Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.

Lithium-sulfur (Li-S) batteries, based on the redox reaction between elemental sulfur and lithium metal, have attracted great interest because of their inherently high theoretical energy density. However, the severe polysulfide shuttle effect and sluggish reaction kinetics in sulfur cathodes, as well as dendrite growth in lithium-metal anodes are great obstacles for their practical application. Herein, a two-in-one approach with superhierarchical cobalt-embedded nitrogen-doped porous carbon nanosheets (Co/N-PCNSs) as stable hosts for both elemental sulfur and metallic lithium to improve their performance simultaneously is reported. Experimental and theoretical results reveal that stable Co nanoparticles, elaborately encapsulated by N-doped graphitic carbon, can work synergistically with N heteroatoms to reserve the soluble polysulfides and promote the redox reaction kinetics of sulfur cathodes. Moreover, the high-surface-area pore structure and the Co-enhanced lithiophilic N heteroatoms in Co/N-PCNSs can regulate metallic lithium plating and successfully suppress lithium dendrite growth in the anodes. As a result, a full lithium-sulfur cell constructed with Co/N-PCNSs as two-in-one hosts demonstrates excellent capacity retention with stable Coulombic efficiency.

No abstract

No abstract

Nintedanib targets core features of SSc in Fra2-transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung disease.