Target Identification and Validation of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate, an Anti-Inflammatory Natural Product

Li, L.; Zeng, H-W.; Liu, F.; Zhang, J-G.; Yue, R-C.; Lu, W-Q.; Yuan, Xin; Dai, W-X.; Hu, Yuan; Sun, Q-Y.; Huang, Jin; H, Li; Ys, Li; Shan, Lei; Zhang, W-D.

doi:10.1177/1721727x1201000306

Cited by 9 publications

(7 citation statements)

References 32 publications

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“…granditlora (Wehrhahn) Grierson (27, 41). HOEC was revealed to act as an anti-inflammatory agent targeting 5-LOX, which confirmed a key role of 5-LOX in the pathogenesis of inflammation, especially rheumatoid arthritis (26). HOEC may be a pro-drug of caffeic acid because of the chemical relevance and bio-functional similarity.…”

Section: Discussionmentioning

confidence: 62%

“…Although the plants of the Incarvillea genus are widely grown for ornamental purposes, especially in China, Incarvillea delavyi , one of the Incarvillea spices, recently received attention for its anti-nociceptive effects (25). In particular, HOEC isolated from Incarvillea mairei , is reported to exhibit anti-inflammatory effects on inflammation-induced mice (26). However, the potential anticancer effects and molecular targets of the plant extract or its lead compound have not yet been studied.…”

Section: Introductionmentioning

confidence: 99%

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(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38

Lim

Lee

Shin

et al. 2014

Cancer Prevention Research

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For decades, skin cancer incidence has increased, mainly due to oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of HOEC, [(+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate], isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 C14l cells without toxicity. PI3-K, ERK1/2 and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3-K, ERK1/2 and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP-1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is as a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38

Lim

Lee

Shin

et al. 2014

Cancer Prevention Research

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“…Targeting the 5-LOX as a vital enzyme in arachidonic acid cascade by HOEC was validated by this biosensor-based affinity detection. In this sensor, mass loading changes due to biomolecular interaction processes result in phase changes of the SAW on the surface of the sensor chip [ 111 ].…”

Section: Classification Of Biosensorsmentioning

confidence: 99%

Emerging biosensors in detection of natural products

Piroozmand

Mohammadipanah

Faridbod

2020

Synthetic and Systems Biotechnology

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Natural products (NPs) are a valuable source in the food, pharmaceutical, agricultural, environmental, and many other industrial sectors. Their beneficial properties along with their potential toxicities make the detection, determination or quantification of NPs essential for their application. The advanced instrumental methods require time-consuming sample preparation and analysis. In contrast, biosensors allow rapid detection of NPs, especially in complex media, and are the preferred choice of detection when speed and high throughput are intended. Here, we review diverse biosensors reported for the detection of NPs. The emerging approaches for improving the efficiency of biosensors, such as microfluidics, nanotechnology, and magnetic beads, are also discussed. The simultaneous use of two detection techniques is suggested as a robust strategy for precise detection of a specific NP with structural complexity in complicated matrices. The parallel detection of a variety of NPs structures or biological activities in a mixture of extract in a single detection phase is among the anticipated future advancements in this field which can be achieved using multisystem biosensors applying multiple flow cells, sensing elements, and detection mechanisms on miniaturized folded chips.

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“…The plants of the Incarvillea genus have long been used as folk medicines for the treatment of inflammatory related diseases in China. In the pharmaceutical activity research of HOEC, 5-LOX and 15-LOX were found to be inhibited in molecular level [26]. The half inhibitory concentration (IC 50 ) of HOEC on 5-LOX and 15-LOX activity are 34.6AE5.7 μM and 7.8AE0.8 μM, respectively.…”

Section: Introductionmentioning

confidence: 99%

Pharmacodynamics simulation of HOEC by a computational model of arachidonic acid metabolic network

Yang

Wang

et al. 2019

Quant. Biol.

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Background: Arachidonic acid (AA) metabolic network is activated in the most inflammatory related diseases, and small-molecular drugs targeting AA network are increasingly available. However, side effects of above mentioned drugs have always been the biggest obstacle. (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a natural product acted as an inhibitor of 5-lipoxygenase (5-LOX) and 15-LOX in vitro, exhibited weaker therapeutic effect in high dose than that in low dose to collagen induced arthritis (CIA) rats. In this study, we tried to elucidate the potential regulatory mechanism by using quantitative pharmacology. Methods: First, we generated an experimental data set by monitoring the dynamics of AA metabolites' concentration in A23187 stimulated and different doses of HOEC co-incubated RAW264.7. Then we constructed a dynamic model of A23187-stimulated AA metabolic model to evaluate how a model-based simulation of AA metabolic data assists to find the most suitable treatment dose by predicting the pharmacodynamics of HOEC. Results: Compared to the experimental data, the model could simulate the inhibitory effect of HOEC on 5-LOX and 15-LOX, and reproduced the increase of the metabolic flux in the cyclooxygenase (COX) pathway. However, a concomitant, early-stage of stimulation-related decrease of prostaglandins (PGs) production in HOEC incubated RAW264.7 cells was not simulated in the model. Conclusion: Using the model, we predict that higher dose of HOEC disrupts the flux balance in COX and LOX of the AA network, and increased COX flux can interfere the curative effects of LOX inhibitor on resolution of inflammation which is crucial for the efficient and safe drug design.Author summary: Arachidonic acid network is a complex system with many pathways to which non-steroidal antiinflammatroy drugs (NSAIDs) target. However, side effects have always been the disadvantage of these medicines. Using a natural LOX inhibitor HOEC as probe, we established a computational model to simulate the flux regulation of arachidonic acid network after HOEC treatment. Meanwhile, the experimental data of metabolites of different pathways were used to validate and optimize the model. Our study provides an alternitive in NSAIDs design. In addition, it can also guide clinical medication to avoid side effects. † These authors contributed equally to this work. 30

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Target Identification and Validation of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate, an Anti-Inflammatory Natural Product

Cited by 9 publications

References 32 publications

(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38

(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38

Emerging biosensors in detection of natural products

Pharmacodynamics simulation of HOEC by a computational model of arachidonic acid metabolic network

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