N6-(2-hydroxyethyl)-Adenosine Induces Apoptosis via ER Stress and Autophagy of Gastric Carcinoma Cells In Vitro and In Vivo

Xie, Hongqing; Li, Xiaotong; Yang, Weiwei; Yu, Liping; Jiang, Xuesheng; Chen, Yajie; Shen, Zhangfei; Li, Conghui; Gu, Meier; Shi, Liangen

doi:10.3390/ijms21165815

Cited by 10 publications

(7 citation statements)

References 47 publications

(56 reference statements)

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“…NSAIDs have been shown to induce reactive oxygen species (ROS) in different cell types including gastric cancer cells [27,38]. DCF stimulated huge production of ROS, inducing oxidative stress and morphological changes in renal tissues consistent with renal damage [1].…”

Section: Discussionmentioning

confidence: 99%

“…HEA is beneficial to renal interstitial fibrosis by preventing inflammation via TGF-β1/Smad and NF-κB signaling pathway [26]. Controversially, HEA induced ROS production and mitochondrial membrane potential depolarization [27], triggering caspase-dependent apoptosis [27], while adenosine possessed anti-inflammatory and antifibrotic bioactivities [28].…”

Section: Introductionmentioning

confidence: 99%

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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

Chyau

Peng

et al. 2021

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Chyau

Peng

et al. 2021

IJMS

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“…The molecular weight of HEA is 311.29, its molecular formula is C 12 H 17 N 5 O 5 , and its structural formula is shown in Figure 1E. It possesses many activities, such as protection against ultraviolet radiation, blood-thinning, anti-inflammatory (Li I.-C. et al, 2019;Wang X. et al, 2019;Chyau et al, 2021), analgesic, and antihypertensive activities (Li I.-C. et al, 2019), protective effects against diabetic kidney disease (Wang X. et al, 2019), as well as inhibiting the proliferation of tumor cells, protecting the brain (Zhang et al, 2016), and inducing apoptosis of gastric carcinoma cells (Xie et al, 2020). HEA is generally regarded as being at the intersection of medical care, cosmetics and biological defense.…”

Section: The Biosynthesis Of Cordyceps Polysaccharidesmentioning

confidence: 99%

New Insights Into the Biosynthesis of Typical Bioactive Components in the Traditional Chinese Medicinal Fungus Cordyceps militaris

Huang

et al. 2021

Front. Bioeng. Biotechnol.

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Cordyceps militaris, a traditional medicinal ingredient with a long history of application in China, is regarded as a high-value fungus due to its production of various bioactive ingredients with a wide range of pharmacological effects in clinical treatment. Several typical bioactive ingredients, such as cordycepin, D-mannitol, cordyceps polysaccharides, and N6-(2-hydroxyethyl)-adenosine (HEA), have received increasing attention due to their antitumor, antioxidant, antidiabetic, radioprotective, antiviral and immunomodulatory activities. Here, we systematically sorted out the latest research progress on the chemical characteristics, biosynthetic gene clusters and pathways of these four typical bioactive ingredients. This summary will lay a foundation for obtaining low-cost and high-quality bioactive ingredients in large amounts using microbial cell factories in the future.

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“…N 6 -(2-hydroxyethyl) adenosine (HEA) is an important bioactive substance with cancer cell inhibition ( Xie et al, 2020 ; Chen et al, 2021 ; Fu et al, 2023 ), kidney protection ( Wang et al, 2019 ; Deng et al, 2020 ), and anti-inflammatory effects ( Lu et al, 2015 ). Therefore, it has attracted much attention for its potential application in the medical industry, especially in the field of cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Exploiting the roles of nitrogen sources for HEA increment in Cordyceps cicadae

Zhu,

Ruan,

et al. 2024

Front. Microbiol.

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Cordyceps cicadae, as a new food ingredient, is a valuable edible and medicinal fungi. However, its resources are severely depleted due to environmental limitations and excessive harvesting practices. N6-(2-hydroxyethyl) adenosine (HEA), as an important product of Cordyceps cicadae, has the potential to be used in medical industry due to its diverse disease curing potential. However, the disclosure of HEA synthesis still severely limited its application until now. In this study, the kinetic curves for adenosine and HEA under shaker fermentation were explored. The kinetics of HEA and adenosine production exhibited a competitive pattern, implicating a possibility of sharing a same step during their synthesis. Due to HEA as a derivative of nitrogen metabolism, the effect of different nitrogen sources (peptone, yeast extract, ammonium sulfate, diammonium oxalate monohydrate, ammonium citrate dibasic, and ammonium citrate tribasic) on HEA production in Cordyceps cicadae strain AH 10-4 had been explored under different incubation conditions (shaker fermentation, stationary fermentation, and submerged fermentation). Our results indicated that the complex organic nitrogen sources were found to improve the accumulation of HEA content under shaker fermentation. In contrast, the optimal nitrogen source for the accumulation of HEA under stationary fermentation and submerged fermentation was ammonium citrate tribasic. But submerged fermentation obviously shortened the incubation time and had a comparable capacity of HEA accumulation by 2.578 mg/g compared with stationary fermentation of 2.535 mg/g, implicating a possibility of scaled-up production of HEA in industry by submerged fermentation. Based on the dramatic HEA production by ammonium sulfate as nitrogen resources between stationary and shaker fermentations, alanine, aspartate and glutamate as well as arginine metabolic pathway were related to the production of HEA by comparative transcriptome. Further investigation indicated that glutamic acid, which is an analog of Asp, showed an optimum production of HEA in comparison with other amino acids.

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N6-(2-hydroxyethyl)-Adenosine Induces Apoptosis via ER Stress and Autophagy of Gastric Carcinoma Cells In Vitro and In Vivo

Cited by 10 publications

References 47 publications

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

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

New Insights Into the Biosynthesis of Typical Bioactive Components in the Traditional Chinese Medicinal Fungus Cordyceps militaris

Exploiting the roles of nitrogen sources for HEA increment in Cordyceps cicadae

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