(+)‐Isobicyclogermacrenal and spathulenol from Aristolochia yunnanensis alleviate cardiac fibrosis by inhibiting transforming growth factor β/small mother against decapentaplegic signaling pathway

Abstract

Cardiac fibrosis contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. Antifibrotic therapies are likely to be a crucial strategy in curbing many fibrosis‐related cardiac diseases. In our previous study, an ethyl acetate extract of a traditional Chinese medicine Aristolochia yunnanensis Franch. was found to have a therapeutic effect on myocardial fibrosis in vitro and in vivo. However, the exact chemicals and their mechanisms responsible for the activity of the crude extract have not been illustrated yet. In the current study, 10 sesquiterpenoids (1–10) were isolated from the active extract, and their antifibrotic effects were systematically evaluated in transforming growth factor β 1 (TGFβ1)‐stimulated cardiac fibroblasts and NIH3T3 fibrosis models. (+)‐Isobicyclogermacrenal (1) and spathulenol (2) were identified as the main active components, being more potent than the well‐known natural antifibrotic agent oxymatrine. Compounds 1 and 2 could inhibit the TGFβ1‐induced cardiac fibroblasts proliferation and suppress the expression of the fibrosis biomarkers fibronectin and α‐smooth muscle actin via down‐regulation of their mRNA levels. The mechanism study revealed that 1 and 2 could inhibit the phosphorylation of TGFβ type I receptor, leading to the decrease of the phosphorylation levels of downstream Smad2/3, then consequently blocking the nuclear translocation of Smad2/3 in the TGFβ/Smad signaling pathway. These findings suggest that 1 and 2 may serve as promising natural leads for the development of anticardiac fibrosis drugs.

Next Chapter in the Legend of Silphion: Preliminary Morphological, Chemical, Biological and Pharmacological Evaluations, Initial Conservation Studies, and Reassessment of the Regional Extinction Event

“…Spathulenol 1Immunomodulator [32], anti-nociceptive [64], antimicrobial [65], alleviates cardiac fibrosis [66], antioxidant [33], antiproliferative, antimycobacterial [33], anti-inflammatory [33,67], antitumor [67].…”

Medicinal Plants with Anti-Leukemic Effects: A Review

“…Complications of intensive chemotherapeutic treatment for a patient suffering from leukemia include risk of death from cardiac and neurological complications [ 4 ], oral mucositis [ 5 ], gastrointestinal and liver toxicities [ 6 ], an infectious complication for ALL patients [ 7 ] and reduced bone mineral density at a high rate for children with ALL [ 8 , 9 ]. In spite of causing several side effects, the overuse of these drugs leads to chemotherapeutic drug resistance in leukemia cells [ 10 ]. Thus, the production of new therapeutic drugs having higher potency and lower toxicity is important to expanding the overall life expectancy.…”

Germacrane Sesquiterpenoids as a New Type of Anticardiac Fibrosis Agent Targeting Transforming Growth Factor β Type I Receptor

“…Sesquiterpenoids from the TCM A. yunnanensis were previously reported to possess certain anticardiac fibrosis effects on TGFβ1-stimulated cardiac fibroblasts . However, the potential target, the SARs, and the in vivo efficacy of these compounds are still unclear.…”

“…Subsequent chemical investigation led to the isolation of a group of sesquiterpenoids . These sesquiterpenoids exhibited certain anticardiac fibrosis effects on TGFβ1-stimulated cardiac fibroblasts, and the mechanistic study revealed their inhibition on the TGFβ/Smad signaling pathway . However, the potential target, the structure–activity relationships (SARs), and the in vivo efficacy of these compounds are still unclear.…”