Potential protection effect of er homeostasis of n6-(2-hydroxyethyl)adenosine isolated from cordyceps cicadae in nonsteroidal anti-inflammatory drug-stimulated human proximal tubular cells

Charng Cherng Chyau, Huei Lin Wu, Chiung Chi Peng, Shiau Huei Huang, Chin Chu Chen, Cheng Hsu Chen, Robert Y. Peng

Research output: Contribution to journalArticlepeer-review


Nonsteroidal anti-inflammatory drugs (NSAIDs) belong to a class of universally and commonly used anti-inflammatory analgesics worldwide. A diversity of drawbacks of NSAIDs have been reported including cellular oxidative stress, which in turn triggers the accumulation of unfolded proteins, enhancing endoplasmic reticulum stress, and finally resulting in renal cell damage. Cordyceps cicadae (CC) has been used as a traditional medicine for improving renal function via its anti-inflammatory effects. N6-(2-hydroxyethyl)adenosine (HEA), a physiologically active compound, has been reported from CC mycelia (CCM) with anti-inflammatory effects. We hypothesize that HEA could protect human proximal tubular cells (HK−2) from NSAID-mediated effects on differential gene expression at the mRNA and protein levels. To verify this, we first isolated HEA from CCM using Sephadex® LH−20 column chromatography. The MTT assay revealed HEA to be nontoxic up to 100 µM toward HK−2 cells. The HK−2 cells were pretreated with HEA (10–20 µM) and then insulted with the NSAIDs diclofenac (DCF, 200 µM) and meloxicam (MXC, 400 µM) for 24 h. HEA (20 µM) effectively prevented ER stress by attenuating ROS production (p < 0.001) and gene expression of ATF−6, PERK, IRE1α, CDCFHOP, IL1β, and NFκB within 24 h. Moreover, HEA reversed the increase of GRP78 and CHOP protein expression levels induced by DCF and MXC, and restored the ER homeostasis. These results demonstrated that HEA treatments effectively protect against DCF-and MXC-induced ER stress damage in human proximal tubular cells through regulation of the GRP78/ATF6/PERK/IRE1α/CHOP pathway.

Original languageEnglish
Article number1577
Pages (from-to)1-17
Number of pages17
JournalInternational journal of molecular sciences
Issue number4
Publication statusPublished - Feb 2021


  • Diclofenac
  • Endoplasmic reticulum (ER), oxidative stress
  • Meloxicam
  • Renal HK−2 cells

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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