scholarly journals Computational Prediction of Biomarkers, Pathways, and New Target Drugs in the Pathogenesis of Immune-Based Diseases Regarding Kidney Transplantation Rejection

2021 ◽  
Vol 12 ◽  
Author(s):  
Rafael Alfaro ◽  
Helios Martínez-Banaclocha ◽  
Santiago Llorente ◽  
Victor Jimenez-Coll ◽  
José Antonio Galián ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Nk Cells ◽  
Protein Interactions ◽  
Graft Rejection ◽  
Therapeutic Targets ◽  
Protein Protein Interactions ◽  
Antibody Mediated Rejection ◽  
Biological Analysis ◽  
Expression Of Genes ◽  
Leukocyte Populations

BackgroundThe diagnosis of graft rejection in kidney transplantation (KT) patients is made by evaluating the histological characteristics of biopsy samples. The evolution of omics sciences and bioinformatics techniques has contributed to the advancement in searching and predicting biomarkers, pathways, and new target drugs that allow a more precise and less invasive diagnosis. The aim was to search for differentially expressed genes (DEGs) in patients with/without antibody-mediated rejection (AMR) and find essential cells involved in AMR, new target drugs, protein-protein interactions (PPI), and know their functional and biological analysis.Material and MethodsFour GEO databases of kidney biopsies of kidney transplantation with/without AMR were analyzed. The infiltrating leukocyte populations in the graft, new target drugs, protein-protein interactions (PPI), functional and biological analysis were studied by different bioinformatics tools.ResultsOur results show DEGs and the infiltrating leukocyte populations in the graft. There is an increase in the expression of genes related to different stages of the activation of the immune system, antigenic presentation such as antibody-mediated cytotoxicity, or leukocyte migration during AMR. The importance of the IRF/STAT1 pathways of response to IFN in controlling the expression of genes related to humoral rejection. The genes of this biological pathway were postulated as potential therapeutic targets and biomarkers of AMR. These biological processes correlated showed the infiltration of NK cells and monocytes towards the allograft. Besides the increase in dendritic cell maturation, it plays a central role in mediating the damage suffered by the graft during AMR. Computational approaches to the search for new therapeutic uses of approved target drugs also showed that imatinib might theoretically be helpful in KT for the prevention and/or treatment of AMR.ConclusionOur results suggest the importance of the IRF/STAT1 pathways in humoral kidney rejection. NK cells and monocytes in graft damage have an essential role during rejection, and imatinib improves KT outcomes. Our results will have to be validated for the potential use of overexpressed genes as rejection biomarkers that can be used as diagnostic and prognostic markers and as therapeutic targets to avoid graft rejection in patients undergoing kidney transplantation.

scholarly journals A transcriptional regulatory circuit for the photosynthetic acclimation of microalgae to carbon dioxide limitation

2020 ◽  
Author(s):  
Olga Blifernez-Klassen ◽  
Hanna Berger ◽  
Birgit Gerlinde Katharina Mittmann ◽  
Viktor Klassen ◽  
Louise Schelletter ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Protein Interactions ◽  
Prolonged Exposure ◽  
Light Harvesting ◽  
Low Carbon ◽  
Protein Protein Interactions ◽  
Regulatory Circuit ◽  
Expression Of Genes ◽  
Transcriptional Regulatory ◽  
Squamosa Promoter Binding Protein

ABSTRACTIn green microalgae, prolonged exposure to inorganic carbon depletion requires long-term acclimation responses, based on a modulated expression of genes and adjusting photosynthetic activity to the prevailing supply of carbon dioxide. Here, we depict a microalgal regulatory cycle, adjusting the light-harvesting capacity at PSII to the prevailing supply of carbon dioxide in Chlamydomonas reinhardtii. It engages a newly identified low carbon dioxide response factor (LCRF), which belongs to the Squamosa promoter binding protein (SBP) family of transcription factors, and the previously characterized cytosolic translation repressor NAB1. LCRF combines a DNA-binding SBP domain with a conserved domain for protein-protein interactions and transcription of the LCRF gene is rapidly induced by carbon dioxide depletion. LCRF activates transcription of the NAB1 gene by specifically binding to tetranucleotide motifs present in its promoter. Accumulation of the NAB1 protein enhances translational repression of its prime target mRNA, encoding the PSII-associated major light-harvesting protein LHCBM6. The resulting reduction of the PSII antenna size helps maintaining a low excitation during the prevailing carbon dioxide limitation. Analyses of low carbon dioxide acclimation in nuclear insertion mutants devoid of a functional LCRF gene confirm the essentiality of this novel transcription factor for the regulatory circuit.

scholarly journals Developing drugs for the ‘undruggable’

BioTechniques ◽  
2020 ◽  
Vol 69 (4) ◽  
pp. 239-241
Author(s):  
Abigail Sawyer
Keyword(s):  
Protein Interactions ◽  
Therapeutic Targets ◽  
Protein Protein Interactions ◽  
Human Interactome ◽  
Novel Therapeutic

There are up to 650,000 ‘undruggable’ protein-protein interactions (PPIs) in the human interactome that can be potentially considered as novel therapeutic targets. How does the ‘undruggable’ become ‘druggable’?

P1602MICROVASCULAR INFLAMMATION WITHOUT DSA OR C4D: AN ORPHAN CATEGORY IN BANFF CLASSIFICATION WITH INTENSE CAPILLARITIS AND CYTOTOXIC T-CELL INFILTRATION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Anna Buxeda ◽  
Laura Llinàs ◽  
Javier Gimeno ◽  
Carlos Arias Cabrales ◽  
Carla Burballa Tarrega ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
T Cell ◽  
Nk Cells ◽  
Lymphocyte Subsets ◽  
Normal Group ◽  
Cell Infiltration ◽  
Cytotoxic T Cell ◽  
Antibody Mediated Rejection ◽  
T Cell Infiltration ◽  
Peritubular Capillaries

Abstract Background and Aims Antibody-mediated rejection (ABMR) associated with donor-specific HLA antibodies (DSA) is the leading cause of late allograft failure after kidney transplantation. Microvascular inflammation (MVI) without detectable circulating DSA or C4d + cannot be classified as ABMR according to Banff-2017. The involvement of intragraft lymphocyte subsets in the development of humoral damage in kidney transplantation (KT) is relevant. We aimed to analyze lymphocyte subset distribution in kidney transplant biopsies (KTBx) with ABMR compared with MVI and with normal KTBx. Method KTBx with ABMR, MVI (g+ptc≥2, without DSA) or normal findings were included. DSA were identified with Luminex single antigen assays. Intragraft lymphocyte subsets’ characterization was performed by immunohistochemistry: T-lymphocytes (CD3, CD4, CD8, Foxp3), B-lymphocytes / plasmatic cells (CD20, CD138), NK cells (CD56), macrophages / monocytes (CD68), cytotoxic cells (TIA1) and activated cells (PD1) were evaluated. Results We analyzed 34 KTBx: 21 ABMR, 5 MVI and 8 KTBx with normal findings. KT with ABMR and MVI had more proteinuria at the time of the biopsy compared with the normal group (575 mg/24h and 964 mg/24h vs 147 mg/24h, p=0.002 and p=0.005 respectively). DSA were more frequently detected in patients with ABMR (95.2% vs 0% and 37.5%, p<0.001 and p=0.003 respectively). KTBx with ABMR and MVI had increased cytotoxic T-cell infiltration apparently corresponding to NK cells in peritubular capillaries (ptc) compared to normal group. Moreover, both groups showed a greater number of macrophages and monocytes in glomeruli. KT with MVI but not with ABMR had a significantly increased activated cell infiltration (PD1+) in ptc compared to the normal group, and showed an increased cytotoxic T-cell infiltration in glomeruli compared to ABMR and normal groups. Conclusion ABMR and MVI have an increased infiltration of NK cells with cytotoxic activity in ptc that differs from the normal group. However, KT with MVI show greater infiltration of activated cells in ptc and cytotoxic T-cell in glomeruli compared to ABMR suggesting the possibility of different activation pathways.

scholarly journals Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling

2021 ◽  
Author(s):  
Shuhui Lim ◽  
Nicolas Boyer ◽  
Nicole Boo ◽  
Chunhui Huang ◽  
Gireedhar Venkatachalam ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Therapeutic Targets ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
Macrocyclic Peptides

Macrocyclic peptides have the potential to address intracellular protein-protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons...

scholarly journals Latest update on chemokine receptors as therapeutic targets

2021 ◽  
Author(s):  
Wing Yee Lai ◽  
Anja Mueller
Keyword(s):  
Protein Interactions ◽  
Chemokine Receptors ◽  
Inflammatory Diseases ◽  
Specific Binding ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Fine Tuning ◽  
Protein Protein Interactions ◽  
Diverse Range ◽  
Chemokine Ligand

The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine system has been linked to inflammatory diseases and cancer, which renders chemokine receptors to be considered as therapeutic targets. In the past two decades, around 45 drugs targeting chemokine receptors have been developed, yet only three are clinically approved. The challenging factors include the limited understanding of aberrant chemokine signalling in malignant diseases, high redundancy of the chemokine system, differences between cell types and non-specific binding of the chemokine receptor antagonists due to the broad ligand-binding pockets. In recent years, emerging studies attempt to characterise the chemokine ligand–receptor interactions and the downstream signalling protein–protein interactions, aiming to fine tuning to the promiscuous interplay of the chemokine system for the development of precision medicine. This review will outline the updates on the mechanistic insights in the chemokine system and propose some potential strategies in the future development of targeted therapy.

Abstract 1122‐000102: Function of Proteins Predictive of Infarct Volume in Mechanical Thrombectomy Subjects

2021 ◽  
Vol 1 (S1) ◽  
Author(s):  
Benton Maglinger ◽  
Christopher McLouth ◽  
Chintan Rupareliya ◽  
Jacqueline Frank ◽  
Madison Sands ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Protein Interactions ◽  
Mechanical Thrombectomy ◽  
Infarct Volume ◽  
Therapeutic Targets ◽  
Translation Initiation Factor ◽  
Protein Protein Interactions ◽  
Vascular Events ◽  
Positive Regulation ◽  
P Values

Introduction : Emergent Large Vessel Occlusion (ELVO) strokes are devastating ischemic vascular events which can cause severe and permanent impairment. The purpose of this study is to investigate protein‐protein interactions at the time of mechanical thrombectomy (MT) which correlate to infarct volume. Uncovering functions of protein‐protein interactions involved in infarct volume will allow for biomarker discovery and potential therapeutic targets. Methods : The Blood And Clot Thrombectomy Registry And Collaboration (BACTRAC) is a continually enrolling tissue bank (clinicaltrials.gov NCT03153683) from stroke patients undergoing MT. N = 61 human carotid plasma samples were analyzed for inflammatory and cardiometabolic protein expression by Olink Proteomics. To determine which proteins had the most significant changes based on infarct volume, a series of 184 paired t‐tests were performed. Within each panel, proteins were then ranked based on the associated p‐values. Benjamini and Hochberg’s linear step‐up procedure was used to control the false discovery rate at 0.05. Pearson correlation revealed proteins which were most significantly related to infarct volume. STRING analysis was used to identify protein‐protein network and biologic functions. Results : Systemic proteins most predictive of infarct volume included adenosine deaminase (ADA), monocyte chemotactic protein 1 (MCP1), eukaryotic translation initiation factor binding protein (EBP1), Nidogen‐1 (NID1), CD40, and leukemia inhibitory factor receptor (LIFR). All correlations between each protein and infarct volume were positive in directionality and were statistically significant with p‐values less than 0.05. STRING output demonstrated relevant biological functions including ‘positive regulation of signal transduction,’ ‘cytokine mediated signaling,’ ‘positive regulation of NFkB transcription factor activity,’ and ‘tumor necrosis factor signaling pathways.’ Conclusions : This study identified proteins predictive of infarct volume at time of MT in ELVO patients. LIF is a cytokine in the IL‐6 family that has been shown to play a role in inflammation and ischemia. ADA deaminates adenosine, which inactivates its neuroprotective property in acute cerebral ischemia. Higher levels of circulating MCP1 have been shown to be associated with increased risk of stroke. These proteomic signaling networks and functions inform the biochemical picture involved in the pathogenesis and outcome of cerebral ischemia. Importantly, these proteins serve as biomarker candidates and possible therapeutic targets.

scholarly journals BIRC3 and BIRC5: multi‐faceted inhibitors in cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raffaele Frazzi
Keyword(s):  
Cancer Cells ◽  
Protein Interactions ◽  
Point Mutations ◽  
Therapeutic Targets ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Main Body ◽  
Protein Protein Interactions ◽  
Smac Mimetics

Abstract Background The evasion from apoptosis is a common strategy adopted by most tumors, and inhibitors of apoptosis proteins (IAPs) are among the most studied molecular and therapeutic targets. BIRC3 (cellular IAP2) and BIRC5 (survivin) are two of the eight members of the human IAPs family. This family is characterized by the presence of the baculoviral IAP repeat (BIR) domains, involved in protein-protein interactions. In addition to the BIR domains, IAPs also contain other important domains like the C-terminal ubiquitin-conjugating (UBC) domain, the caspase recruitment (CARD) domain and the C-terminal Ring zinc-finger (RING) domain. Main body BIRC3 and BIRC5 have been characterized in some solid and hematological tumors and are therapeutic targets for the family of drugs called “Smac mimetics”. Many evidences point to the pro-survival and antiapoptotic role of BIRC3 in cancer cells, however, not all the data are consistent and the resulting picture is heterogeneous. For instance, BIRC3 genetic inactivation due to deletions or point mutations is consistently associated to shorter progression free survival and poor prognosis in chronic lymphocytic leukemia patients. BIRC3 inactivation has also been associated to chemoimmunotherapy resistance. On the contrary, the progression from low grade gliomas to high grade gliomas is accompanied by BIRC3 expression increase, which bears relevant prognostic consequences. Due to the relationship between BIRC3, MAP3K14 and the non-canonical NF-kB pathway, BIRC3 inactivation bears consequences also on the tumor cells relying on NF-kB pathway to survive. BIRC5, on the contrary, is commonly considered an anti-apoptotic molecule, promoting cell division and tumor progression and it is widely regarded as potential therapeutic target. Conclusions The present manuscript collects and reviews the most recent literature concerning the role played by BIRC3 and BIRC5 in cancer cells, providing useful information for the choice of the best therapeutic targets.

scholarly journals Gene Regulation via the Combination of Transcription Factors in the INDETERMINATE DOMAIN and GRAS Families

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 613
Author(s):  
Takuya Aoyanagi ◽  
Shun Ikeya ◽  
Atsushi Kobayashi ◽  
Akiko Kozaki
Keyword(s):  
Transcription Factors ◽  
Protein Interactions ◽  
Tissue Formation ◽  
Protein Protein Interactions ◽  
Short Root ◽  
Gras Family ◽  
Della Proteins ◽  
Culture Cells ◽  
Expression Of Genes ◽  
Dna Binding Properties

INDETERMINATE DOMAIN (IDD) family proteins are plant-specific transcription factors. Some Arabidopsis IDD (AtIDD) proteins regulate the expression of SCARECROW (SCR) by interacting with GRAS family transcription factors SHORT-ROOT (SHR) and SCR, which are involved in root tissue formation. Some AtIDD proteins regulate genes involved in the synthesis (GA3ox1) or signaling (SCL3) of gibberellic acid (GA) by interacting with DELLA proteins, a subfamily of the GRAS family. We analyzed the DNA binding properties and protein–protein interactions of select AtIDD proteins. We also investigated the transcriptional activity of the combination of AtIDD and GRAS proteins (AtIDD proteins combined with SHR and SCR or with REPRESSOR of ga1-3 (RGA)) on the promoters of SCR, SCL3, and GA3ox1 by conducting a transient assay using Arabidopsis culture cells. Our results showed that the SCR promoter could be activated by the IDD and RGA complexes and that the SCL3 and GA3ox1 promoters could be activated by the IDD, SHR, and SCR complexes, indicating the possibility that these complexes regulate and consequently coordinate the expression of genes involved in GA synthesis (GA3ox1), GA signaling (SCL3), and root formation (SCR).

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