Blockade of Smad signaling by 3′-deoxyadenosine: a mechanism for its anti-fibrotic potential

Abstract

Cordyceps militaris has been used in Eastern countries for the treatment of various diseases including chronic kidney diseases. However, there are no reports that identified its active entities and molecular mechanisms underlying its therapeutic effectiveness. 3 0 -Deoxyadenosine is a major nucleoside derivative isolated from C. militaris. Some reports suggested that both C. militaris and 3 0 -deoxyadenosine have anti-inflammatory and anti-fibrotic effects. In the present report, we investigated whether and how 3 0 -deoxyadenosine interferes with fibrogenic processes in the kidney. For this purpose, we examined effects of 3 0 -deoxyadenosine on the expression of collagens triggered by transforming growth factor-b (TGF-b1) and bone morphogenetic protein-4 (BMP-4), especially focusing on the regulation of Smad signaling in vitro and in vivo. We found that 3 0 -deoxyadenosine suppressed expression of collagens induced by TGF-b1 and BMP-4 dose dependently. This suppression occurred at the transcriptional level and was correlated with blunted activation of the CAGA box and the BMP-responsive element. The suppressive effect on the TGF-b/BMP signaling was mediated mainly by adenosine transporter and partially by the A3 adenosine receptor, but not A1/A2 adenosine receptors. 3 0 -Deoxyadenosine reduced levels of both phosphorylated and total Smad proteins (Smad1, 2 and 3) dose dependently. It was mainly ascribed to transcriptional suppression, but not to enhanced protein degradation and eIF2a-mediated translational suppression. Consistent with the in vitro results, in vivo administration with 3 0 -deoxyadenosine reduced the levels of phosphorylated and total Smad proteins, as well as the levels of Smad mRNAs, in the kidney subjected to unilateral ureteral obstruction. It was associated with blunted induction of type I collagen and a-smooth muscle actin, a decrease in the number of interstitial myofibroblasts and reduced fibrotic area. These results suggest that 3 0 -deoxyadenosine interferes with the TGF-b and BMP signaling via downregulation of Smads, which may underlie the anti-fibrotic effect of this agent. 3 0 -Deoxyadenosine may be useful for therapeutic intervention in various TGF-b-related fibrotic disorders.

Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions

“…The other functional component, cordycepin, can reduce TGF-β1, Smad2/3, α-SMA, and COL1A1 protein levels. Previous study reported that cordycepin can interfere with the TGF-β1 signaling pathway by inhibiting Smad protein levels and phosphorylation, thereby preventing the activation of HSCs [13]. Although DOW cannot reduce TAA-induced TGF-β1, Smad2/3, and p-Smad2/3 protein levels, it can considerably reduce α-SMA and COL1A1 protein levels.…”

“…Previous studies have shown that CM-fermented cordycepin has antioxidative and anti-inflammatory effects [11,12]. Cordycepin, a CM metabolite, can inhibit Smad phosphorylation and phosphate levels, thereby interfering with TGF-β1 signaling and inhibiting the activation of HSCs [13]. The described studies have indicated that using DOW as the culturing water can help increase the active components of CM and its liver protection functions.…”

Use ofOphiocordyceps sinensis(syn.Cordyceps sinensis) combined with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) versus ACEI/ARB alone in the treatment of diabetic kidney disease: a meta-analysis

“…101 Cordycepin (3 0 -deoxyadenosine) interferes with the TGF-b1 and bone morphogenetic protein signaling through downregulation of Smads, which might be the underlying anti-fibrotic effect of this agent. 102 Moreover, cordycepin markedly blocks TGFb1-mediated activation of renal interstitial fibroblast cells through up regulating anti-fibrotic hepatocyte growth factor (HGF) at both the gene and protein levels. 103 In addition, one study proved that bailing capsule can reduce the expression of TGF-b1 and CTGF in rats with DKD, which can reduce renal tissue injury.…”

Therapeutic Potential and Biological Applications of Cordycepin and Metabolic Mechanisms in Cordycepin-Producing Fungi

“…The inhibition of MMP is a promising strategy in skin cancer and photoaging therapy [95]. Moreover, COR represses lung fibrosis by increasing E-cadherin expression and decreasing vimentin levels [96] and inhibits kidney fibrosis by inactivating targets (CAGA box, BRE and Smad1/2/3) and stimulating eIF2α [97]. In addition, COR plays a significant role in suppressing atopic dermatitis [69].…”