Carlson
- Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY, United States
| | - Jun Siong Low
- Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
| | - Tyler Rice
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
| | - Robert W. Thacker
- Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY, United States
- Smithsonian Tropical Research Institute, Balboa, Panama
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Advani D, Sharma S, Kumari S, Ambasta RK, Kumar P. Precision Oncology, Signaling and Anticancer Agents in Cancer Therapeutics. Anticancer Agents Med Chem 2021; 22:433-468. [PMID: 33687887 DOI: 10.2174/1871520621666210308101029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/05/2021] [Accepted: 01/12/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The global alliance for genomics and healthcare facilities provides innovational solutions to expedite research and clinical practices for complex and incurable health conditions. Precision oncology is an emerging field explicitly tailored to facilitate cancer diagnosis, prevention and treatment based on patients' genetic profile. Advancements in "omics" techniques, next-generation sequencing, artificial intelligence and clinical trial designs provide a platform for assessing the efficacy and safety of combination therapies and diagnostic procedures. METHOD Data were collected from Pubmed and Google scholar using keywords: "Precision medicine", "precision medicine and cancer", "anticancer agents in precision medicine" and reviewed comprehensively. RESULTS Personalized therapeutics including immunotherapy, cancer vaccines, serve as a groundbreaking solution for cancer treatment. Herein, we take a measurable view of precision therapies and novel diagnostic approaches targeting cancer treatment. The contemporary applications of precision medicine have also been described along with various hurdles identified in the successful establishment of precision therapeutics. CONCLUSION This review highlights the key breakthroughs related to immunotherapies, targeted anticancer agents, and target interventions related to cancer signaling mechanisms. The success story of this field in context to drug resistance, safety, patient survival and in improving quality of life is yet to be elucidated. We conclude that, in the near future, the field of individualized treatments may truly revolutionize the nature of cancer patient care.
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Affiliation(s)
- Dia Advani
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
| | - Sudhanshu Sharma
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
| | - Smita Kumari
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
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36
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Oral zinc carnosine reduces multi-organ damage caused by gut ischemia/reperfusion in mice. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104361] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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37
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Dong Y, Hao L, Fang K, Han XX, Yu H, Zhang JJ, Cai LJ, Fan T, Zhang WD, Pang K, Ma WM, Wang XT, Han CH. A network pharmacology perspective for deciphering potential mechanisms of action of Solanum nigrum L. in bladder cancer. BMC Complement Med Ther 2021; 21:45. [PMID: 33494738 PMCID: PMC7836472 DOI: 10.1186/s12906-021-03215-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Solanum nigrum L. decoction has been used as a folklore medicine in China to prevent the postoperative recurrence of bladder cancer (BC). However, there are no previous pharmacological studies on the protective mechanisms of this activity of the plant. Thus, this study aimed to perform a systematic analysis and to predict the potential action mechanisms underlying S. nigrum activity in BC based on network pharmacology. METHODS Based on network pharmacology, the active ingredients of S. nigrum and the corresponding targets were identified using the Traditional Chinese Medicines for Systems Pharmacology Database and Analysis Platform database, and BC-related genes were screened using GeneCards and the Online Mendelian Inheritance in Man database. In addition, ingredient-target (I-T) and protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, and then the pathways directly related to BC were integrated manually to reveal the pharmacological mechanism underlying S. nigrum-medicated therapeutic effects in BC. RESULTS Seven active herbal ingredients from 39 components of S. nigrum were identified, which shared 77 common target genes related to BC. I-T network analysis revealed that quercetin was associated with all targets and that NCOA2 was targeted by four ingredients. Besides, interleukin 6 had the highest degree value in the PPI network, indicating a hub role. A subsequent gene enrichment analysis yielded 86 significant GO terms and 89 significant pathways, implying that S. nigrum had therapeutic benefits in BC through multi-pathway effects, including the HIF-1, TNF, P53, MAPK, PI3K/Akt, apoptosis and bladder cancer pathway. CONCLUSIONS S. nigrum may mediate pharmacological effects in BC through multi-target and various signaling pathways. Further validation is required experimentally. Network pharmacology approach provides a predicative novel strategy to reveal the holistic mechanism of action of herbs.
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Affiliation(s)
- Yang Dong
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China.,Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China
| | - Lin Hao
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China.,Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China
| | - Kun Fang
- Xuzhou Clinical Medical College of Integrated Traditional Chinese and Western Medicine Affiliated to Nanjing University of Traditional Chinese Medicine, Xuzhou, China
| | - Xiao-Xiao Han
- Center of Reproductive Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hui Yu
- Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Jian-Jun Zhang
- Department of Urology, Suqian People's Hospital of Nanjing Drum-Tower Hospital Group, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Long-Jun Cai
- Department of Urology, Suqian People's Hospital of Nanjing Drum-Tower Hospital Group, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Tao Fan
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Wen-da Zhang
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Kun Pang
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Wei-Ming Ma
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Xi-Tao Wang
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Cong-Hui Han
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China. .,Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China. .,Department of Biotechnology, College of Life Sciences, Jiangsu Normal University, Xuzhou, China.
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Song J, Xu Y, Yang Z, Liu Y, Zhang P, Wang X, Sun C, Guo Y, Qiu S, Shao G, Ma K. Coexistence of atypical adenomatous hyperplasia, minimally invasive adenocarcinoma and invasive adenocarcinoma: Gene mutation analysis. Thorac Cancer 2021; 12:693-698. [PMID: 33442956 PMCID: PMC7919134 DOI: 10.1111/1759-7714.13798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 11/30/2022] Open
Abstract
Multiple primary lung cancer (MPLC) refers to the simultaneous occurrence of two or more lung primary malignant tumors in one individual. The detection rate of MPLC has increased significantly in recent years, and the distinction between MPLC and lung metastasis has strong clinical significance. Whole exome sequencing (WES) can clearly identify the heterogeneity between MPLC nodules. Here, we report a case of a 50‐year‐old Asian female without a history of smoking. She underwent a lung computed tomography (CT) scan and three ground‐glass nodules (GGNs) were found which were pathologically confirmed as atypical adenomatous hyperplasia (AAH), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA), respectively. We performed WES on the three pulmonary nodules and analyzed the sequencing results. We believe that this is the first published report of a case of “three phases” of lung adenocarcinoma analyzed by WES. Under the same genetic background and internal environment, these three nodules showed significant genetic differences and developed into “three phases” of lung adenocarcinoma. Analysis of the WES results supported the lung adenocarcinoma model from AAH to MIA and IA, and explored possible potential driver genes and therapeutic targets. Key points Significant findings of the study We used WES to analyze the gene mutation status of three tumors in one individual. We found that even if under the same genetic background, AAH, MIA and IA showed significant genetic differences and developed into “three phases” of lung adenocarcinoma. What this study adds Analysis of the WES results supported the lung adenocarcinoma model from AAH to MIA and IA, and explored possible potential driver genes and therapeutic targets.
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Affiliation(s)
- Junya Song
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Yinghui Xu
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Zhiguang Yang
- Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, China
| | - Yunpeng Liu
- Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, China
| | - Peng Zhang
- Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, China
| | - Xu Wang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Chao Sun
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Ye Guo
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Shi Qiu
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Guoguang Shao
- Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, China
| | - Kewei Ma
- Cancer Center, The First Hospital of Jilin University, Changchun, China
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Baumgartner L, Wuertz-Kozak K, Le Maitre CL, Wignall F, Richardson SM, Hoyland J, Ruiz Wills C, González Ballester MA, Neidlin M, Alexopoulos LG, Noailly J. Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research. Int J Mol Sci 2021; 22:E703. [PMID: 33445782 PMCID: PMC7828304 DOI: 10.3390/ijms22020703] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/17/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations' processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.
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Affiliation(s)
- Laura Baumgartner
- BCN MedTech, Department of Information and Communication Technologies, Universitat Pompeu Fabra, 08018 Barcelona, Spain; (L.B.); (C.R.W.); (M.A.G.B.)
| | - Karin Wuertz-Kozak
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY 14623, USA;
- Schön Clinic Munich Harlaching, Spine Center, Academic Teaching Hospital and Spine Research Institute of the Paracelsus Medical University Salzburg (Austria), 81547 Munich, Germany
| | - Christine L. Le Maitre
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK;
| | - Francis Wignall
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, UK; (F.W.); (S.M.R.); (J.H.)
| | - Stephen M. Richardson
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, UK; (F.W.); (S.M.R.); (J.H.)
| | - Judith Hoyland
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, UK; (F.W.); (S.M.R.); (J.H.)
| | - Carlos Ruiz Wills
- BCN MedTech, Department of Information and Communication Technologies, Universitat Pompeu Fabra, 08018 Barcelona, Spain; (L.B.); (C.R.W.); (M.A.G.B.)
| | - Miguel A. González Ballester
- BCN MedTech, Department of Information and Communication Technologies, Universitat Pompeu Fabra, 08018 Barcelona, Spain; (L.B.); (C.R.W.); (M.A.G.B.)
- Catalan Institution for Research and Advanced Studies (ICREA), Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Michael Neidlin
- Department of Mechanical Engineering, National Technical University of Athens, 15780 Athens, Greece; (M.N.); (L.G.A.)
| | - Leonidas G. Alexopoulos
- Department of Mechanical Engineering, National Technical University of Athens, 15780 Athens, Greece; (M.N.); (L.G.A.)
| | - Jérôme Noailly
- BCN MedTech, Department of Information and Communication Technologies, Universitat Pompeu Fabra, 08018 Barcelona, Spain; (L.B.); (C.R.W.); (M.A.G.B.)
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Chabot T, Cheraud Y, Fleury F. Relationships between DNA repair and RTK-mediated signaling pathways. Biochim Biophys Acta Rev Cancer 2020; 1875:188495. [PMID: 33346130 DOI: 10.1016/j.bbcan.2020.188495] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/06/2020] [Accepted: 12/13/2020] [Indexed: 10/22/2022]
Abstract
Receptor Tyrosine Kinases (RTK) are an important family involved in numerous signaling pathways essential for proliferation, cell survival, transcription or cell-cycle regulation. Their role and involvement in cancer cell survival have been widely described in the literature, and are generally associated with overexpression and/or excessive activity in the cancer pathology. Because of these characteristics, RTKs are relevant targets in the fight against cancer. In the last decade, increasingly numerous works describe the role of RTK signaling in the modulation of DNA repair, thus providing evidence of the relationship between RTKs and the protein actors in the repair pathways. In this review, we propose a summary of RTKs described as potential modulators of double-stranded DNA repair pathways in order to put forward new lines of research aimed at the implementation of new therapeutic strategies targeting both DNA repair pathways and RTK-mediated signaling pathways.
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Affiliation(s)
- Thomas Chabot
- Mechanism and regulation of DNA repair team, UFIP, CNRS UMR 6286, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France
| | - Yvonnick Cheraud
- Mechanism and regulation of DNA repair team, UFIP, CNRS UMR 6286, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France
| | - Fabrice Fleury
- Mechanism and regulation of DNA repair team, UFIP, CNRS UMR 6286, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
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Li S, Khan MH, Wang X, Cai M, Zhang J, Jiang M, Zhang Z, Wen XA, Liang H, Yang F. Synthesis of a series of novel In(III) 2,6-diacetylpyridine bis(thiosemicarbazide) complexes: structure, anticancer function and mechanism. Dalton Trans 2020; 49:17207-17220. [PMID: 33201167 DOI: 10.1039/d0dt02266g] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The anticancer function and anticancer mechanism of indium (In) complexes still remain mysterious to date. Furthermore, it is greatly challenging to design a multi-functional metal agent that not only kills cancer cells but also inhibits their invasion and metastasis. Thus, to develop novel next-generation anticancer metal agents, we designed and synthesized a series of novel In(iii) 2,6-diacetylpyridine bis(thiosemicarbazide) complexes (C1-C4) for the first time and then investigated their structure-activity relationships with human urinary bladder cancer (T-24) cells. In particular, C4 not only showed higher cytotoxicity to cancer cells and less toxicity toward normal cells relative to cisplatin but also inhibited cell invasion and metastasis of T-24 cells. Interestingly, C4 acted against T-24 cells exhibiting multiple mechanisms: (1) arresting the S-phase of cell cycle via regulation of cytokine kinases, (2) activating the mitochondrial-mediated apoptosis, endoplasmic reticulum-stress-mediated cell death, PERK and c-Jun N-terminal kinase 1 (JNK) cell signaling pathways, and (3) inhibiting the expression of telomerase via the regulation of c-myc and h-TERT proteins. Our results suggested that C4 may be developed as a potential multi-functional and multi-targeting anticancer candidate.
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Affiliation(s)
- Shanhe Li
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China.
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Fan X, Zeng Y, Fan Z, Cui L, Song W, Wu Q, Gao Y, Yang D, Mao X, Zeng B, Zhang M, Ni Q, Li Y, Wang T, Li D, Yang M. Dihydromyricetin promotes longevity and activates the transcription factors FOXO and AOP in Drosophila. Aging (Albany NY) 2020; 13:460-476. [PMID: 33291074 PMCID: PMC7835053 DOI: 10.18632/aging.202156] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 07/20/2020] [Indexed: 12/23/2022]
Abstract
Drugs or compounds have been shown to promote longevity in various approaches. We used Drosophila to explore novel natural compounds can be applied to anti-aging. Here we reported that a flavonoid named Dihydromyricetin can increase stress that tolerance and lipid levels, slow down gut dysfunction and extend Drosophila lifespan. Dihydromyricetin can also lessen pERK and pAKT signaling, consequently activating FOXO and AOP to modulate longevity. Our results suggested that DHM could be used as an effective compound for anti-aging intervention, which could likely be applied to both mammals and humans.
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Affiliation(s)
- Xiaolan Fan
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yao Zeng
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Ziqiang Fan
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Liang Cui
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Wenhao Song
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Qi Wu
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Yue Gao
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Deying Yang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Xueping Mao
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Bo Zeng
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Mingwang Zhang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Qingyong Ni
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yan Li
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Tao Wang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Diyan Li
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Mingyao Yang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
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Muniyappa R, Chen H, Montagnani M, Sherman A, Quon MJ. Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling. Am J Physiol Endocrinol Metab 2020; 319:E629-E646. [PMID: 32776829 PMCID: PMC7642854 DOI: 10.1152/ajpendo.00247.2020] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Previously, we have used mathematical modeling to gain mechanistic insights into insulin-stimulated glucose uptake. Phosphatidylinositol 3-kinase (PI3K)-dependent insulin signaling required for metabolic actions of insulin also regulates endothelium-dependent production of the vasodilator nitric oxide (NO). Vasodilation increases blood flow that augments direct metabolic actions of insulin in skeletal muscle. This is counterbalanced by mitogen-activated protein kinase (MAPK)-dependent insulin signaling in endothelium that promotes secretion of the vasoconstrictor endothelin-1 (ET-1). In the present study, we extended our model of metabolic insulin signaling into a dynamic model of insulin signaling in vascular endothelium that explicitly represents opposing PI3K/NO and MAPK/ET-1 pathways. Novel NO and ET-1 subsystems were developed using published and new experimental data to generate model structures/parameters. The signal-response relationships of our model with respect to insulin-stimulated NO production, ET-1 secretion, and resultant vascular tone, agree with published experimental data, independent of those used for model development. Simulations of pathological stimuli directly impairing only insulin-stimulated PI3K/Akt activity predict altered dynamics of NO and ET-1 consistent with endothelial dysfunction in insulin-resistant states. Indeed, modeling pathway-selective impairment of PI3K/Akt pathways consistent with insulin resistance caused by glucotoxicity, lipotoxicity, or inflammation predict diminished NO production and increased ET-1 secretion characteristic of diabetes and endothelial dysfunction. We conclude that our mathematical model of insulin signaling in vascular endothelium supports the hypothesis that pathway-selective insulin resistance accounts, in part, for relationships between insulin resistance and endothelial dysfunction. This may be relevant for developing novel approaches for the treatment of diabetes and its cardiovascular complications.
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Affiliation(s)
- Ranganath Muniyappa
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Hui Chen
- Clinical and Integrative Diabetes and Obesity Integrated Review Group, Center for Scientific Review, National Institutes of Health, Bethesda, Maryland
| | - Monica Montagnani
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy
| | - Arthur Sherman
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Michael J Quon
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
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Pesaraklou A, Matin MM. Cerium oxide nanoparticles and their importance in cell signaling pathways for predicting cellular behavior. Nanomedicine (Lond) 2020; 15:1709-1718. [PMID: 32664817 DOI: 10.2217/nnm-2020-0104] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Cerium oxide nanoparticles (CeO2-NPs) have prolifically attracted immense interest of researchers due to their prominent anti-oxidant nature. However, these characteristics are accompanied by some ambiguities in other studies reporting their oxidant and toxic properties. In this regard previous literature has pointed to the importance of the NPs morphology and environmental conditions as well as biomolecules that induce a different response by initiating a cascade of activities. Therefore, due to the fact that signaling proteins are key mediators in cellular responses, the cognizance of the CeO2-NP-targeted signaling pathways could facilitate predicting the cellular behavior and thus more efficient applications of these NPs for clinical purposes. Consequently, a comprehensive review is necessary in this field, to clarify the impacts of CeO2-NPs on various signaling pathways.
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Affiliation(s)
- Atefeh Pesaraklou
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, 9177948974, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, 9177948974, Iran.,Novel Diagnostics & Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, 9177948974, Iran.,Stem Cells & Regenerative Medicine Research Group, Academic Center for Education, Culture & Research (ACECR), Khorasan Razavi Branch, Mashhad, 9177949367, Iran
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Finkle JD, Bagheri N. Hybrid analysis of gene dynamics predicts context-specific expression and offers regulatory insights. Bioinformatics 2020; 35:4671-4678. [PMID: 30994899 PMCID: PMC6853664 DOI: 10.1093/bioinformatics/btz256] [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: 11/02/2018] [Revised: 03/07/2019] [Accepted: 04/11/2019] [Indexed: 12/02/2022] Open
Abstract
Motivation To understand the regulatory pathways underlying diseases, studies often investigate the differential gene expression between genetically or chemically differing cell populations. Differential expression analysis identifies global changes in transcription and enables the inference of functional roles of applied perturbations. This approach has transformed the discovery of genetic drivers of disease and possible therapies. However, differential expression analysis does not provide quantitative predictions of gene expression in untested conditions. We present a hybrid approach, termed Differential Expression in Python (DiffExPy), that uniquely combines discrete, differential expression analysis with in silico differential equation simulations to yield accurate, quantitative predictions of gene expression from time-series data. Results To demonstrate the distinct insight provided by DiffExpy, we applied it to published, in vitro, time-series RNA-seq data from several genetic PI3K/PTEN variants of MCF10a cells stimulated with epidermal growth factor. DiffExPy proposed ensembles of several minimal differential equation systems for each differentially expressed gene. These systems provide quantitative models of expression for several previously uncharacterized genes and uncover new regulation by the PI3K/PTEN pathways. We validated model predictions on expression data from conditions that were not used for model training. Our discrete, differential expression analysis also identified SUZ12 and FOXA1 as possible regulators of specific groups of genes that exhibit late changes in expression. Our work reveals how DiffExPy generates quantitatively predictive models with testable, biological hypotheses from time-series expression data. Availability and implementation DiffExPy is available on GitHub (https://github.com/bagherilab/diffexpy). Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Justin D Finkle
- Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL 60208, USA
| | - Neda Bagheri
- Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL 60208, USA.,Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.,Center for Synthetic Biology, Northwestern University, Evanston, IL 60208, USA.,Chemistry of Life Processes, Northwestern University, Evanston, IL 60208, USA
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Abstract
A key goal of cancer systems biology is to use big data to elucidate the molecular networks by which cancer develops. However, to date there has been no systematic evaluation of how far these efforts have progressed. In this Analysis, we survey six major systems biology approaches for mapping and modelling cancer pathways with attention to how well their resulting network maps cover and enhance current knowledge. Our sample of 2,070 systems biology maps captures all literature-curated cancer pathways with significant enrichment, although the strong tendency is for these maps to recover isolated mechanisms rather than entire integrated processes. Systems biology maps also identify previously underappreciated functions, such as a potential role for human papillomavirus-induced chromosomal alterations in ovarian tumorigenesis, and they add new genes to known cancer pathways, such as those related to metabolism, Hippo signalling and immunity. Notably, we find that many cancer networks have been provided only in journal figures and not for programmatic access, underscoring the need to deposit network maps in community databases to ensure they can be readily accessed. Finally, few of these findings have yet been clinically translated, leaving ample opportunity for future translational studies. Periodic surveys of cancer pathway maps, such as the one reported here, are critical to assess progress in the field and identify underserved areas of methodology and cancer biology.
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Affiliation(s)
- Brent M Kuenzi
- Division of Genetics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Trey Ideker
- Division of Genetics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
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The Antiglycation Effect of Monomethyl Branched Chained Fatty Acid and Phytochemical Compounds and their Synergistic Effect on Obesity Related Colorectal Cancer Cell Panel. ROMANIAN JOURNAL OF DIABETES NUTRITION AND METABOLIC DISEASES 2020. [DOI: 10.2478/rjdnmd-2019-0039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Abstract
Background and aims: monomethyl branched chain fatty acids (mmBCFA) and phytochemicals including: Hydroxycitric Acid, Chlorogenic Acid and Piperine have been considered as an interesting agent for researches due to their role in diabetes and cancer. The present study examines the antiglycation effect of mmBCFA and phytochemicals and investigate their Synergistic effect on different colorectal cancer cell lines.
Methods: This study was carried out by using murine monocyte-macrophage cell line and Methylglyoxal (MGO) to enhance the glycation process, furthermore to examine the antiproliferative effect of both the mmBCFA and phytochemicals we use Sulforhodamine B (SRB) assay against obesity related-colorectal cancer cell line panel.
Results: Both phytochemicals and mmBCFA have a higher antiglycation effect than Aminoguanidine (AMG) significantly, moreover, all of the phytochemicals and mmBCFA have antiproliferative against SW620, CACO2 and SW480, nevertheless none of these agents was equipotent to Cisplatin, furthermore, the synergetic effect observed only when we co-incubate Piperine with mmBCFA.
Conclusions: phytochemicals such as Hydroxycitric Acid, Chlorogenic Acid and Piperine and mmBCFA could be used as treatment to prevents the accumulation of advanced glycation end-products (AGEs) in diabetes. Furthermore, the co-incubation between these compounds can inhibit cancer growth, as alternative therapeutic strategy against obesity related-colorectal cancer.
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Playford RJ, Marchbank T. Pancreatic secretory trypsin inhibitor reduces multi-organ injury caused by gut ischemia/reperfusion in mice. PLoS One 2020; 15:e0227059. [PMID: 31923181 PMCID: PMC6953855 DOI: 10.1371/journal.pone.0227059] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 12/10/2019] [Indexed: 11/18/2022] Open
Abstract
Intestinal ischemia/reperfusion (I/R) injury occurs during transplantation, mesenteric arterial occlusion, trauma and shock, causing systemic inflammation, multiple organ dysfunction and high mortality. Pancreatic secretory trypsin inhibitor (PSTI), a serine protease inhibitor expressed in gut mucosa may function as a mucosal protective/repair peptide. We examined whether PSTI affected mesenteric I/R-induced injury. Hypoxia/normoxia (H/N) caused 50% drop in cell viability of AGS, RIE1 and Caco-2 cells but PSTI (10 μg/ml) given prior- or during-hypoxic period improved survival by 50% (p<0.01). Similarly, Caco-2 monolayers exposed to H/N had 300% increase in transepithelial permeability, PSTI truncated this by 50% (p<0.01). Mice underwent mesenteric I/R by clamping jejunum, causing severe mucosal injury, increased apoptotic markers and 3-fold increases in plasma IL-6, IL1β, TNFα, and tissue lipid peroxidation (MDA) and inflammatory infiltration (MPO) levels. Lungs showed similar significant injury and inflammatory infiltrate markers. Smaller increases in MDA and MPO were seen in kidney & liver. PSTI (20 mg/kg) reduced all injury markers by 50–80% (p<0.01). In vitro and in vivo studies showed PSTI reduced pro-apoptotic Caspase 3, 9 and Baxα levels, normalised Bcl2 and caused additional increases in HIF1α, VEGF and Hsp70 above rises caused by I/R alone (all p<0.01). PSTI also prevented reduction of tight junction molecules ZO1 and Claudin1 (all p<0.01) but did not affect increased ICAM-1 caused by I/R in gut or lung. PSTI may be a useful clinical target to prevent I/R injury.
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Affiliation(s)
- Raymond J. Playford
- Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom
| | - Tania Marchbank
- Centre of Immunobiology, Blizard Institute, Barts and The London School of Medicine, Queen Mary, University of London, London, United Kingdom
- * E-mail:
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SIRT5 inhibits bovine preadipocyte differentiation and lipid deposition by activating AMPK and repressing MAPK signal pathways. Genomics 2019; 112:1065-1076. [PMID: 31816429 DOI: 10.1016/j.ygeno.2019.12.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 12/02/2019] [Accepted: 12/05/2019] [Indexed: 12/30/2022]
Abstract
SIRT5 (sirtuin 5) is located in the mitochondria and plays an important role in biological processes such as maintaining the balance of lipid metabolism and promoting fatty acid oxidation mobilization. In this study, the bovine preadipocyte differentiation and obese mouse models were constructed; combined with transcriptome sequencing (RNA-seq) and morphological identification, the regulatory and molecular mechanisms underlying the effects of SIRT5 on bovine preadipocyte differentiation and lipid metabolism were studied. The results reveal that during the differentiation of preadipocytes, SIRT5 inhibited the expression of key genes that promote lipid formation and differentiation in fatty acid biosynthesis and PPAR pathways. SIRT5 significantly activated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway and repressed the mitogen-activated protein kinase (MAPK) pathway. Eventually, SIRT5 significantly inhibited the differentiation of bovine preadipocytes and simultaneously inhibited lipid synthesis and lipid deposition in adipocytes. The verification experiments performed using obese mice also yielded consistent results in vivo.
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Bouchnita A, Volpert V, Koury MJ, Hellander A. A multiscale model to design therapeutic strategies that overcome drug resistance to tyrosine kinase inhibitors in multiple myeloma. Math Biosci 2019; 319:108293. [PMID: 31809782 DOI: 10.1016/j.mbs.2019.108293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 11/10/2019] [Accepted: 11/26/2019] [Indexed: 02/06/2023]
Abstract
Drug resistance (DR) is a phenomenon characterized by the tolerance of a disease to pharmaceutical treatment. In cancer patients, DR is one of the main challenges that limit the therapeutic potential of the existing treatments. Therefore, overcoming DR by restoring the sensitivity of cancer cells would be greatly beneficial. In this context, mathematical modeling can be used to provide novel therapeutic strategies that maximize the efficiency of anti-cancer agents and potentially overcome DR. In this paper, we present a new multiscale model devoted to the interaction of potential treatments with multiple myeloma (MM) development. In this model, MM cells are represented as individual objects that move, divide, and die by apoptosis. The fate of each cell depends on intracellular and extracellular regulation, as well as the administered treatment. The model is used to explore the combined effects of a tyrosine-kinase inhibitor (TKI) with a pentose phosphate pathway (PPP) inhibitor. We use numerical simulations to tailor effective and safe treatment regimens that may eradicate the MM tumors. The model suggests that an interval for the daily dose of the PPP inhibitor can maximize the responsiveness of MM cells to the treatment with TKIs. Then, it demonstrates that the combination of high-dose pulsatile TKI treatment with high-dose daily PPP inhibitor therapy can potentially eradicate the tumor.The predictions of numerical simulations using such a model can be considered as testable hypotheses in future pre-clinical experiments and clinical studies.
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Affiliation(s)
- Anass Bouchnita
- Division of Scientific Computing, Department of Information Technology, Uppsala University, Uppsala 75105, Sweden; Ecole Centrale Casablanca, Ville Verte, Bouskoura, 20000 Casablanca, Morocco.
| | - Vitaly Volpert
- Institut Camille Jordan, Université Lyon 1, Villeurbanne 69622, France; INRIA Team Dracula, INRIA Lyon La Doua, Villeurbanne 69603, France; Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow 117198, Russian Federation
| | - Mark J Koury
- Vanderbilt University Medical Center, Nashville, TN 37232-6307, USA
| | - Andreas Hellander
- Division of Scientific Computing, Department of Information Technology, Uppsala University, Uppsala 75105, Sweden
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