1.1 Green tea
1.2 Transplant rejection
1.3 Immunomodulation in transplant rejection
1.4 Green tea and immunomodulation in transplant rejection
1.5 Systems biology approach
2. Materials and methods
- 1)Organize and curate data from the scientific literature
- 2)Extract molecular pathway diagrams from the curated literature
- 3)Convert each molecular pathway diagram to a mathematical model
- 4)Integrate the ensemble of mathematical models to derive an integrated model of immunomodulation of transplant rejection
- 5)Use the integrated model of immunomodulation of transplant rejection to execute computer simulations
2.2 Organize and curate data from the scientific literature
- 1.Create a list of Medical Subject Headings (MeSH) keywords to optimize recall and precision of peer-reviewed articles
- 2.Search and retrieve the relevant peer-reviewed articles published between January 1985 to May 2018 from PubMed, Medline, and Google Scholar. These set of articles are stored as an “Initial Set” repository
- 3.Screen the titles and abstracts of articles in the Initial Set repository to identify most relevant articles based on our inclusion criteria. These set of articles are stored as the “Final Set” repository
- 4.Perform full-length review of peer-reviewed articles from the Final Set repository
- Group 1) Articles on immunomodulation of transplant rejection pathways;
- Group 2) Articles on green tea bioactive compounds interacting with immunomodulation of transplant rejection pathways; and,
- Group 3) Articles on pharmacokinetic properties of green tea bioactive compounds.
2.3 Extract molecular pathway diagrams from the curated literature
- 1.Identify and extract:
- a.Chemical species involved in immunomodulation of transplant rejection
- b.Types of cells involved in immunomodulation of transplant rejection
- c.Cellular components (e.g. cytosol, mitochondria, nucleus, etc.) where the chemical species are present in each cell type
- 2.Identify and diagrammatically represent biochemical interactions in immunomodulation of transplant rejection
- 3.Interconnect biochemical reactions to create molecular pathway diagram in each cell type involved in immunomodulation of transplant rejection
- 1.Bioactive compounds of green tea
- 2.Concentration levels of bioactive compounds in green tea
- 1.Pharmacokinetics of bioactive compounds of green tea
- 2.Reaction rate constants of biochemical reactions between bioactive compounds of green tea and their molecular targets in the immunomodulation of transplant rejection molecular pathways
2.4 Convert each molecular pathway diagram to a mathematical model
- 1.Convert biochemical reactions involved in each of the molecular pathway into ordinary differential equations (mathematical expressions that describe the rate of change)
- 2.Represent each molecular pathway of immunomodulation of transplant rejection as a system of ordinary differential equations
- 3.Encode the system of differential equations in a computer software source code format known as Systems Biology Markup Language (SBML) [] to construct a mathematical model for a particular molecular pathway of immunomodulation of transplant rejection
- 4.Store each model as a separate SBML file
2.5 Integrate the ensemble of mathematical models to derive an integrated model of immunomodulation of transplant rejection
- 2.5.1. Presentation Layer: The Presentation layer provides an interface to the user where the individual molecular pathway models are uploaded for their dynamic integration. Another important feature of the Presentation layer is that it resolves any nomenclature conflicts in the molecular species and annotates biochemical reaction duplicates across the individual molecular pathway models and prepares them for integration by the Controller.
- 2.5.2 Controller Layer: In the Controller layer, computations are performed using the integrated model to arrive at the integrated solution. The Controller layer has three components which participate in deriving the integrated solution: the Monitor, the Communication Manager, and the Mass Balance. The Monitor tracks the completion of calculations by each model at every time step. The Communication Manager controls instructs initiation as well as pausing of calculations by each model for every time step. The Mass Balance ensures mass conservation of all molecular species as it integrates the calculations from the ensemble of models for every time step.
- 2.5.3. Communication Layer: The Communication layer facilitates messaging between the Controller and Models. For example, the Controller may send the input values of molecular species at time t = n (Sn) and an instruction to a model to run a calculation over a time step. After performing the calculation for that time step, the model may pass the solution for that molecular species at time t = n+1 (Sn+1) back to the Controller. Such messages can be performed in parallel between the multitude of individual models and the Controller.
- 2.5.4. Database Layer: The Database layer has two components: Solutions and Ontology. Solutions stores the memory that tracks molecular species concentrations across all models for every time step. Ontology manages the molecular species nomenclature and biochemical reaction duplicates across all the models and ensures consistency while the Controller is calculating the integrated solution.
- 2.5.5. Model Layer: The Models layer houses the individual molecular pathway models. The CytoSolve architecture is designed in such a way that the individual models may reside on different servers, vary in complexity, and may have different computational source code formats (e.g. SBML, CellML, MATLAB, etc.).
- 1.Upload individual SBML files, constructed in Section 2.4, to CytoSolve engine
- 2.Update the initial conditions for the molecular species in all the mathematical models in the graphical user interface
- 3.Update simulation period was specified in the graphical user interface
- 4.Review and confirm molecular species and reaction duplicates across all the immunomodulation of transplant rejection models in the graphical user interface
- 5.Commence integration of individual models of immunomodulation of transplant rejection
2.6 Use the integrated model of immunomodulation in transplant rejection to execute computer simulations
- 1.Effect of EGCG on IL-12 mediated synthesis of pro-inflammatory biomarkers TNF-α and IFNγ in CD4+ T cells. These biomarkers promote Th1 and Th17 phenotypes and subsequent transplant rejection.
- 2.Effect of EGCG on IL-6 mediated synthesis of pro-inflammatory biomarker IL-17 in CD4+ T cells. IL-17 promotes Th17 phenotype and subsequent transplant rejection.
- 3.Effect of EGCG on TNF-α/STAT5 mediated synthesis of anti-inflammatory biomarker Foxp3 in naive T cells. Foxp3 promotes Treg phenotype and the subsequent transplant tolerance.
- 4.Effect of EGCG on TNF-α/NFkB mediated synthesis of pro-inflammatory biomarkers NO and IL-6 in naive T cells. These biomarkers promote Th17 phenotype and subsequent transplant rejection.
- 5.Effect of EGCG on TCR mediated synthesis of pro-inflammatory biomarker IL-2 in naive T cells. IL-2 promotes Th1 and Th17 phenotypes and subsequent transplant rejection.
- 6.Effect of EGCG on IMPDH mediated synthesis of pro-proliferation biomarker XMP in T cells. This biomarker promotes T cell proliferation and subsequently supports transplant rejection.
- 7.Effect of EGCG on HMGB1 mediated synthesis of pro-inflammatory biomarkers TNF-α, IL-1β, and IFNγ in dendritic cells. These biomarkers promote Th17 phenotype and subsequent transplant rejection.
- 8.Effect of EGCG on HSP60 mediated synthesis of pro-inflammatory biomarkers TNF-α, IL-1β, and IFNγ in dendritic cells. These biomarkers promote Th17 phenotype and subsequent transplant rejection.
- 9.Effect of EGCG on Nrf mediated synthesis of HO-1 in dendritic cells. HO-1 promotes Treg and Th2 phenotypes and subsequent transplant tolerance.
2.7 Computational model inputs
- 1.Input biochemical reactions for interaction between bioactive compounds of green tea and immunomodulation of transplant rejection molecular pathways
- 2.Input the kinetic rate constants for each of the biochemical reaction
- 3.Input the initial concentrations for each of the molecular species in the biochemical reactions
- 4.Input the time period for the simulation of integrative models, and dose levels of bioactive compounds in green tea
- 5.Execute the updated integrative model of immunomodulation of transplant rejection
|Green tea dose (mg/kg)||EGCG Cmax (nM)||Epicatechin Cmax (nM)||GA Cmax (nM)|
2.8 Computational model outputs
- 1.Time-dependent concentration of TNF-α
- 2.Time-dependent concentrations of IFNγ
- 3.Time-dependent concentrations of NO
- 4.Time-dependent concentrations of IL-17
- 5.Time-dependent concentrations of IL-2
- 6.Time-dependent concentrations of XMP
- 7.Time-dependent concentrations of IL-1β
- 8.Time-dependent concentrations of Foxp3
- 9.Time-dependent concentrations of HO-1
2.9 Analysis of computational model output
- 1.Export the raw data to Microsoft Excel
- 2.Extract the steady state levels of TNF-α, IFNγ, nitric oxide (NO), IL-17, IL-2, XMP, IL-1β, Foxp3, and HO-1
- 3.Plot steady state levels of TNF-α, IFNγ, nitric oxide (NO), IL-17, IL-2, XMP, IL-1β, Foxp3, and HO-1 in presence and absence of individual bioactive compounds in green tea
3.1 Molecular mechanisms of immunomodulation in transplant rejection
3.1.1 Systematic literature review
3.1.2 Molecular mechanisms identified in immunomodulation in transplant rejection
- I.IL-12 mediated Th1 differentiation: Expression of IL-12, an immunomodulatory cytokine, is elevated during the process of allograft rejection []. IL-12 promotes Th1 differentiation of CD4+ T cells. IL-12 triggers activation of Jak2, which in turn phosphorylates STAT4. STAT4 is a transcription factor responsible for expression cytokines such as IL-2, IFN-γ and TNF-α that promote the differentiation of Th1 cells. The sustained signaling of IL-12 mechanism creates an inflammatory environment that results in graft rejection after transplantation [,].
- II.IL-6 mediated Th17 differentiation: IL-6 plays a key role in promotion of acute graft rejection. In naïve CD4+ T-cells, IL-6 initiates signaling cascade via JAK/STAT3/RORγt leads to expression of pro-inflammatory cytokines such as IL-17, IL-21, and IL-22, which promote the Th17 phenotype. Additionally, in concert with TGF- β, IL-6 was shown to promote the Th17 phenotype. IL-6 also has been implicated in promoting Th1 response, leading to transplant ejection [26,27,28].
- III.TNF-α signaling pathways: TNF-α has is reported to initiate rejection response, especially during cardiac transplantation. Activated T cells initiate macrophage induced TNF-α release []. The signaling pathway by TNF-α via TNFR1 receptor initiates pro-inflammatory pathways that lead to increased expression of pro-inflammatory cytokine IL-17. IL-17 drives the promotion of Th17 phenotype and subsequent transplant rejection [,]. TNF-α binding to its receptor TNFR2 triggers proliferation of Treg cells via expression of TGF-β and IL-10, and consequently, graft tolerance [].
- IV.TCR signaling pathway: In graft rejection, antigen specificity for T cells is provided by TCR that leads to a strong immune responses to transplanted graft and rapid graft rejection []. TCR signaling induces the synthesis of IL-2, a potent pro-proliferative cytokine, via PLCγ1/PIP2/DAG/MKK/JNK-AP-1 signaling transduction pathway leading to an adaptive immune response against the graft [,].
- V.IMPDH metabolism: IMPDH mediates de-novo purine synthesis which is crucial for proliferation of T cells []. Expression of the IMPDH-I mRNA is upregulated during the first 3 months following renal transplantation and that this induction is dramatically strengthened during acute rejection episodes [,]. Inhibiting IMPDH activity can thus reduce the proliferation of T-cells and can promote the setting of organ transplantation [].
- VI.HSP60 induced TLR-4 signaling pathway: During transplant, ligands such as extracellular matrix components and HSP60, bind to the TLR4 receptors on dendritic cells. TLR4 has been shown to play a critical role in renal graft rejection caused by ischemia-reperfusion injury via upregulation of pro-inflammatory cytokines such as IL-6, MCP-1, IFN-γ, IL-1β, TNF-α [40,41,42].
- VII.HMGB1 induced TLR4 signaling pathway: During transplant, endogenous ligands like HMGB1 bind to the TLR4 receptors on dendritic cells. TLR4 has been shown to play a critical role in renal graft rejection caused by ischemia-reperfusion injury via upregulation of pro-inflammatory cytokines such as IL-6, MCP-1, IFN-γ, IL-1β, TNF-α [40,41,42].
- VIII.TGF-β mediated Treg differentiation: Treg cell activity plays an essential role in the success of transplantations. TGF- β promotes expression of regulatory cytokines TGF-β and IL-10 via SMAD3/4-Foxp3. TGF-β and IL-10 overexpression promotes Treg cell activity and favors graft survival [,,].
- IX.Nrf2 Signaling pathway: Anti-oxidative properties of Nrf2 mediated gene expressions may help in graft survival during transplantation. Nrf2 binds to antioxidant response element and initiates the expression of a group of detoxifying and antioxidant genes, such as Hemeoxygenase-1 (HO-1), glutathione S- transferase (GST) and NAD(P)H: quinone oxidoreductase-1 (NQO1) [,]. Upregulation of Nrf2 antioxidant pathway in dendritic cells also leads to the promotion of anti-inflammatory Tregs phenotype [].
Green tea epigallocatechin-3-gallate suppresses autoimmune arthritis through indoleamine-2,3-dioxygenase expressing dendritic cells and the nuclear factor, erythroid 2-like 2 antioxidant pathway.J Inflamm (United Kingdom). 2015; 12: 1-15
- Min S.Y.
- Yan M.
- Kim S.B.
- Ravikumar S.
- Kwon S.R.
- Vanarsa K.
- et al.
3.2 Green tea bioactive compounds and their interactions with immunomodulatory pathways
3.2.1 Green tea bioactive compounds
- I.Epigallocatechin Gallate (EGCG): The most abundant catechin present in green tea is EGCG, and is considered as one of the most bioactive molecules with strong antioxidant activity. This compound is obtained by formal condensation of gallic acid with the (3R)-hydroxy group of Epigallocatechin (EGC). It represents approximately 59% of all catechins []. Among green tea catechins, EGCG is abundant in green tea leaves, and has been shown to exhibit strong health-promoting activity, according to structure activity relationship assessment on EGCG, two close parallel aromatic rings and a third aromatic ring vertical to the two parallel rings may play a key role in the pharmacophore activity. This activity may be associated with the number of –OH groups in the catechin. EGCG is a biologically active compound with known anti-inflammatory, anti-carcinogenic, immune regulatory and free radical-scavenging properties. EGCG can control gene expression by epigenetic modification, which affects the regulation of immune system and enhances the population of regulatory T-cells []. EGCG also suppresses the proliferation of autoreactive T cells, reduces the production of pro-inflammatory cytokines, and decreases Th1 and Th17 populations in lymphoid tissues [].
- II.Epicatechin: Epicatechin represents approximately 6.4% of the total catechin content. It is a flavan-3-ol, widely distributed in nature and present in large amounts in green tea with effective antioxidant activity. Consumption of epicatechin-rich foods is associated with several health benefits such as modulation of reactive oxygen species production, redox signaling, and pro-inflammatory cascades [].
- III.Gallic Acid: Gallic acid (GA) and its derivatives are biologically active compounds, which are widely present in plants, especially in green tea. Gallic acid is a strong natural antioxidant []. It has a wide range of biological activities, including anti-inflammatory, anti-microbial and anti-cancer activities [].
3.2.2 Summary of green tea on immunomodulation pathways affecting transplant rejection
|Pro-inflammatory||ROS induced inhibition of Nrf pathway|
|TCR induced IL-2 pathway|
|TNF-α induced IL-17 pathway|
|Anti-inflammatory||Nrf-induced antioxidant enzymes pathway|
|TNF-α induced TGF-β pathway|
3.2.3 Pro-inflammatory pathways affected by EGCG
- (I)Effect of EGCG on NF-κB: NF-κB is a transcription factor that mediates the gene expression of several pro-inflammatory cytokines and causes acute rejection during transplantation. EGCG effectively inhibits the binding activity of NF-κB to the DNA in a non-competitive manner that results in a reduced transactivation of NF-κB-driven genes. Transactivation of NF-κB is inhibited by EGCG by downregulating p53 phosphorylation and IKBα degradation []. Additionally, EGCG significantly down-regulates p38 MAPK and ERK 1/2 phosphorylation, which leads to the inhibition of expression of pro-inflammatory mediators that causes tissue rejection via NF-κB and AP-1 transactivation [,,]. Suppressor of cytokine signaling 1 (SOCS1) inhibits NF-κB and thus downregulates the expression of cytokines that causes graft rejection. EGCG induces SOCS1 expression through pro-oxidant pathway [,].
- (II)Effect of EGCG on AP-1: Activator Protein-1 (AP-1), is a transcription factor, whose elevated activity has been shown to cause tissue rejection. EGCG reduces AP-1 mediated genes such as IL-6, MCP-1, IL-1β by inhibiting the phosphorylation of JNK and nuclear expression of JNK and c-Jun. EGCG inhibits AP-1 in a non-competitive manner [].
- (III)Effect of EGCG on ZAP-70: In TCR signaling pathway, ZAP-70 acts as a linker for the activation of T cells, phospholipase Cγ1, extracellular signaling-regulated kinase, and MAPK kinase activities in CD3-activated T cells. By binding to ZAP-70 with high affinity, EGCG effectively suppresses ZAP-70 mediated IL-2 release and aids in graft survival [].
- (IV)Effect of EGCG on STAT1: STAT1 is a transcription factor, which can associate with STAT4 and mediate Th1 differentiation via JAK2 phosphorylation and ultimately, promote tissue rejection. EGCG is found bind to STAT1 and thus reduce proliferation of Th1 population and modulate graft rejection [].
- (V)Effect of EGCG on JAK2: EGCG inhibits the kinase activity of JAK2 in competitive manner, by directly binding to the binding pocket of JAK2 and thus reduces STAT activation that is required for Th1 differentiation during acute rejections [,].
- (VI)Effect of EGCG on JNK: EGCG inhibits JNK phosphorylation and thus reduces JNK mediated cytokines expression during graft rejection. It is considered to inhibit in non-competitive manner due to its antioxidant property [,].
- (VII)Effect of EGCG on Tollip: EGCG increases the expression of Toll interacting protein (Tollip), a strong inhibitor of TLR4 signaling. EGCG induces Tollip through 6-laminin receptor signaling pathway [,].
- (VIII)Effect of EGCG on STAT3: STAT3 is an important transducer that mediates Th17 differentiation during tissue rejections. EGCG effectively inhibits STAT3 by binding competitively to the SH2 domain (Arg-609, key transducer in STAT3) and blocks its phosphorylation [].
- (IX)Effect of EGCG on IMPDH: IMPDH, an enzyme that catalyzes the NADP-dependent oxidation of IMP to XMP in de novo synthesis, plays a key role in T-cell activation. EGCG inhibits IMPDH and thus suppresses acute rejections after transplantation [].
3.2.4 Anti-inflammatory pathways affected by EGCG
- (I)Effect of EGCG on Nrf2-Keap1: Dissociation of the Kelch-like ECH-associated protein 1 (Keap1) from Keap1-Nrf2 complex is an important regulatory step that could mediate graft survival. EGCG directly binds to Keap1 and release Nrf2 from this complex. EGCG induces Nrf2 with an IC50 of 50 μM in a non-competitive manner []. EGCG significantly reduces oxidative stress by enhancing the expression of HO-1 via activation of the Nrf2/HO-1 pathway [].
- (II)Effect of EGCG on STAT5: STAT5 is an important regulatory transducer in TNFα pathway that mediates Treg phenotype to promote graft survival. EGCG induces STAT5 activation and favors Treg phenotype thereby promoting graft survival [].
3.2.5 Pro-inflammatory pathways affected by epicatechin
- (I)Effect of epicatechin on NF-κB: Epicatechin inhibits NF-κB activation by reducing phosphorylation of IKK (Ser178/180) and IκBα (Ser32). It non-competitively inhibits NF-κB and results in a reduced transactivation of NF-κB-driven genes that causes tissue rejection [,].
- (II)Effect of epicatechin on AP-1: Elevated activity of transcription factor AP-1 has been shown to cause tissue rejection. Epicatechin inhibits of AP-1 activity, thereby reducing the expression of AP-1 mediated genes such as IL-6, MCP-1, IL-1β via inhibiting the phosphorylation of JNK, nuclear expression of JNK and c-Jun [,].
- (III)Effect of epicatechin on STAT3: STAT3 is the main transducer of IL-17, promoting Th17 population during transplantation. Epicatechin effectively inhibits STAT3 phosphorylation by attenuating JAK2 [].
3.2.6 Pro-inflammatory pathways affected by GA
- (I)Effect of GA on NF-κB: Gallic acid inhibits NF-κB activation by inhibiting IκBα degradation and thus blocking p65 NF-κB translocation into nucleus. Gallic acid non-competitively inhibits NF-κB and results in a reduced transactivation of NF-κB-driven genes that causes tissue rejection [,].
- (II)Effect of GA on AP-1: Activator Protein-1 (AP-1) is a transcription factor whose elevated activity has been shown to cause tissue rejection. GA inhibits AP-1 activity thereby reducing AP-1 mediated genes such as IL-6, MCP-1, IL-1β and thus helps in graft survival [].
3.3 In silico analysis of green tea effects on immunomodulation of transplant rejection
3.3.1 Effect of EGCG on IL-12 mediated Th1 differentiation
3.3.2 Effect of EGCG on IL-6 mediated Th17 differentiation
3.3.3 Effect of EGCG on TNF-α mediated Treg differentiation
3.3.4 Effect of EGCG on TNF-α mediated Th17 differentiation
3.3.5 Effect of EGCG on IL-2 in TCR signaling pathway
3.3.6 Effect of EGCG on IMPDH metabolism
3.3.7 Effect of EGCG on HMGB1-induced TLR4 signaling pathways
3.3.8 Effect of EGCG on HSP60-induced TLR4 signaling pathways
3.3.9 Effect of EGCG on Nrf2 signaling pathway
5. Conclusions and future directions
Appendix A. Supplementary data
Multimedia component 1
- Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis.J Immunol. 2003; 170: 4335-4341
- Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care.J Trauma Acute Care Surg. 2012; 72: 1491-1501
- Tea beverage in chemoprevention and chemotherapy of prostate cancer.Acta Pharmacol Sin. 2007; 28: 1392-1408
- A method for fast determination of epigallocatechin gallate (EGCG), epicatechin (EC), catechin (C) and caffeine (CAF) in green tea using HPLC.Ciência Tecnol Aliment. 2006; 26: 394-400
- Green tea (Camellia sinensis) and L-theanine: medicinal values and beneficial applications in humans—a comprehensive review.Biomed Pharmacother. 2017; 95: 1260-1275
- Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells.Mol Vis. 2011; 17: 533-542
- Green tea catechin metabolites exert immunoregulatory effects on CD4+ T Cell and natural killer cell activities.J Agric Food Chem. 2016; 64: 3591-3597
- New insights into graft-versus-host disease and graft rejection.Annu Rev Pathol. 2018; 13: 219-245
- Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs.Gastroenterology. 2011; 140: 51-64
- T cell allorecognition pathways in solid organ transplantation.Front Immunol. 2018; 9: 1-14
- Immunosuppressive drugs for kidney transplantation.N Engl J Med. 2004; 351: 2715-2729
- HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2008; 358: 353-361
- The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation.Immunol Res. 2013; 57: 197-209
- Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression.Biochem J. 2015; 465: 295-303
- Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression.Blood. 2007; 110: 1225-1232
- T cell death and transplantation tolerance.Immunity. 2001; 14: 407-416
- Recently discovered T cell subsets cannot keep their commitments.J Am Soc Nephrol. 2009; 20: 1677-1680
- Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+T-cell subsets.Am J Pathol. 2012; 180: 221-234
- La EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1α with Th17/Treg control.PloS One. 2014; 9: e86062
- Inhibitory effects of epigallocatechin-3 gallate, a polyphenol in green tea, on tumor-associated endothelial cells and endothelial progenitor cells.Canc Sci. 2009; 24: 1-20
- The green tea catechin epigallocatechin gallate ameliorates graft-versus-host disease.PloS One. 2017; 12: e0169630
- CytoSolve: a scalable computational method for dynamic integration of multiple molecular pathway models.Cell Mol Bioeng. 2011; 4: 28-45
- In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology.Biophys J. 2013; 104: 2295-2306
- Pericytes of the neurovascular unit: key functions and signaling pathways.Nat Neurosci. 2016; 19: 771-783
- Multiscale mathematical modeling to support drug development.IEEE Trans Biomed Eng. 2011; 58: 3508-3512
- The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease.Clin Exp Immunol. 2007; 148: 32-46
- Green tea EGCG, T cells, and T cellmediated autoimmune diseases. In: Azzi, editor. Proceedings of the molecular aspects of medicine.Mol Aspect of Med. 2012;
- IL-6 promotes cardiac graft rejection mediated by CD4+ cells.J Immunol. 2011; 187: 5764-5771
- Tumour necrosis factor alpha and the cardiovascular system: its role in cardiac allograft rejection and heart disease.Cardiovasc Res. 1999; 43: 850-859
- Regulation of Stat3 activation by MEK kinase 1.J Biol Chem. 2001; 276: P21004-P21011
- GITRL modulates the activities of p38 MAPK and STAT3 to promote Th17 cell differentiation in autoimmune arthritis.Oncotarget. 2016; 7: 8590-8600
- Role of TNF-TNF receptor 2 signal in regulatory T cells and its therapeutic implications.Front Immunol. 2018; 9: 1-11
- T-cell activation and transplantation tolerance.Transplant Rev. 2012; 26: 212-222
- New insights into mechanisms of allograft rejection.Am J Med Sci. 1997; 22: 381-400
- The critical role of innate immunity in kidney transplantation.Nephron. 2016; 132: 227-237
- Mycophenolate mofetil and its mechanisms of action.Immunopharmacology. 2000; 47: 85-118
- Inosine monophosphate dehydrogenase variability in renal transplant patients on long-term mycophenolate mofetil therapy.Br J Clin Pharmacol. 2010; 69: 38-50
- Inosine-5’-monophosphate dehydrogenase: regulation of expression and role in cellular proliferation and T lymphocyte activation.Prog Nucleic Acid Res Mol Biol. 1998; 61: 181-209
- Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene.J Clin Invest. 2000; 106: 599-606
- Role of Toll-like receptor-4 in renal graft ischemia-reperfusion injury.Am J Physiol Cell Physiol. 2014; 306: F801-F811
- The role of Toll-like receptor 4 in infectious and noninfectious inflammation.Mediat Inflamm. 2016; 2016: 6978936
- Allograft injury mediated by reactive oxygen species: from conserved proteins of drosophila to acute and chronic rejection of human transplants. Part III: interaction of (oxidative) stress-induced heat shock proteins with toll-like receptor-bearing cells.Transplant Rev. 2003; 16: 192-204
- Role of T cells in graft rejection and transplantation tolerance.Expet Rev Clin Immunol. 2010; 6: 155-169
- Green tea epigallocatechin-3-gallate suppresses autoimmune arthritis through indoleamine-2,3-dioxygenase expressing dendritic cells and the nuclear factor, erythroid 2-like 2 antioxidant pathway.J Inflamm (United Kingdom). 2015; 12: 1-15
- Potential role of green tea catechins in the management of oxidative stress-associated infertility.Reprod Biomed Online. 2017; 34: 487-498
- The immunological benefits of green tea (Camellia sinensis).Int J Biol. 2016; 9: 10-17
- (−)-Epicatechin in the prevention of tumor necrosis alpha-induced loss of Caco-2 cell barrier integrity.Arch Biochem Biophys. 2015; 573: 84-91
- Gallic acid, a natural antioxidant, in aqueous and micellar environment: spectroscopic studies.Curr Top Biophys. 2002; 26: 217-227
- Gallic acid inhibits histamine release and pro-inflammatory cytokine production in mast cells.Toxicol Sci. 2006; 91: 123-131
- TLR4 signaling inhibitory pathway induced by green tea polyphenol epigallocatechin-3-gallate through 67-kDa laminin receptor.J Immunol. 2010; 185: 33-45
- Estrogen receptor-α36 is involved in epigallocatechin-3-gallate induced growth inhibition of ER-negative breast cancer stem/progenitor cells.J Pharmacol Sci. 2016; 130: 85-93
- Epigallocatechin-3-gallate suppresses galactose-α1,4-galactose- β1,4-glucose ceramide expression in TNF-α stimulated human intestinal epithelial cells through inhibition of MAPKs and NF-κB.J Kor Med Sci. 2005; 20: 548-554
- Green tea polyphenol epigallocatechin gallate inhibits cell signaling by inducing SOCS1 gene expression.Int Immunol. 2010; 22: 359-366
- Suppressor of cytokine signaling 1 (SOCS1) limits NF B signaling by decreasing p65 stability within the cell nucleus.Faseb J. 2011; 25: 863-874
- Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure- activity relationship and mechanisms involved.Canc Res. 1999; 59: 4610-4617
- (-)-Epigallocatechin gallate regulates CD3-mediated T cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase.J Biol Chem. 2008; 283: 28370-28379
- Effects of green tea polyphenols on murine transplant-reactive T cell immunity.Clin Immunol. 2004; 110: 100-108
- The janus kinase (JAK) FERM and SH2 domains: bringing specificity to JAK-receptor interactions.Front Endocrinol (Lausanne). 2017; 8: 1-11
- Epigallocatechin-3-gallate (EGCG) suppresses the trafficking of lymphocytes to epidermal melanocytes via inhibition of JAK2: its implication for vitiligo treatment.Biol Pharm Bull. 2015; 38: 1700-1706
- Effects of tea catechins on cancer signaling pathways.Enzymes. 2014; 36: 195-221
- Transcription of the Tollip gene is elevated in intestinal epithelial cells through impaired O-GlcNAcylation-dependent nuclear translocation of the negative regulator Elf-1.Biochem Biophys Res Commun. 2011; 412: 704-709
- Green tea polyphenol EGCG upregulates Tollip expression by suppressing Elf-1 expression.J Immunol. 2017; 199: 3261-3269
- Mechanism of the inhibition of the STAT3 signaling pathway by EGCG.Oncol Rep. 2013; 30: 2691-2696
- Inhibitory effect of curcumin on IMP dehydrogenase, the target for anticancer and antiviral chemotherapy agents.Biosci Biotechnol Biochem. 2010; 74: 185-187
- Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1.Free Radic Biol Med. 2017; 108: 840-857
- Targeting HO-1 by epigallocatechin-3-gallate reduces contrast-induced renal injury via anti-oxidative stress and anti-inflammation pathways.PloS One. 2016; 11: e0149032
- Epigallocatechin-3-gallate ameliorates both obesity and autoinflammatory arthritis aggravated by obesity by altering the balance among CD4+T-cell subsets.Immunol Lett. 2014; 157: 51-59
- Epicatechin, catechin, and dimeric procyanidins inhibit PMA-induced NF-kappaB activation at multiple steps in Jurkat T cells.FASEB J. 2004; 18: 167-169
- (−)-Epicatechin, a natural flavonoid compound, protects astrocytes against hemoglobin toxicity via Nrf2 and AP-1 signaling pathways.Mol Neurobiol. 2017; 54: 7898-7907
- A molecular modeling study of inhibitors of nuclear factor kappa-B (p50)- DNA binding.J Comput Aided Mol Des. 2003; 17: 825-836
- Regulatory T cells and Foxp3.Immunol Rev. 2011; 241: 260-268
- Study of nutritional value of dried tea leaves and infusions of black, green and white teas from Chinese plantations.Rocz Panstw Zakl Hig. 2017; 68: 237-245
- Quantitative analysis of major constituents in green tea with different plucking periods and their antioxidant activity.Molecules. 2014; 19: 9173
- Ischemia-reperfusion injury enhances lymphatic endothelial VEGFR3 and rejection in cardiac allografts.Am J Transplant. 2016; 16: 1160-1172
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