Last update 01 Nov 2024

TfR1 x TRIM63

Last update 01 Nov 2024

Basic Info

Related Targets

TfR1TRIM63

Drugs associated with TfR1 x TRIM63

AOC-MuRF1 (Avidity Biosciences)

Target

TRIM63 x TfR1

Mechanism

TRIM63 inhibitors [+1]

Active Org.

Avidity Biosciences, Inc.

Originator Org.

Avidity Biosciences, Inc.

Active Indication

Muscular Atrophy

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TfR1 x TRIM63

100 Translational Medicine associated with TfR1 x TRIM63

0 Patents (Medical) associated with TfR1 x TRIM63

Literatures (Medical) associated with TfR1 x TRIM63

01 Jul 2024·Pulmonary Circulation

Immature reticulocyte fraction: A novel biomarker of hemodynamic severity in pulmonary arterial hypertension

Article

Author: Channick, Richard N. ; Wilkinson, Jared D. ; Liang, Lloyd L. ; Saggar, Rajan ; Brownstein, Adam J. ; Kim, Airie

AbstractVarious erythropoietic abnormalities are highly prevalent among patients with pulmonary arterial hypertension (PAH) and associated with worse disease severity. Given the poorly understood yet important roles of dysregulated erythropoiesis and iron metabolism in PAH, we sought to further characterize the hematologic and iron profiles in PAH and their relationship to PAH severity. We recruited 67 patients with PAH and 13 healthy controls. Hemodynamics attained within 1 year of blood sample collection were available for 36 patients. Multiple hematologic, iron, and inflammatory parameters were evaluated for their association with hemodynamics. The subset with hemodynamic data consisted of 29 females (81%). The most common etiologies were idiopathic PAH (47%) and connective tissue disease‐related PAH (33%). 19 (53%) had functional class 3 or 4 symptomatology, and 12 (33%) were on triple pulmonary vasodilator therapy. Immature reticulocyte fraction (IRF) had significant positive correlations with mean pulmonary artery (PA) pressure (mPAP) (0.59, p < 0.001), pulmonary vascular resistance (0.52, p = 0.001), and right atrial pressure (0.46, p = 0.005), and significant negative correlations with cardiac index (−0.43, p = 0.009), PA compliance (PAC) (−0.60, p < 0.001), stroke volume index (SVI) (−0.57, p < 0.001), and mixed venous oxygen saturation (−0.51, p = 0.003). IRF correlated with markers of iron deficiency (ID) and erythropoiesis. On multivariable linear regression, IRF was associated with elevated mPAP and reduced SVI and PAC independent of EPO levels, transferrin saturation, and soluble transferrin receptor levels. We identified IRF as a novel and potent biomarker of PAH hemodynamic severity, possibly related to its associations with erythropoiesis, ID, and tissue hypoxia.

01 Apr 2022·Journal of Cachexia, Sarcopenia and MuscleQ1 · MEDICINE

Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload

Q1 · MEDICINE

ArticleOA

Author: Martin, Brice ; Noirez, Philippe ; Leroyer, Patricia ; Rebillard, Amélie ; Loréal, Olivier ; Guggenbuhl, Pascal ; Derbré, Frédéric ; Nay, Kévin ; Dufresne, Suzanne ; Martin, David ; Robin, François ; Orfila, Luz ; Ropert, Martine

AbstractBackgroundIron excess has been proposed as an essential factor in skeletal muscle wasting. Studies have reported correlations between muscle iron accumulation and atrophy, either through ageing or by using experimental models of secondary iron overload. However, iron treatments performed in most of these studies induced an extra‐pathophysiological iron overload, more representative of intoxication or poisoning. The main objective of this study was to determine the impact of iron excess closer to pathophysiological conditions on structural and metabolic adaptations (i) in differentiated myotubes and (ii) in skeletal muscle exhibiting oxidative (i.e. the soleus) or glycolytic (i.e. the gastrocnemius) metabolic phenotypes.MethodsThe impact of iron excess was assessed in both in vitro and in vivo models. Murine differentiated myotubes were exposed to ferric ammonium citrate (FAC) (i.e. 10 and 50 μM) for the in vitro component. The in vivo model was achieved by a single iron dextran subcutaneous injection (1 g/kg) in mice. Four months after the injection, soleus and gastrocnemius muscles were harvested for analysis.ResultsIn vitro, iron exposure caused dose‐dependent increases of iron storage protein ferritin (P < 0.01) and dose‐dependent decreases of mRNA TfR1 levels (P < 0.001), which support cellular adaptations to iron excess. Extra‐physiological iron treatment (50 μM FAC) promoted myotube atrophy (P = 0.018), whereas myotube size remained unchanged under pathophysiological treatment (10 μM FAC). FAC treatments, whatever the doses tested, did not affect the expression of proteolytic markers (i.e. NF‐κB, MurF1, and ubiquitinated proteins). In vivo, basal iron content and mRNA TfR1 levels were significantly higher in the soleus compared with the gastrocnemius (+130% and +127%; P < 0.001, respectively), supporting higher iron needs in oxidative skeletal muscle. Iron supplementation induced muscle iron accumulation in the soleus and gastrocnemius muscles (+79%, P < 0.001 and +34%, P = 0.002, respectively), but ferritin protein expression only increased in the gastrocnemius (+36%, P = 0.06). Despite iron accumulation, muscle weight, fibre diameter, and myosin heavy chain distribution remained unchanged in either skeletal muscle.ConclusionsTogether, these data support that under pathophysiological conditions, skeletal muscle can protect itself from the related deleterious effects of excess iron.

01 Jan 1995·The AnalystQ3 · CHEMISTRY

Iron species in iron homeostasis and toxicity

Q3 · CHEMISTRY

Article

Author: Ward, Roberta J. ; Crichton, Robert R.

Iron homeostasis in prokaryotic cells appears to be regulated essentially at the level of the genome by the Fur protein. When iron is in short supply the uptake and assimilation pathways are de-repressed and siderophores are synthesized together with the outer, inner (plasma) membrane, periplasmic and cytosolic components necessary for the uptake of ferri-siderophores. When iron is no longer limiting the Fe2+ the Fur complex acts as a transcriptional repressor, and shuts down the synthesis of all the components of iron assimilation. In euykarotic cells, iron homeostasis is dependent upon the iron regulatory factor (IRF), a cytoplasmic protein that can bind to specific stem loops, iron responsive elements (IREs) on the messenger ribonucleic acid molecules (mRNAs) of proteins involved in iron storage (ferritin), utilization (erythroid delta-aminolaevulinate synthase, AIS), and uptake (transferrin receptor). During ion depletion the IRE is in a high affinity form, which, by binding strongly to the corresponding mRNAs, down regulates iron storage and utilization, while up-regulating transferrin receptor expression. When the cells are iron replete, IRF binding to IREs is weak, allowing transferrin receptor mRNA to be degraded. In this paper it is shown that in physiological conditions of iron overload and depletion, IRF functions in vivo in the manner already described for in vitro models. The nature and the speciation of the various iron species within the low molecular weight pool of eukaryotic cells remains unclear.

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