A Double-Blind, Parallel, Randomized Extension Trial to Evaluate Safety and Efficacy of TMI-005 (Apratastat) in Subjects with Rheumatoid Arthritis on Methotrexate Who Have Completed Protocol 3140A1-200-WW

Start Date20 Jul 2005

Sponsor / Collaborator-

EUCTR2004-000012-13-IT / Not yet recruitingNot Applicable

A Double-Blind, Placebo-controlled, Parallel, Randomized Study to evaluate the Efficacy and Safety of 3 Oral Dose levels of TMI-005 in Subjects with Active Rheumatoid Arthritis on A Background of Methotrexate -

Start Date18 Feb 2005

Sponsor / Collaborator-

EUCTR2004-000012-13-CZ / Not yet recruitingPhase 2

A Double-Blind, Placebo-Controlled, Parallel, Randomized Study To Evaluate The Efficacy And Safety Of 3 Oral Dose Levels Of TMI-005 In Subjects With Active Rheumatoid Arthritis On A Background Of Methotrexate

Start Date26 Oct 2004

Sponsor / Collaborator-

100 Clinical Results associated with MMPs x ADAM17

100 Translational Medicine associated with MMPs x ADAM17

0 Patents (Medical) associated with MMPs x ADAM17

282

Literatures (Medical) associated with MMPs x ADAM17

01 Sep 2024·Journal of Applied Physiology

Chronic intermittent hypoxia facilitates the development of angiotensin II-induced abdominal aortic aneurysm in male mice

Article

Author: Sharma, Neekun ; Morales-Quinones, Mariana ; Manrique-Acevedo, Camila ; Gozal, David ; Chen, Shiyou ; Soares, Rogerio N. ; Martinez-Lemus, Luis A. ; Chandrasekar, Bysani ; Higashi, Yusuke ; Khalyfa, Abdelnaby ; Cai, Dunpeng ; Padilla, Jaume

IH facilitates Ang II-induced abdominal aortic diameter expansion and AAA development in C57BL/6J male mice. IH upregulates the expression of specific MMPs such as MMP8, MMP12, and ADAM17. IH directly suppresses RECK expression and increases MMPs activity in SMCs. Human AAA tissues exhibit a downregulation of RECK and an upregulation of ADAM17 and MMPs.

01 Jan 2024·Liver International

FXR agonists INT‐787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet‐induced ob/ob mouse model of NASH

Article

Author: Croce, Anna C ; Cadamuro, Massimiliano ; Cagna, Marta ; Vairetti, Mariapia ; Adorini, Luciano ; Di Pasqua, Laura G ; Fabris, Luca ; Palladini, Giuseppina ; Ferrigno, Andrea ; Perlini, Stefano

AbstractBackground and AimsWe have previously shown in a model of hepatic ischaemia/reperfusion injury that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) restores reversion‐inducing‐cysteine‐rich protein with Kazal motifs (RECK), an inverse modulator of metalloproteases (MMPs) and inhibitor of the sheddases ADAM10 and ADAM17 involved in inflammation and fibrogenesis. Here, the effects of FXR agonists OCA and INT‐787 on hepatic levels of RECK, MMPs, ADAM10 and ADAM17 were compared in a diet‐induced ob/ob mouse model of non‐alcoholic steatohepatitis (NASH).MethodsLep ob/ob NASH mice fed a high‐fat diet (HFD) or control diet (CD) for 9 weeks (wks) were treated with OCA or INT‐787 0.05% dosed via HFD admixture (30 mg/kg/day) or HFD for further 12 wks. Serum alanine transaminase (ALT) and inflammatory cytokines, liver RECK, MMP‐2 and MMP‐9 activity as well as ADAM10, ADAM17, collagen deposition (Sirius red), hepatic stellate cell activation (α‐SMA) and pCK+ reactive biliary cells were quantified.ResultsOnly INT‐787 significantly reduced serum ALT, IL‐1β and TGF‐β. A downregulation of RECK expression and protein levels observed in HFD groups (at 9 and 21 wks) was counteracted by both OCA and INT‐787. HFD induced a significant increase in liver MMP‐2 and MMP‐9; OCA administration reduced both MMP‐2 and MMP‐9 while INT‐787 markedly reduced MMP‐2 expression. OCA and INT‐787 reduced both ADAM10 and ADAM17 expression and number of pCK+ cells. INT‐787 was superior to OCA in decreasing collagen deposition and α‐SMA levels.ConclusionINT‐787 is superior to OCA in controlling specific cell types and clinically relevant anti‐inflammatory and antifibrotic molecular mechanisms in NASH.

01 Dec 2023·Journal of Molecular Medicine

Soluble LDL-receptor is induced by TNF-α and inhibits hepatocytic clearance of LDL-cholesterol

Article

Author: Zegeye, Mulugeta M ; Kumawat, Ashok K ; Nakka, Sravya S ; Sirsjö, Allan ; Andersson, Jonas S O ; Ljungberg, Liza U ; Söderberg, Stefan

AbstractDefective LDL-C clearance and hence its elevation in the circulation is an established risk factor for cardiovascular diseases (CVDs) such as myocardial infarction (MI). A soluble LDL-receptor (sLDL-R) has been detected in human plasma which correlates strongly with circulating LDL-C and classical conditions that promote chronic inflammation. However, the mechanistic interplay between sLDL-R, inflammation, and CVDs remains to be investigated. Here, we report that stimulation of HepG2 cells with TNF-α induces the release of sLDL-R into culture supernatants. In addition, TNF-α induces gene expression of peptidases ADAM-17 and MMP-14 in HepG2 cells, and inhibiting these peptidases using TMI 1 significantly reduces the TNF-α induced sLDL-R release. We found that a soluble form of recombinant LDL-R (100 nM) can strongly bind to LDL-C and form a stable complex (KD = E-12). Moreover, incubation of HepG2 cells with this recombinant LDL-R resulted in reduced LDL-C uptake in a dose-dependent manner. In a nested case-control study, we found that baseline sLDL-R in plasma is positively correlated with plasma total cholesterol level. Furthermore, a twofold increase in plasma sLDL-R was associated with a 55% increase in the risk of future MI [AOR = 1.55 (95% CI = 1.10–2.18)]. Nevertheless, mediation analyses revealed that a significant proportion of the association is mediated by elevation in plasma cholesterol level (indirect effect β = 0.21 (95% CI = 0.07–0.38). Collectively, our study shows that sLDL-R is induced by a pro-inflammatory cytokine TNF-α via membrane shedding. Furthermore, an increase in sLDL-R could inhibit hepatic clearance of LDL-C increasing its half-life in the circulation and contributing to the pathogenesis of MI.Key messages

TNF-α causes shedding of hepatocytic LDL-R through induction of ADAM-17 and MMP-14.

sLDL-R binds strongly to LDL-C and inhibits its uptake by hepatocytic cells.

Plasma sLDL-R is positively correlated with TNF-α and cholesterol.

Plasma sLDL-R is an independent predictor of myocardial infarction (MI).

Plasma cholesterol mediates the association between sLDL-R and MI.

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