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Event: 2245

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Altered Cell Differentiation Signaling

Short name
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Altered cell differentiation signaling
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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
cell differentiation abnormal
cell surface receptor signaling pathway increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Deposition of energy leading to bone loss KeyEvent Vinita Chauhan (send email) Open for citation & comment Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
rat Rattus norvegicus Moderate NCBI
mouse Mus musculus Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific Low

Key Event Description

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Cell differentiation pathways are the processes through which unspecialized cells, such as stem cells, develop into specialized cells with distinct functions (Soumelis and Liu, 2006). These pathways are tightly regulated by a complex interplay of signaling molecules and their receptors, the binding dynamics of transcription factors, and epigenetic modifications. Signaling molecules like growth factors and cytokines bind to cell surface receptors, triggering intracellular cascades that activate specific transcription factors. Transcription factors regulate dynamically during cell differentiation, they can be classified as static, dynamic, enhanced and suppressed states. These transcription factors then bind to DNA, regulating the expression of genes necessary for the specialized function of the cell. Epigenetic modifications, such as DNA methylation and histone modification, further ensure that the gene expression patterns are stably maintained over cell divisions (Tanabe, 2015). 

Disruptions in cell differentiation pathways can occur due to various mechanisms, including genetic mutations, epigenetic alterations, and environmental factors. Mutations in genes encoding signaling molecules, receptors, or transcription factors can lead to aberrant activation or suppression of these pathways, preventing proper cell differentiation. Epigenetic alterations, such as aberrant DNA methylation or histone modification patterns, can also result in inappropriate gene expression, further hindering the differentiation process (Miller and Grant, 2013). Environmental factors, including exposure to toxins, radiation, or pathogens, can induce oxidative stress or DNA damage, leading to the activation of stress response pathways that interfere with normal differentiation. Persistent activation or inhibition of these pathways can lead to aberrant cell fate decisions (Kharrazian, 2021). These disruptions can have significant consequences, contributing to developmental disorders, cancer, and other diseases (Wu et al., 2023).  

Key Differentiation Pathways: Description and Components for Measurement 

WNT/β-Catenin Pathway: 

The WNT/β-Catenin pathway plays a role in regulating the differentiation of various cell types by controlling gene expression. It is crucial for embryonic development, tissue homeostasis, and stem cell maintenance (Clevers et al., 2014). In particular, WNT signalling regulates bone cell homeostasis, and activation of this pathway results in increased bone mass and strength (Baron and Kneissel, 2013). The pathway is activated by WNT proteins binding to Frizzled receptors and LRP5/6 co-receptors, leading to the stabilization and nuclear translocation of β-catenin (Qin et al. 2024). One key component of this pathway is WNT Ligands, secreted proteins which initiate the signaling cascade. WNT ligands are lipid modified and have a variety of roles in embryonic development (Basson, 2012). Frizzled receptors are cell surface receptors that bind to WNT ligands. β-Catenin acts as the central mediator that enters the nucleus to activate target gene transcription, and TCF/LEF transcription factors bind to β-catenin to regulate gene expression (Nusse and Clevers, 2017; Steinhart and Angers, 2018). 

Notch Pathway: 

The Notch pathway plays a role in cell differentiation by influencing cell fate decisions, particularly in the nervous system, blood cells, and epithelial cells (Brandstadter and Maillard. 2019). The pathway also is a key contributor in maintaining cell polarity, proliferation, apoptosis and epithelial-mesenchymal transition (Parambath et al., 2024) This pathway operates through direct cell-cell interactions and is activated when Notch receptors on one cell bind to Delta or Jagged ligands on an adjacent cell. This binding triggers the cleavage of the Notch receptor and releases the Notch Intracellular Domain (Basson, 2012). The NICD then translocates to the nucleus, where it associates with the transcriptional regulator RBP-Jκ to activate target genes. Key components of this pathway include the transmembrane Notch receptors (Notch1-4) and their ligands, Delta and Jagged, which are essential for the pathway's activation and function (Miyamoto and Weinmaster. 2009) 

Hedgehog Pathway: 

The Hedgehog pathway is essential for the differentiation and development of various tissues, including the neural tube, limbs, and skin, as well as helping to maintain stem cells in adults. Activation of this pathway begins when Hedgehog ligands bind to the Patched (PTCH) receptor. This binding alleviates PTCH's inhibition of the Smoothened (SMO) receptor, thereby activating downstream signaling (Carballo et al. 2018). A key component of the Hedgehog pathway includes the Hedgehog ligands (Sonic, Indian and Desert), which are secreted proteins that initiate the pathway (Basson, 2012). The PTCH receptor inhibits the pathway in the absence of these ligands, while the SMO receptor activates the pathway once Hedgehog binds to PTCH. GLI transcription factors then regulate target gene expression in response to the activation of the pathway (Briscoe and Therond, 2013).  

TGF-β/SMAD pathway:  

The TGF-β/SMAD pathway is important for the differentiation of various cell types, including mesenchymal, epithelial, and immune cells. It also plays significant roles in cell proliferation, apoptosis, and extracellular matrix production (Flanders et al., 2009). Activation of this pathway occurs when TGF-β ligands bind to type II and type I serine/threonine kinase receptors, leading to the phosphorylation and activation of SMAD proteins. The key components of this pathway include TGF-β ligands, which are transforming growth factor-beta (TGF-β) proteins that initiate signaling, and the type I and II receptors that propagate the signal. Upon activation, receptor-regulated SMADs (SMAD2/3) are phosphorylated and form complexes with the common-mediator SMAD (SMAD4). These complexes then regulate gene expression to mediate the pathway's effects (Derynck and Zhang, 2003). 

JAK-STAT Pathway: 

The JAK-STAT pathway mediates responses to cytokines and growth factors, thereby influencing the differentiation of immune cells, hematopoietic cells, and other cell types. Activation of this pathway begins when cytokines bind to their receptors, leading to the activation of Janus Kinases (JAKs) (Hu et al. 2023). JAKs phosphorylate signal transducers and activators of transcription (STATs), allowing them to dimerize and translocate to the nucleus to regulate gene expression (Garrido-Trigo and Salas. 2019). Cytokine receptors are key components of the JAK-STAT pathway, which bind cytokines and activate JAKs. Other key components include JAKs, which are tyrosine kinases responsible for phosphorylating and activating STATs, and STATs which are transcription factors that mediate gene expression in response to cytokine signaling (Bezbradica and Medzhitov, 2009). 

Hippo Pathway:  

The Hippo pathway plays a role in controlling organ size by regulating cell proliferation, apoptosis, and stem cell self-renewal. It also influences the differentiation of various cell types. Activation of this pathway involves a kinase cascade that ultimately phosphorylates and inactivates the transcriptional co-activators YAP and TAZ. Key components of the Hippo pathway include MST1/2 (Mammalian Ste20-like Kinase), which initiates the kinase cascade, and LATS1/2 (Large Tumor Suppressor Kinase), which phosphorylate and inhibit YAP/TAZ (Zhou et al. 2024). When not phosphorylated, yes-associated protein/ transcriptional co-activator with PDZ-binding motif (YAP/TAZ) act as transcriptional co-activators that regulate gene expression. They partner with TEAD (TEA Domain Transcription Factors) to regulate target gene expression, thereby influencing cell behaviour and fate.  

ERK/MAPK pathway: 

The ERK/MAPK pathway is essential for regulating cell proliferation, differentiation, and survival, playing a pivotal role in the differentiation of various cell types in response to growth factors and other extracellular signals. Activation of this pathway involves a kinase cascade where MAPK/ERK is activated by MEK, which is in turn activated by RAF (Bahar et al. 2023). Key components of the ERK/MAPK pathway include RAF (Rapidly Accelerated Fibrosarcoma Kinase), which initiates the kinase cascade, and MEK (MAPK/ERK Kinase), which activates ERK through phosphorylation. ERK (Extracellular Signal-Regulated Kinase) then phosphorylates various target proteins, including transcription factors such as ELK1 and c-FOS, to regulate gene expression and influence cell behaviour (Arthur and Ley, 2013; Yue and López, 2020). 

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Pathway 

Method of Measurement 

Description 

Reference 

OECD Approved Assay 

WNT/β-Catenin 

Western Blot 

Detects β-catenin protein levels by using specific primary antibodies. 

Zhang et al., 2019 

No 

Immunofluorescence 

Evaluated β-catenin expression in the nucleus and cytoplasm 

Rong et al., 2022 

No 

qPCR 

Measures expression of Wnt/β-catenin signaling pathway-related genes and mRNA levels.  

Wang et al., 2023 

No 

Luciferase reporter assay 

Evaluates WNT/β-catenin pathway activity by performing reporter gene assays with luciferase expression vectors containing wild-type and mutant TCF/LEF binding sites, comparing luciferase activities 

Fröhlich et al., 2023 

No 

Notch 

qPCR  

Quantifies mRNA levels of Notch1,3 and 4 as well as notch signalling downstream targets.  

Ibrahim et al., 2017 

No 

Immunofluorescence  

Evaluated notch fluorescence levels using anti-Notch1 primary antibody  

Rong et al., 2022 

No 

Western Blot 

Measures protein expression of Notch1 using bicinchoninc acid protein assay kit.

Rong et al., 2022 

No 

Hedgehog 

Immunohistochemistry 

Measures expression of levels of SHH pathway members. 

Ke et al., 2020 

No 

Western Blot 

Detects GLI protein levels and their activation state. 

Ke et al., 2020 

No 

TGF-β/SMAD 

ELISA 

Quantifies TGF-β ligand concentration in samples. 

Rouce et al., 2016 

No 

Immunofluorescence 

Visualizes nuclear vs. cytoplasmic localization of SMAD2/3. 

Liu et al, 2016 

No 

Western Blot 

Detects phosphorylation status of SMAD2/3 proteins. 

Liu et al., 2016 

No 

qRT-PCR 

Quantifies mRNA levels of AKT1 and PI3K.   

Xia and Tang 2023   

No 

JAK-STAT 

Western Blot 

Measures levels of JAK2 and STAT3.   

Broughton and Burfoot, 2001; Mao et al., 2023   

No 

Electrophoretic Mobility Shift Assay (EMSA)    

Measures DNA-binding activity of STAT proteins to specific response elements.   

Broughton and Burfoot; Jiao et al., 2003  

No 

Hippo 

Western Blot  

Detects expression levels of Hippo pathway proteins. 

Wang et al., 2024; Chen et al., 2020 

No 

Immunofluorescence  

Visualizes nuclear vs. cytoplasmic localization of Hippo pathway expression. 

Chen et al., 2020; 

No 

Chromatin immunoprecipitation (ChIP) 

Measures expression of genes regulated by the Hippo pathway. 

Wang et al., 2024;  

No 

ERK/MAPK 

Western Blot  

Detects the phosphorylation state of MAPK family members (ERK, JNK, p38), indicating activation. 

Tan et al. 2022; Xia and Tang 2023 

No 

qRT-PCR 

Quantifies mRNA levels of JNK, MAPK1(ERK), and MAPK14(p38) 

Xia and Tang 2023 

No 

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Taxonomic applicability: Altered signaling is applicable to all animals as cell signaling occurs in animal cells. This includes vertebrates such as humans, mice and rats (Nair et al., 2019).  

Life stage applicability: Life stage applicability is pathway dependent. 

Sex applicability: This key event is not sex specific.  

Evidence for perturbation by a stressor: Multiple studies show that signaling pathways can be disrupted by many types of stressors including ionizing radiation and altered gravity (Su et al., 2020; Yentrapalli et al., 2013).  

References

List of the literature that was cited for this KE description. More help

Arthur, J. S. and S. C. Ley (2013), “Mitogen-activated protein kinases in innate immunity”, Nature Reviews Immunology, Vol. 13/9, Springer, New York, https://doi.org/10.1038/nri3495   

Bahar, M. E., Kim, H. J., and Kim, D. R. (2023), “Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal transduction and targeted therapy, Vol. 8/1,  https://doi.org/10.1038/s41392-023-01705-z 

Baron, R. and M. Kneissel (2013), “WNT signaling in bone homeostasis and disease: from human mutations to treatments”, Nature medicine, Vol. 19/2, doi:10.1038/nm.3074 

Basson, M. A. (2012), “Signaling in cell differentiation and morphogenesis”, Cold Spring Harbor perspectives in biology, Vol. 4/6, doi:10.1101/cshperspect.a008151 

Bezbradica, J. S. and R. Medzhitov (2009), “Integration of cytokine and heterologous receptor signaling pathways”, Nature immunology, Vol. 10, https://doi.org/10.1038/ni.1713 

Briscoe, J. and P. P. Therond (2013), “The mechanisms of Hedgehog signalling and its roles in development and disease”, Nature Reviews Molecular Cell Biology, Vol. 14/7, Springer, London, https://doi.org/10.1038/nrm3598 

Carballo, G. B. et al. (2018), “A highlight on Sonic hedgehog pathway”. Cell communication and signaling : CCS, Vol 16/1. https://doi.org/10.1186/s12964-018-0220-7  

Chen, Y. et al. (2020), “Systematic analysis of the Hippo pathway organization and oncogenic alteration in evolution”, Scientific reports, Vol. 10/1, Springer, London, https://doi.org/10.1038/s41598-020-60120-4  

Cheng, Y. P. et al. (2017), “Acid sphingomyelinase/ceramide regulates carotid intima-media thickness in simulated weightless rats”, Pflugers Archiv European Journal of Physiology, Vol. 469, Springer, New York, https://doi.org/10.1007/s00424-017-1969-z 

Clevers, H. et al. (2014), “Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control”, Science (New York, N.Y.), Vol. 346/6205, American Association for the Advancement of Science, New York https://doi.org/10.1126/science.1248012  

Derynck, R. and Y. E. Zhang (2003), “Smad-dependent and Smad-independent pathways in TGF-beta family signalling”, Nature, Vol. 425/6958, Springer, London, https://doi.org/10.1038/nature02006  

Flanders, K. C. and L. M. Wakefield (2009), “Transforming growth factor-(beta)s and mammary gland involution; functional roles and implications for cancer progression”, Journal of mammary gland biology and neoplasia, Vol. 14/2, Springer, London, https://doi.org/10.1007/s10911-009-9122-z  

Fröhlich, J., Rose, K., and Hecht, A. (2023), “Transcriptional activity mediated by β-CATENIN and TCF/LEF family members is completely dispensable for survival and propagation of multiple human colorectal cancer cell lines”, Scientific reports, Vol.13, https://doi.org/10.1038/s41598-022-27261-0 

Garrido-Trigo, A., and Salas, A. (2020), “Molecular Structure and Function of Janus Kinases: Implications for the Development of Inhibitors”, Journal of Crohn's & colitis, Vol. 14. https://doi.org/10.1093/ecco-jcc/jjz206   

Hu, Q., et al. (2023), “JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens”, Frontiers in bioengineering and biotechnology, Vol.11, Frontiers, Lausanne, 1110765. https://doi.org/10.3389/fbioe.2023.1110765 

Ibrahim, S. A., et al. (2017), “Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways”, Molecular cancer, Vol.16 https://doi.org/10.1186/s12943-017-0621-z 

Ke, B. et al. (2020), “Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer”, Journal of Cancer, Vol. 11/13, https://doi.org/10.7150/jca.42900  

Kharrazian D. (2021), “Exposure to Environmental Toxins and Autoimmune Conditions”, Integrative medicine (Encinitas, Calif.), Vol. 20/2.

Liu, L. et al. (2016), “Smad2 and Smad3 have differential sensitivity in relaying TGFβ signaling and inversely regulate early lineage specification”, Scientific reports, Vol. 6, Springer, London, https://doi.org/10.1038/srep21602  

Miller, J. L. and P. A. Grant (2013), “The role of DNA methylation and histone modifications in transcriptional regulation in humans”, Sub-cellular biochemistry, Vol. 61, https://doi.org/10.1007/978-94-007-4525-4_13  

Miyamoto, A, and G. Weinmaster (2009), “Notch Signal Transduction: Molecular and Cellular Mechanisms”, Encyclopedia of Neuroscience, https://doi.org/10.1016/B978-008045046-9.01026-3 

Nair, A. et al. (2019), “Conceptual Evolution of Cell Signaling”, International journal of molecular sciences, Vol. 20/13, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms20133292 

Nusse, R. and H. Clevers (2017), “Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities”, Cell, Vol. 169/6, Elsevier, Amsterdam, https://doi.org/10.1016/j.cell.2017.05.016 

Parambath, S. et al. (2024), “Notch Signaling: An Emerging Paradigm in the Pathogenesis of Reproductive Disorders and Diverse Pathological Conditions”, International journal of molecular sciences, Vol. 25, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms25105423 

Qin, et al. (2024), “Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk”, Genes & Disease, Vol. 11, https://doi.org/10.1016/j.gendis.2023.01.030. 

Rong, X. et al. (2022), “ED-71 Prevents Glucocorticoid-Induced Osteoporosis by Regulating Osteoblast Differentiation via Notch and Wnt/β-Catenin Pathways”, Drug design, development and therapy, Vol. 16, https://doi.org/10.2147/DDDT.S377001 

Rouce, R. et al. (2016), “The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia”, Leukemia, Vol. 30/4, Springer, London, https://doi.org/10.1038/leu.2015.327  

Sita, G. et al. (2023), “The Unfolded Protein Response in a Murine Model of Alzheimer's Disease: Looking for Predictors”, International journal of molecular sciences, Vol. 24/22, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms242216200 

Soumelis, V. and Y. J. Liu (2006), “From plasmacytoid to dendritic cell: morphological and functional switches during plasmacytoid pre-dendritic cell differentiation”, European journal of immunology, Vol. 36/9, Wiley, Hoboken, https://doi.org/10.1002/eji.200636026 

Steinhart, Z. and S. Angers (2018), “Wnt signaling in development and tissue homeostasis”, Development (Cambridge, England), Vol. 145/11, The Company of Biologists, Cambridge, https://doi.org/10.1242/dev.146589 

Su, Y. T. et al. (2020), “Acid sphingomyelinase/ceramide mediates structural remodeling of cerebral artery and small mesenteric artery in simulated weightless rats”, Life Sciences, Vol. 243, Elsevier, Amsterdam, https://doi.org/10.1016/j.lfs.2019.117253 

Tan, B. et al. (2022), “Changes in the histopathology and in the proteins related to the MAPK pathway in the brains of rats exposed to pre and postnatal radiofrequency radiation over four generations”, Journal of chemical neuroanatomy, Vol.126, Elsevier, Amsterdam, https://doi.org/10.1016/j.jchemneu.2022.102187   

Tanabe S. (2015), “Signaling involved in stem cell reprogramming and differentiation”, World journal of stem cells, Vol, 7/7, Baishideng publishing group, Pleasanton,  https://doi.org/10.4252/wjsc.v7.i7.992   

Wang, D. et al. (2024), “Circular RNA HSDL2 promotes breast cancer progression via miR-7978 ZNF704 axis and regulating hippo signaling pathway”, Breast cancer research : BCR, Vol. 26/1, Springer, London https://doi.org/10.1186/s13058-024-01864-z 

Wu, H. et al., (2023), “Molecular mechanisms of environmental exposures and human disease. Nature reviews” Genetics, Vol. 24/5, Springer, London, https://doi.org/10.1038/s41576-022-00569-3 

Xia, Z., Li, Q. and Z. Tang (2023), “Network pharmacology, molecular docking, and experimental pharmacology explored Ermiao wan protected against periodontitis via the PI3K/AKT and NF-κB/MAPK signal pathways.” Journal of ethnopharmacology, Vol. 303, Elsevier, Amsterdam, https://doi.org/10.1016/j.jep.2022.115900   

Yentrapalli, R. et al. (2013), “The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation”, PloS one, Vol. 8/8, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0070024 

Yue, J. and J. M. López (2020), “Understanding MAPK Signaling Pathways in Apoptosis”, International journal of molecular sciences, Vol. 21/7, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms21072346      

Zhang, Y. et al. (2019), “Captopril attenuates TAC-induced heart failure via inhibiting Wnt3a/β-catenin and Jak2/Stat3 pathways”, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, Vol. 113, https://doi.org/10.1016/j.biopha.2019.108780 

Zhou, X., Li, W. Y., and Wang, H. Y. (2017), “The roles and mechanisms of MST1/2 in the innate immune response.” Yi chuan = Hereditas, Vol. 39, https://doi.org/10.16288/j.yczz.17-066