S-Propargyl-Cysteine, a Novel Hydrogen Sulfide Donor, Inhibits Inflammatory Hepcidin and Relieves Anemia of Inflammation by Inhibiting IL-6/STAT3 Pathway

Abstract

Anemia of inflammation (AI) is clinically prevalent and greatly threatens public health. Traditional remedies have raised controversy during clinical practice, calling for alternative therapies. We have recently found that hydrogen sulfide (H2S) inhibits inflammatory hepcidin, the critical mediator of AI. However, due to the chemical property of H2S, there remains an urgent need for a stable H2S donor in AI treatment. Here we reported that S-propargyl-cysteine (SPRC), a novel water-soluble H2S donor, suppressed hepatic hepcidin and corrected hypoferremia induced by lipopolysaccharide. The effects of SPRC were reversed by inhibition of cystathionine γ-lyase, one of the major endogenous H2S synthases. Moreover, SPRC reduced serum hepcidin, improved transferrin saturation, and maintained erythrocyte membrane integrity in a chronic mouse AI model. Consistently, splenomegaly was ameliorated and splenic iron accumulation relieved. Mechanism study indicated that serum IL-6 content and hepatic Il-6 mRNA were decreased by SPRC, in parallel with reduced hepatic JAK2/STAT3 activation. On the whole, our data reveal the inhibition of inflammatory hepcidin by SPRC, and suggest SPRC as a potential remedy against AI.

Iron status in the elderly: A review of recent evidence

“…The authors therefore concluded that ferritin, not inflammatory biomarkers, is responsible for controlling hepcidin levels in their group of IBD patients. These findings are potentially opening the possibility of using hepcidin suppressant (Eijk et al, 2014;M. Wang et al, 2016;Sebastiani, Wilkinson and Pantopoulos, 2016) drugs in order to correct IDA in patients with IBD.…”

“…For example in patients with ACD oral iron supplementation will be ineffective. Novel therapies, including hepcidin inhibitors (Eijk et al, 2014;M. Wang et al, 2016;Sebastiani et al, 2016) may prove to be particularly useful in cases of AI.…”

“…Finally, emerging therapies to combat anemia, such as erythropoiesis stimulating agents require further considerations due to potential side effects. Therapies for AI (currently in pre-clinical stages) may include hepcidin inhibitors (Eijk et al, 2014;M. Wang et al, 2016;Sebastiani, Wilkinson and Pantopoulos, 2016) and other agents modulating ferroportin levels (Fung and Nemeth, 2013).…”

Recent Development of Hydrogen Sulfide Releasing/Stimulating Reagents and Their Potential Applications in Cancer and Glycometabolic Disorders

“…Recently, it was documented that SPRC could prevent doxorubicin-induced cardiotoxicity ( Wu et al, 2016a ), which is similar to the effects of NaHS used in previous studies ( Wang et al, 2012 ). In addition, SPRC exhibited anti-inflammation ( Wang et al, 2016 ), anti-apoptosis and anti-oxidation in high glucose treated cardiomyocytes ( Yang et al, 2015 ).…”

Hydrogen Sulfide (H2S)-Releasing Compounds: Therapeutic Potential in Cardiovascular Diseases

“…L -cysteine is a substrate for the endogenous production of H 2 S ( Salvi et al, 2016b ), mitochondria-targeted anethole dithiolethione (AP39), and (AP123) ( Gerő et al, 2016 ). Please see Table 1 for more information on common H 2 S donors as well as CBS and CSE inhibitors ( Lertratanangkoon et al, 1999 ; Lima et al, 2006 ; Szabó, 2007 ; Li et al, 2008 ; Kulkarni et al, 2009 ; Sun et al, 2009 ; Tyagi et al, 2009 ; Liu et al, 2010 , 2011 ; Wang et al, 2010 , 2016 ; Kodela et al, 2012 ; Predmore et al, 2012 ; Guo et al, 2013 ; Kondo et al, 2013 ; Lisjak et al, 2013 ; Luo et al, 2013 ; Martelli et al, 2013 , 2014 ; Barr et al, 2015 ; Fonseca et al, 2015 ; Iciek et al, 2015 , 2016 ; Liang D. et al, 2015 ; Polhemus et al, 2015 ; Tsai et al, 2015 ; Vannini et al, 2015 ; Chao et al, 2016 ; Qian et al, 2016 ; Salvi et al, 2016a ; Tain et al, 2016 ; Testai et al, 2016 ; Wu et al, 2016 ; Ali et al, 2018 ; Cao et al, 2018 ; Du et al, 2018 ; Ezeriņa et al, 2018 ; Liang et al, 2018 ; Lin S. et al, 2018 ; Ning et al, 2018 ; Powell et al, 2018 ; Qiu et al, 2018 ; Shimizu et al, 2018 ; Sone et al, 2018 ; Zhao et al, 2018 ; Zhou et al, 2018 ).…”