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Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
ADAM17 is a transmembrane protease that functions as an ecto-domain sheddase. Its expression level is upregulated when the SARS-CoV-2 S-protein binds to ACE-2. Whereas TMPRSS2 cleaves the cytoplasmic tail, ADAM17 cleaves the ectodomain of ACE-2 thus mediating viral entry [72]. Besides directly contributing to viral pathology, the release of ACE-2 by ADAM 17 into the extracellular environment raises the concern of co-morbidity, such as promoting vascular diseases as a “collateral” of the infection. Alpha-anti trypsin has been identified as a potential inhibitor for ADAM17 against SARS-CoV-2 infection [73]. Many other inhibitors against ADAM17 have been described for other diseases [74], however, not many of them have been tested against SARS-CoV-2.
Biochemistry of Exercise Training: Effects on Bone
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Panagiota Klentrou, Rozalia Kouvelioti
RANKL is a homotrimeric protein produced by osteoblasts and other cells, including activated T cells (63, 145, 154). The secreted type of RANKL is a result of proteolytic division or alternative splicing on the membrane form. Matrix metalloproteases (MMP3 or 7) and ADAM (a disintegrin and metalloprotease domain) are responsible for RANKL proteolytic cleavage (55, 95). RANKL, which is secreted by pre-osteoblasts, osteoblasts, osteocytes, and periosteal cells (24, 107, 137), activate RANK that is expressed by osteoclasts and its precursors (58). RANKL has assignments for stimulating pre-osteoclast differentiation (85), adherence osteoclasts to bone tissue and their following activation (85, 88), and maintenance (88).
CDISC Data Compliance Checks
Published in Sunil Gupta, Clinical Data Quality Checks for CDISC Compliance Using SAS, 2019
In the final submission, key SDTMs such as TA, DM, EX and DS need to be included. The example below is one method to confirm these required SDTMs. Proc FORMAT creates $SDTM and $ADAM formats, which group SDTMs and ADaMs. $SDTM format is applied to MEMNAME to display required and other categories. Additional SDTMs can be added to the required list.
Local delivery of interleukin 7 with an oncolytic adenovirus activates tumor-infiltrating lymphocytes and causes tumor regression
Published in OncoImmunology, 2022
Tatiana V. Kudling, James H.A. Clubb, Dafne C.A. Quixabeira, Joao M. Santos, Riikka Havunen, Alexander Kononov, Camilla Heiniö, Victor Cervera-Carrascon, Santeri Pakola, Saru Basnet, Susanna Grönberg-Vähä-Koskela, Victor Arias, Ivan Gladwyn-Ng, Katri Aro, Leif Bäck, Jari Räsänen, Ilkka Ilonen, Kristian Borenius, Mikko Räsänen, Otto Hemminki, Antti Rannikko, Anna Kanerva, Johanna Tapper, Akseli Hemminki
The analysis of the tumor microenvironment showed a clear shift toward proinflammatory signaling in ex vivo patient samples infected with Ad5/3-E2F-d24-hIL7, particularly, increased IFNg production, which, in turn, stimulates expression of Ccl5, Cxcl9 and Cxcl10 – key chemokines involved in the recruitment of T cells and NK cells. Indeed, we observed higher number of CD4+ and CD8+ migrated cells when used supernatants obtained after infection with IL7 armed virus. Transcriptomic analysis showed upregulation of several migration-related genes in CD4+ cells – CCR5, DPP4, ITGA4, MYO1G. Interestingly, we observed significant upregulation of ADAM19 gene in both CD4+ and CD8 + T cell, however, the role of this particular protein in immune cells is still unclear. ADAM proteins are membrane disintegrins and metalloproteinases, which convert nearby membrane-anchored cytokine precursors, cytokine receptors, Notch receptors, phagocytic receptors or cell adhesion molecules into soluble bioactive mediators.31 In T cells, ADAMs can be involved in cell development and activation via cleavage of negative regulatory proteins, such as LAG3,32 and regulate cell migration not only due to the proteolytic activity of ADAMs on the T cells themselves, but also due to the protease activity on the tissue cells serving as substrate of cell migration.33 Nevertheless, additional experiments are needed to understand the role of ADAM19 in T cells activation and migration upon Ad5/3-E2F-d24-hIL7 infection.
Novel ligands and modulators of triggering receptor expressed on myeloid cells receptor family: 2015-2020 updates
Published in Expert Opinion on Therapeutic Patents, 2021
Harbinder Singh, Vikrant Rai, Sunil K. Nooti, Devendra K. Agrawal
A Disintegrin and metalloproteinase domain-containing protein (ADAM10/17) is a cellular surface protein. These ADAMs cleave human TREM-2 at His157-Ser158 peptide bond and thus release sTREM-2. Further cleavage of transmembrane region of sTREM-2 by other enzymes (ℽ-secretase) release DAP12 and blocks sTREM-2 signaling. Inhibiting or initiating the shedding of TREM-2 is another approach of intervention [111]. However, due to the vast range of substrates of ADAM10/17, it is unable to inhibit specific protease or substrate activity because this may lead to various unwanted side effects. So, there is a pressing need for specific and fine-tuned modulation to block TREM-2 shedding. At the German center for neurodegenerative diseases, scientists targeted the cleavage site of TREM-2 to interrupt receptor shedding by ADAMs that increased the membrane concentration of receptor and amplify the signaling. They developed antibody 4D9 that could bind to the stalk region of TREM-2 and disrupt the proteolytic shedding [112]. Additionally, this antibody was also found to activate TREM-2 signaling and increase Aβ uptake thus cause microglia survival. Furthermore, in 2020, they also tested the antibody 4D9 in mouse model of AD and found that antibody significantly reduced the level of Aβ plaques but did not improve cognitive ability [113].
Plasma PrPC and ADAM-10 as novel biomarkers for traumatic brain injury and concussion: a pilot study
Published in Brain Injury, 2021
Amit Persad, Nam Pham, Farzad Moien-Afshari, William Gormley, Sandra Yan, Rebekah Mannix, Changiz Taghibiglou
Here, we are reporting on plasma expression of ADAM10 and PrPC. The mechanism of ADAM10 plasma expression is unclear although it may be associated with exosomes (41,42). Another possible mechanism includes simple membrane disruption in the presence of trauma or trauma-associated hyperpermeability (43) of the blood-brain barrier. ADAM10 regulates PrPC activity via ectodomain shedding through its activity as a metalloproteinase. As such, impaired ADAM10 activity results in reduced shedding of PrPC. With reduced cellular shedding of PrPC, increased release of PrPC via exosomes has been demonstrated as a compensatory mechanism (44). In addition, ADAM10 has been shown to be released in exosomes (45) and to regulate exosomal secretion (46) from neuronal and glial cells (47,48). ADAM10 is a target of interest both for its role in regulation of PrPC, which is a molecule of interest based on our previous study, and its role in ectodomain cleavage. The ADAM family of metalloproteinases are single-membrane-spanning molecules localized to the plasma membrane that both regulate ectodomain cleavage and play roles in cell-cell adhesion. As such, ADAM10 might play roles in cell permeability post-injury and is known for its roles in neurodegenerative conditions and inflammation (49).