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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.
Tylosis with Esophageal Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
As a rare, autosomal dominant disorder showing focal hyperkeratotic skin on the palms and soles, oral leukoplakia, and esophageal cancer, tylosis with esophageal cancer (TOC) differs from other PPK conditions in harboring mutations in the RHBDF2 gene and having the tendency to develop and squamous cell carcinoma of the esophagus. The RHBDF2 (iRhom2) protein encoded by the RHBDF2 gene appears to play a key role in the regulation of the trafficking and activation of ADAM17, a membrane bound sheddase, which in turn participates in the cleavage and release of membrane-bound TNFα and EGFR ligands. Gain-of-function mutations in the highly conserved cytoplasmic N-terminus of RHBDF2 (iRhom2) increase its stability, leading to increased ADAM17 activity and upregulated shedding of ADAM17-dependent substrates (e.g., EGFR-family ligands and TNFα). Given the involvement of EGFR pathway dysregulation in epithelial malignancies (e.g., sporadic squamous cell carcinoma of the esophagus), the aberrant EGFR signaling and TNFα shedding may underlie the tumorigenesis of TOC. In the absence of effective therapy for TOC, further investigation on the EGFR signaling pathway may offer a potential approach for mitigating this genetic condition.
Junctional adhesion molecule (JAM) family
Published in C. Yan Cheng, Spermatogenesis, 2018
Proteolytic cleavage of JAMs has been reported in endothelial models. The process itself as well as the cleaved fragments are crucial for the control of the JAM function. For instance, a significant increase in disintegrin-/ADAM17-mediated JAM-A cleavage has been reported in inflamed vascular endothelium.73 Soluble JAM-A has been shown to reduce the transendothelial migration of neutrophils in vitro and decreases the infiltration of neutrophil in vivo.73 Soluble JAM-C is found to be elevated in the serum of patients with rheumatoid arthritis and is capable of inducing angiogenesis.74 Like JAM-A, the cleavage of JAM-C is mediated partially by disintegrin, ADAM10, and ADAM17.74 Up to now, no studies have been done to examine if proteolytic cleavage of JAMs occurs in the testis, let alone its regulatory effects on spermatogeneis.
Soluble ACE2 and angiotensin II levels are modulated in hypertensive COVID-19 patients treated with different antihypertension drugs
Published in Blood Pressure, 2022
Mohamed A. Elrayess, Hadeel T. Zedan, Rand A. Alattar, Hatem Abusriwil, Mahmoud Khatib A. A. Al-Ruweidi, Shamma Almuraikhy, Jabeed Parengal, Bassem Alhariri, Hadi M. Yassine, Ali A. Hssain, Arun Nair, Musaed Al Samawi, Alaaeldin Abdelmajid, Jassim Al Suwaidi, Mohamed Omar Saad, Muna Al-Maslamani, Ali S. Omrani, Huseyin C. Yalcin
In this study, circulating ACE2 levels were elevated in patients with severe disease compared to patients with mild or moderate disease severity. Additionally, ACE2 levels correlated positively with the length of hospital stay, CRP, and D-dimer levels, regardless of the antihypertensive medication used. According to recent studies, increased ACE2 expression in the lungs increases the risk of being infected with SARS-CoV-2 [3], and increased ACE2 shedding is associated with elevated levels of circulating ACE2 and poor prognosis in patients with heart failure [11]. The significance of soluble ACE2 shedding is not completely understood, but it could be related to membrane expression, with a relatively constant rate of conversion between soluble and membrane-bound forms. It is also possible that increased circulating ACE2 is a result of the upregulation or downregulation in the proteases that are responsible for cleaving ACE2 from the membrane [38]. Several studies have suggested that inflammation may be responsible for the cleavage of ACE2 [9–11], which may result in the increased release of soluble ACE2. Moreover, some studies suggest that ADAM17 is upregulated because of the internalisation of the virus, with ADAM17 primarily responsible for shedding membrane-bound and catalysing its conversion into soluble ACE2.
Neuregulin 1 treatment improves glucose tolerance in diabetic db/db mice, but not in healthy mice
Published in Archives of Physiology and Biochemistry, 2020
Gaël Ennequin, Kevin Caillaud, Vivien Chavanelle, Allison Teixeira, Monique Etienne, Xinyan Li, Nathalie Boisseau, Pascal Sirvent
Protein samples were separated on Criterion Stain-Free precast gels in a BioRad Mini PROTEAN Tetra-Cell unit and transferred to nitrocellulose membranes using a BioRad Trans Blot Turbo transfer. Membranes were blocked with 5% nonfat dry milk in Tris-buffered saline (pH 7.5) containing 0.1% Tween 20 (TBST) at room temperature for 1 h. Then, membranes were incubated in 2% BSA with the relevant primary antibodies at 4 °C overnight. Anti-ErbB-3 (1:200), -phosphorylated ErbB-3 (1:200), -p38 (1:1000), -phosphorylated p38 (1:1000), -AKT (1:1000), -phosphorylated AKT on Ser473 (1:1000), -FOXO1 (1:1000) and -phosphorylated FOXO1 (1:1000) antibodies were purchased from Cell Signaling (Beverly, MA, USA). Anti-ErbB-1 (1:200), -ErbB-4 (1:200), -phosphorylated ErbB-1 (1:200), -phosphorylated ErbB-4 (1:200) and -tissue inhibitor of metalloproteinase 3 (TIMP3; 1:1000) antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). The anti-NRG1 N120A/9 antibody (1:1000) was from Millipore (Merck Millipore, Billerica, MA, USA). The anti-A disintegrin and metalloprotease 17 (ADAM17) and -phosphorylated ADAM17 (1:1000) antibodies were from Abcam (Cambridge, MA, USA). Expression of total and phosphorylated proteins was normalised to the expression level in the untreated (NaCl) healthy control, and then phosphorylation was calculated as the phosphorylated protein/total protein ratio.
ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance
Published in OncoImmunology, 2020
Jacob J. Orme, Khalid A. Jazieh, Tiancheng Xie, Susan Harrington, Xin Liu, Matthew Ball, Benjamin Madden, M. Cristine Charlesworth, Tariq U. Azam, Fabrice Lucien, Bharath Wootla, Yanli Li, Jose Caetano Villasboas, Aaron S. Mansfield, Roxana S. Dronca, Haidong Dong
In the present work, we showed that tumor-associated metzincin metalloproteinases ADAM10 and ADAM17 cleave PD-L1 from the surface of tumor cells to induce apoptosis in CD8 + T cells and dampen anti-tumor immunity. These findings represent a novel mechanism of resistance to PD-(L)1 inhibitors. This newfound activity of tumor ADAM10 and ADAM17 may explain several phenomena observed in human cancers. First, high serum sPD-L1 is a predictor of poor response to PD-1 inhibition in some malignancies and predicts poor outcomes overall in hepatocellular carcinoma, cholangiocarcinoma, lung cancer, melanoma, myeloma, NK T cell lymphoma, and others.29–37 Tumor ADAM10 and ADAM17 cleave sPD-L1 that may mediate this PD-1 inhibitor resistance by inducing CD8 + T cell death. sPD-L1 may also act as a sink for circulating PD-L1 inhibitors (see Figure 4(e)).