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Altered Serum Metabolite Profiling and Relevant Pathways Analysis in Rats Stimulated by Honeybee venom: A New Insight into Allergy to Honeybee Venom Yazhou Zhao, Jianmei Zhang, Yanping Chen, Zhiguo Li, Hongyi Nie, Wenjun Peng, and Songkun Su J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b04160 • Publication Date (Web): 11 Jan 2018 Downloaded from http://pubs.acs.org on January 11, 2018
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Journal of Agricultural and Food Chemistry
Altered Serum Metabolite Profiling and Relevant Pathways Analysis in Rats Stimulated by Honeybee venom: A New Insight into Allergy to Honeybee Venom Yazhou Zhao1,2, Jianmei Zhang2, Yanping Chen3, Zhiguo Li1, Hongyi Nie1, Wenjun Peng2,* and Songkun Su1,*
1
College of Bee Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002,
P. R. China, 2
Institute of Apicultural Research, Chinese Academy of Agricultural Sciences,
Beijing 100093, P. R. China 3
USDA-ARS, Bee Research Laboratory, Beltsville, MD 20705, USA
* Corresponding authors: Wenjun Peng, Email:
[email protected] Tel: 86-10-62597059; Songkun Su, Email:
[email protected] Tel: 86-591-83739448
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ABSTRACT To improve our understanding of the disturbed metabolic pathways and cellular
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responses triggered by honeybee venom stimulation, we compared the changes in
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serum metabolites rats, either stimulated or not by honeybee venom by performing 1H
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NMR spectrometry-based metabonomics to identify potential biomarkers.
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study, 65 metabolites were structurally confirmed and quantified and the following
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results were obtained.
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selected as potential biomarkers 3 hrs after venom stimulation.
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pathway analysis showed that methane metabolism, glyoxylate and dicarboxylate
In this
Firstly, by pattern recognition analysis, 14 metabolites were Secondly, metabolic
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metabolism, tricarboxylic acid cycle, glycine, serine and threonine metabolism,
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arginine and proline metabolism were affected.
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metabolic modifications indicated that rats could recover without medical treatment
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24 hrs after venom stimulation.
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serum metabolites in rats after honeybee venom stimulation has enhanced our
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understanding of the organism’s response to honeybee venom.
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KEYWORDS: honeybee venom stimulation, serum metabonomics, metabolite
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profiling, 1H NMR
Finally, the time-dependent
In summary, this new insight into the changes in
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INTRODUCTION The accelerated urbanization process and changing natural environment have led
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to frequent incidences of honeybee sting allergy 1. According to European and
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American population-based studies, the lifetime occurrence of a systemic reaction to
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honeybee venom ranges from 0.3 to 7.5% in adults, and depends on various factors
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like geography, study population, venom used for diagnosis and the subject’s
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profession and hobbies 2. Studies have shown that honeybee venom administration
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could stimulate the function of the immune system 3 and affect the release of cortisol
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production which is known as a natural anti-inflammatory agent 4. The typical
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reaction of one organism to honeybee venom ranges from a smaller local reaction to a
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larger effect, and in a most serious circumstance lead to anaphylaxis and death 5.
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General clinical manifestations of the allergy are limited to the local inflammatory
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reaction which includes pain, swelling, erythema, and itching, and these symptoms
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spontaneously disappear within 24 hours without medical intervention 6. However, a
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serious clinical case is one where a patient previously sensitized to one or more
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venom components manifests immediate hypersensitivity. This condition can be
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easily triggered by honeybee venom stimulation and requires urgent medical care.
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The symptoms can vary from local inflammatory reactions to severe allergic reactions
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that subsequently lead to glottis edema, intense urticaria, and bronchospasm
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accompanied by anaphylactic shock 7. Some studies have documented that honeybee
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venom can stimulate severe allergic reactions and cause various organs including
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kidney, heart, nervous system and eye dysfunction 8. Further, the relationship between
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honeybee venom and anaphylactic shock or myocardial infarction has also been
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established 9.
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can cause rhabdomyolysis, thrombocytopenia, acute renal failure, hepatitis, mental
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status change, and cardiac arrest. The mechanism behind the effects of venom on
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physiological conditions have been widely studied and explained.
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chemometric tests indicated statistically significant differences in the serum levels of
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L-glutamine (Gln), L-glutamic acid (Glu), L-methionine (Met) and
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3-methyl-L-histidine (3MHis) between stimulated and non-stimulated subjects 10.
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Furthermore, it has been found that honeybee venom changes the serum peptidomic
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profiles 11,like phospholipase A2, a glycoprotein that is the most potent and allergenic
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protein affected by honeybee venom.
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direct stimulation by cross-linking IgE on mast cells and basophils, honeybee venom
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has also been shown to increase leukotriene production through the hydrolysis of
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phospholipids 12.
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with the lack of a thorough understanding of the complex biomolecular networks
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responding to honeybee venom has generated multiple challenges with respect to the
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diagnosis and management of venom allergy.
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In addition, it has been shown that a high level of honeybee venom
For instance,
Also, besides eliciting a response through
However, the complex composition of honeybee venom along
Metabonomics, which is a systematic approach of studying compounds in cells,
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tissues, and biofluids, directly reflects the phenotypic feature of an organism and
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provides critical insights into the disease process, biochemical function, and drug
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toxicity 13. Thus, identification of characteristic biomarkers reflecting physiological or
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pathophysiological responses to bee venom, can help to establish specific and
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accurate monitoring and diagnostic methods and development of new drugs 14.
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Nuclear magnetic resonance (NMR)-based serum metabolite profiling is a promising
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technique to analyze complex metabolic alterations. NMR has been applied as an
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analytical platform for metabonomics due to its inherent quantitative nature and
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ability to generate a wealth of chemical information about “NMR active” nuclei.
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NMR analysis has no bias towards any of the metabolites and is often praised for its
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suitability for long-term and large-scale epidemiological studies 15. Moreover, NMR is
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suitable for metabonomic profiling involving analysis of biofluids or tissues by
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measurement of the low molecular weight (
