Wei Zhou1, Joonseok Oh2, Lee Wonhwa3, Soyoung Kwak4, Wei Li5, Amar G Chittiboyina6, Daneel Ferreira2, Mark T Hamann2, Seung Ho Lee7, Jong-Sup Bae8, MinKyun Na9. 1. College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Republic of Korea; College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea. 2. Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. 3. College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701 and 700-422, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 702-701 and 700-422, Republic of Korea. 4. College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701 and 700-422, Republic of Korea. 5. College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea. 6. National Center for Natural Products Research, The University of Mississippi, University, MS 38677, USA. 7. College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Republic of Korea. 8. College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701 and 700-422, Republic of Korea. Electronic address: baejs@knu.ac.kr. 9. College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address: mkna@cnu.ac.kr.
Abstract
BACKGROUND: Endangered plant species are a vital resource for exploring novel drug prototypes. A Korean endangered plant Rhododendron brachycarpum G. Don is a broad-leaved shrub native to northern Korea and central Japan. The high mobility group box 1 protein (HMGB1) could be a specific target for the discovery of novel antiseptic agents. METHODS: Gauge-invariant atomic orbital (GIAO) NMR chemical shift calculations were applied for investigation of stereochemical details with accuracy improved by application of DP4 analysis. In vitro antiseptic mechanisms were investigated utilizing immunofluorescence staining, ELISA and cell-cell adhesion assay. Cecal ligation and puncture (CLP) operation was employed to evaluate in vivo potential alleviating severe sepsis and septic shock. RESULTS: The first bicyclic megastigmane glucoside rhododendroside A (1) along with known megastigmane glucosides (2-5) were isolated from the leaves of R. brachycarpum. The structure of 1 was established by NMR analysis as well as comparison of the experimental chemical shifts with those of computed values employing DP4 application. In the CLP operation model that simulates severe sepsis, rhododendroside A (1) improved the survival rate up to 60%. CONCLUSIONS: Our results exhibit that R. brachycarpum may produce a unique scaffold that is developed into a drug lead mitigating HMGB1-induced vascular pro-inflammatory stimuli and thus alleviating severe sepsis and related manifestations. GENERAL SIGNIFICANCE: Discovery of new drug leads would warrant conservation efforts of endangered species.
BACKGROUND: Endangered plant species are a vital resource for exploring novel drug prototypes. A Korean endangered plant Rhododendron brachycarpum G. Don is a broad-leaved shrub native to northern Korea and central Japan. The high mobility group box 1 protein (HMGB1) could be a specific target for the discovery of novel antiseptic agents. METHODS: Gauge-invariant atomic orbital (GIAO) NMR chemical shift calculations were applied for investigation of stereochemical details with accuracy improved by application of DP4 analysis. In vitro antiseptic mechanisms were investigated utilizing immunofluorescence staining, ELISA and cell-cell adhesion assay. Cecal ligation and puncture (CLP) operation was employed to evaluate in vivo potential alleviating severe sepsis and septic shock. RESULTS: The first bicyclic megastigmane glucosiderhododendroside A (1) along with known megastigmane glucosides (2-5) were isolated from the leaves of R. brachycarpum. The structure of 1 was established by NMR analysis as well as comparison of the experimental chemical shifts with those of computed values employing DP4 application. In the CLP operation model that simulates severe sepsis, rhododendroside A (1) improved the survival rate up to 60%. CONCLUSIONS: Our results exhibit that R. brachycarpum may produce a unique scaffold that is developed into a drug lead mitigating HMGB1-induced vascular pro-inflammatory stimuli and thus alleviating severe sepsis and related manifestations. GENERAL SIGNIFICANCE: Discovery of new drug leads would warrant conservation efforts of endangered species.
Keywords:
Endangered species; High mobility group box 1 protein; Nuclear magnetic resonance chemical shift calculations; Rhododendron brachycarpum; Sepsis
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