- Email: [email protected]
Recent developments and emerging trends of mass spectrometry for herbal ingredients analysis
Accepted Manuscript Recent developments and emerging trends of mass spectrometry for herbal ingredients analysis Aihua Zhang, Hui Sun, Guangli Yan, Xijun Wang PII:
S0165-9936(17)30111-5
DOI:
10.1016/j.trac.2017.07.007
Reference:
TRAC 14955
To appear in:
Trends in Analytical Chemistry
Received Date: 27 March 2017 Revised Date:
1 July 2017
Accepted Date: 10 July 2017
Please cite this article as: A. Zhang, H. Sun, G. Yan, X. Wang, Recent developments and emerging trends of mass spectrometry for herbal ingredients analysis, Trends in Analytical Chemistry (2017), doi: 10.1016/j.trac.2017.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Recent developments and emerging trends of mass spectrometry for herbal ingredients analysis
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Aihua Zhang, Hui Sun, Guangli Yan, Xijun Wang* Sino-America Chinmedomics Technology Collaboration Center, National TCM Key Laboratory of Serum Pharmacochemistry, Chinmedomics Research Center of TCM State Administration, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin
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150040, China.
Address correspondence to: Prof. Xijun Wang
Sino-America Chinmedomics Technology Collaboration Center, National TCM Key Laboratory of Serum Pharmacochemistry, Chinmedomics Research Center of TCM State Administration, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China. Email: [email protected]
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Abstract:
Herbal preparation has recently increased health awareness and its efficacy is brought about by the multi-constituents. Therefore, the application of mass spectrometry (MS) in herbal preparation has been dramatically growing due to the improved detection capabilities. It offered high sensitivity, high-throughput and selectivity, has better accuracy, and can be utilized to quantitative, qualitative and imaging. High-throughput screening method integrated with MS platform is an excellent tool to analyse the multi-components of herbal preparation in the post-genomic era. For
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providing an up-to-date overview of MS application on the HM-derived compounds, the papers published in the latest years involving quantitative and qualitative analysis of chemical constituents and MS platform integrated with high-throughput screening method are summarized in this review. Examples of the application of MS in the HM
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sciences focusing on chemical analysis are highlighted, and new developments and future prospects are also highlighted. Keywords:
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Mass spectrometry; herbal preparation; chemical constituents; natural products; identification
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1. Introduction
The discovery of natural product artemisinin from the herb Artemisia annua that brought breakthroughs in the therapy of tropical parasitic diseases was awarded for Youyou Tu that received the Nobel Prize for Medicine 2015 [1]. It demonstrates the importance of herbal medicine (HM)-derived drugs. Today, increasing studies have focused on natural compounds extracted from herbal preparation [2,3]. The bioactive compounds from herbal medicine have continued to play an important role in drug discovery, and more than 50% drugs used in pharmacopoeia are derived
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from herbs [4-6]. The most well-known examples include taxanes (docetaxel, paclitaxel), vinca alkaloids (vinorelbine, vindesine, vinblastine, vincristine), podophyllotoxin and its derivative (teniposide and etoposide), anthracyclines (idarubicin, epirubicin, daunorubicin, doxorubicin), camptothecin and its derivatives (irinothecan and topothecan),
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and others [7-12]. Based on the therapeutic effects, thousands of herbal preparations have been practiced for many millennia and thus been widely accepted by Asian communities. There is a higher possibility of discovering a bioactive conpound from HM based on their therapeutic effects, rather than from other natural sources via random
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screening.
Currently, more and more attention has been focused on drug discovery from natural compounds of HM [13]. The HM are complex, and their components may act on multiple targets. Various techniques have allowed researchers to acquire more insights into these components are lacking. Hence, fast, sensitive and effective analytical tools and methods are needed to acquire a better understanding of the phytoconstituents of HM and to enhance its quality
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control. Fortunately, mass spectrometry (MS) can provide us with useful structural information for chemical constituents derived from HM [14-16]. MS can capture the candidate molecules, facilitate their identification of novel chemical structures. Recently, MS has been recognized as yielding huge potential for high-throughput discovery of
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new lead compounds from HM [17]. The effectiveness of the MS-based methods was demonstrated for the discovery of bioactive compounds and elucidation of the action mechanisms of herbal preparation [18-21]. These studies
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suggest that the MS approach provides a new research paradigm for translating HM from experience-based medicine to an evidence-based medicine. Many scientists have attempted to develop an appropriate approach rely upon MS for the screening effective compounds from HM, due to high-throughput MS characteristics [22-27]. In this context, the implementation of the MS platform integrated with high-throughput screening strategies is very essential for quantitative and qualitative analysis of herbal constituents. This critical review covers the use of MS with related techniques and methodologies for phytoconstituents discovery, identification, determination, and also highlights high-throughput screening method suitable for effective ingredients in medicinal plants illustrated by recent successful cases.
2. Natural products for disease treatment Herbal medicines are widely used for a long period, predominately as over the counter preparations. The main driver 3
for the use of herbal is the unmet needACCEPTED of patients. There MANUSCRIPT is another an impressive revival of seeking new drugs from natural compounds. HM is a valuable source of novel chemical structures and contains multiple active ingredients that have the possibility of be beneficial for disease prevention and treatment [28-32]. Currently, it is the primary form of health care in the developing countries, and also is widely used as a supplement in developed countries. HM is the most widely practiced form of herbalism worldwide and has always contributed extensively towards the development of modern medicine. To discover novel lead compounds, herbal ingredients, single herbs and formula in
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HM is important areas for disease therapy. Treatment effect of formula in HM that involves multi-targets and multipathways may be superior than that of the single agent targeting a single target [33-36]. The formulas consist of a combination of multi-constituents and have been widely used because of their effects protecting against many
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diseases [37,38]. However, due to the extreme complexity of chemical components and potential actions, a comprehensive understanding of HM using conventional phytochemical tools still faces many challenges, which have hindered the process of TCM modernization. To address this, research in this field requires a comprehensive
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approach to identify active ingredients. Establishing high throughput screening method is indispensable for the purpose. Traditional bioassays are time-consuming and are not able to easily identify the different constituents. Recently, MS is an ideal method to address these challenges and has demonstrated its merits for analyzing the known compounds and elucidation of unknown compounds in HM [39-43]. Recently, a number of studies describing the effective strategies for active constituents in HM have been reported and greatly expedited identification and
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characterization of the phytoconstituents [44-47]. With the progress of MS technology and method, the action mechanisms of HM will be further demonstrated, more and more herbs and formulas will be used as an effective
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therapy.
3. Evolving MS platform for HM: determining the need
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In the past decade, there has been growing interests in the usage of HM due to the increasing awareness of people in their health benefits [48]. HM is usually composed of multi-components responsible for their efficacies. Therefore, the systematic identification of the chemical components in HM is important in order to deciphering the action basis of the therapeutic effects. However, due to difficulties of isolation and preparation, conventional phytochemical tool is unrealistic and unpractical to studies on the high polarity, non-chromophores and low abundance compounds. It is a time-consuming and labor-intensive process, because of chemical diversity of HM. So, there is imperative to develop a sensitive and feasible method for qualitative analysis of the phytoconstituents in HM. Numerous efforts were made to identify the effective constituents from HM [49-52]. Various analytical techniques are used in HM which could be divided into two categories: MS and nuclear magnetic resonance (NMR). More attention has been paid to develop the chemical constituents analysis with MS [53-56]. These techniques have led to considerable development in screening phytoconstituents from HM. In addition, high resolution MS could rapidly identify the active compound, tandem MS 4
ACCEPTED MANUSCRIPT may combine the bioactive screening steps as one and providing more useful information for the HM study. Primarily, MS is used to sensitively and specifically detecting known constituents and identifying unknown constituents. MS-based screening assay could provide a powerful and practical approach for rapid screening from HM [57]. The combination of rapid and sensitive analytical tools with MS, the so-called “hyphenated techniques”, can play an increasingly important role in the phytopharmaceuticals. Particularly, these hyphenated techniques is an important tool used for high-throughput screening and rapid identification of compounds from HM [58]. For example,
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ultra-high pressure liquid chromatography (UPLC) can increase the speed of analysis, improving separation sensitivity, resolution and efficiency, and reduce the solvent consumption, compared to other analytical approaches. Commonly used MS detector types include single quadrupoles, triple quadrupoles, ion traps, orbitraps, time-of-flight
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(TOF). Applications of UPLC coupled with different detection tools for determining herbal constituents of HM have been recently reported. For example, Zhang QQ et al. had established a fast UPLC-QTOF/MS method to characterize multiple constituents in Danhong injection [59]. A total of 63 compounds, including 2C-glycosyl quinochalcones, 33
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phenolic acids, 6 flavonoid O-glycosides, 6 organic acids, 5 amino acids, 4 iridoid glycosides, and 3 nucleosides, were tentatively characterized. Dong P et al. had developed UHLC-QTOF/MS to quickly identify the chemical components and understand the chemical profiles of Zibu Piyin Recipe [60]. A total of 155 compounds in Zibu Piyin Recipe was tentatively identified using the optimized method. Zou D et al. established UPLC- Orbitrap-MS approach
HM prescription [61].
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for systematically screening and characterizing the chemical constituents of Wuzi-Yanzong-Wan which is a classical
4. Mass spectrometry identification in vivo ingredients
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Identification of the phytoconstituents in HM preparations is crucial to revealing the therapeutic basis and action mechanism. The traditional practice of isolation, purification, and biological activity screening in vitro is
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time-consuming and poorly efficiency. Identification of the bioactive ingredients from HM by traditional approach remains a challenge. Fortunately, the integration of mass spectrometry based technologies efforts with with integrative approach, has driven the development of a new drug discovery paradigm. It provides highly specific structural information related to ingredient and metabolite identity such as isotope distribution patterns, an ions accurate mass, and characteristic fragment ions used for structural elucidation [62-66]. The compounds absorbed into the blood had chances to bring about bioactivities [67]. However, the concentrations of some compounds after oral administration of HM, are quite low, and therefore increase the complexity of the detection in vivo. In recent years, the scientists have developed a lot of methods to clarify the chemical components for HM, such as serum pharmacochemistry, and fingerprint chromatography [68-70]. In views of this, the screening strategy of plasma pharmacochemistry was proposed and introduced that bioactive components can reveal their therapeutic effects only when they can be discovered in blood with suitable concentrations after administration of 5
MANUSCRIPT herbal preparation [71]. This strategy ACCEPTED is effective and straightforward and has been widely accepted to screen and investigating the bioactive components in HM. Serum pharmacochemistry approach has been used to profile the active constituents by the MS technique [72-76]. This approach is demonstrated to be effective tool for bioactive compound screening and identification in vivo ingredients and reported on some herbal preparations [77-81]. In a study, the plasma pharmacochemistry strategy integrating and MS analysis was used to screening the in vivo components of Daming capsule [82]. Six anthraquinones with fast and high absorption were screened as potentially
HM, providing new insights into the development and research of new drugs.
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5. High-throughput MS screening approach
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active compounds of Daming capsule. It facilitated the identification and screening of functional components from
Complex diseases are serious threats to human health. Recently, the drug discovery approach of “single drug and single target” was found to be limited against complex diseases [83]. New multicomponent drugs development is
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imperative, and a suitable solution establishment. HM is a sophisticated systems and has been recognized as a renewable resource for the discovery of novel drugs. The rapid screening method offers an efficient way to discover bioactive compounds from HM. To bridge the gap between HM system and modern molecular biology, MS will be considered one of the most helpful tools available. High-throughput MS has become fundamental tool to the development of innovative drug for complex diseases. Utilizing MS, researchers can reveal therapeutic effects
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generated from multi-ingredients, multi-targets of HM, develop innovative drugs. Ling Y et al had establish a rapid and sensitive MS method to rapidly determine the active ingredients in a well-known formula Cong-Ming-Tang for the amnesia treatment [84]. It allowed the identification of 55 compounds
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including 4 sucrose esters, 4 xanthone C-glycosides, 15 triterpene saponins, 11 oligosaccharide multi-esters, 2 lignans 15 triterpene acids and 4 phenylpropanoids. Sixteen compounds were unambiguously identified by comparing the MS
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data, and 38 compounds were tentatively characterized from Cong-Ming-Tang. A called screening method by combining MS for mitochondria-targeted bioactive constituents was developed for searching mitochondria-targeted compounds from Scutellariae Radix [85]. Nineteen bioactive compounds were identified by MS, of which 17 were new mitochondria-targeted compounds, and the bioactivity of 9 hit compounds was confirmed using in vitro test. A study using human neuroblastoma SH-SY5Y cells was to screen bioactive compounds of Radix Bupleuri and discover the anti-schizophrenic candidate drugs [86]. The components such as saikosaponin B1, saikosaponin B2, saikosaponin A, saikosaponin D and saikosaponin C were identified and detected by the MS method under the optimized conditions. A study has been undertaken to establish the hyphenated MS method of bioactivity-guided fractionation to identify the bioactive constituents of a well-known formula Xiao Chai Hu Decoction (XCHD) [87]. As a result, 79 compounds including flavonoids, saikosaponins, polysaccharides, licoricesaponins, ginsenosides and gingerols were detected, 69 of them were tentatively characterized. A segmented selected reaction monitoring MS 6
ACCEPTED MANUSCRIPT strategy were established to simultaneously monitoring 63 licorice metabolites in vivo, and obtained the pharmacokinetics profiles of 55 metabolites [88]. In a study, an efficient strategy based on bioassay-guided method with MS technology was established to accurately and rapidly screen active constituents in HM [89]. These results may be significant significance for in-depth understanding of components and drug discovery from medicinal herbs.
6. Application and practices of the combined MS strategy
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HM has complex chemical compositions, including the alkaloids, flavonoids, terpenoids, saponins and phenolic acids that demonstrated to have potential pharmacological properties [90]. Clarifying which constituents have therapeutic effects is of great importance for understanding their action mechanism. The exploration of chemical constituents
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from HM may provide candidates for high-throughput screenings of most promising drug candidates [91]. However, in contrast to the chemical synthetic drugs, compounds from HM are likely to have complex structures which slow down the identification process and contribute to some problems that were related to supply and manufacturing.
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Conventional approaches are generally inaccurate, not very specific, and lacking sensitivity, meaning that new promising drug candidates present in minor levels can easily be overlooked.
A study presented an integrated strategy that used UHPLC/LTQ-Orbitrap-MS for the rapid characterization and discovery of the bioactive molecules from Uncaria rhynchophylla (UR) [92]. Ultimately, a total of 92 alkaloids (32 alkaloid O-glycosides and 60 free alkaloids) were characterized, 56 of which are potential new alkaloids for UR. A
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new strategy of metabolite discovery and identification was established by HPLC-HRMS technique [93]. This technique was developed to discovering comprehensive metabolites from multiple bioactive constituents. Altogether, 115 metabolites of 5 flavonoid monomers (baohuoside I, epimedin C, icariin, epimedin A, epimedin B) were
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discovered and identified in vivo via this new strategy. A combined MS strategy using both phytochemical and biological approaches was used to screen the chemical constituents of Glycyrrhiza uralensis (licorice) [94]. A total of
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122 compounds were identified by MS from the roots and rhizomes of licorice. These constituents were then further screened using enzyme- and cell-based bioassay. The bioactive compounds such as isoprenylated phenolics were found for the first time. In a study, plasma pharmacochemistry method by LC-MS were performed to screen the active components in Daming capsule [82]. These integrated strategies would be powerful tools for combinatorial screening for lead-like drug candidate in discovery and development for HM. A novel methodology based on a dose-dependent targeted knockout (DDTK) technique were used to identify the chemical profiling of licorice [95]. MS incorporated with the DDTK technique were employed to identify the compounds. Among the detected 232 compounds, twenty-seven compounds were unequivocally identified and 165 compounds, including twenty-nine different compounds were tentatively characterized. It opens the door the further identification of compounds from complicated HM. Chinmedomics by integrating serum pharmacochemistry and metabolomics technology has been proposed by Wang XJ et al, was to discover effective constituents of ShenQiWan protecting against kidney-yang 7
ACCEPTED MANUSCRIPT deficiency syndrome [96]. With the serum pharmacochemistry and MS, a total of 56 compounds were tentatively characterized in vivo and 17 potential biomarkers in urine were analyzed via the metabolomics method (Figure 1). Correlation analysis between potential biomarkers in urine and constituents in vivo showed that 28 compounds had a close relationship with therapeutic effects. The combination of proposed novel methods with mass spectrometry techniques provide a powerful tool in the discovery of new and novel bioactive compounds.
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7. Conclusion and Perspectives
HM has attracted more and more attention since it can exhibit complementary therapeutic effects against diseases. It is urgent to investigate the phytoconstituents, establish the integrated evaluation system and discover the active
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constituents in the HM. In recent years, MS was considered as a useful tool for the identification of phytoconstituents. Within the pharmaceutical industry, there has been a tendency to increasing the throughput natural compounds screening. MS application has opened the possibility to provide more data in a time-efficient manner. In this review,
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we describe how conjunction of MS with related techniques and method could provide us with useful structural information for discovery and exploration of chemical constituents from HM, and also summarise some of the strategies that are drawn up in HM research. In this review, we wanted to introduce an integrated MS platform in qualitative and quantitative analysis of chemical constituents. The use of this method has reiterated the importance of MS in the HM, and numerous studies have demonstrated that utility of MS combined the differential screening
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strategies were established with the aim of identifying phytoconstituents from HM, and it will increase the success rate in the discovery project of natural medicine.
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Acknowledgments
This work was supported by grants from the Key Program of Natural Science Foundation of State (Grant No.
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81430093, 81373930, 81673586, 81302905), National Key Subject of Drug Innovation (Grant No. 2015ZX09101043-005, 2015ZX09101043-011), Natural Science Foundation of Heilongjiang Province of China (H2015038), Program for Youth Innovative Talents in Heilongjiang Province of China (UNPYSCT-2015118).
Competing financial interests
The authors declare no competing financial interests.
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ACCEPTED MANUSCRIPT 92. Pan H, Yang W, Zhang Y, Yang M, Feng R, Wu W, Guo D. An integrated strategy for the systematic characterization and discovery of new indole alkaloids from Uncaria rhynchophylla by UHPLC/DAD/LTQOrbitrap-MS. Anal Bioanal Chem. 2015;407(20):6057-70. 93. Jin Y, Wu CS, Zhang JL, Li YF. A new strategy for the discovery of epimedium metabolites using high-performance liquid chromatography with high resolution mass spectrometry. Anal Chim Acta. 2013;768:111-7. 94. Ji S, Li Z, Song W, Wang Y, Liang W, Li K, Tang S, Wang Q, Qiao X, Zhou D, Yu S, Ye M. Bioactive
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discovering effective constituents from ShenQiWan acting on ShenYangXu syndrome. Chin J Nat Med.
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Fig. 1 Schematic of the proposed integrated chinmedomics strategy for the discovery of novel bioactive molecules
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from herbal medicines.
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ACCEPTED MANUSCRIPT Highlights 1. Herbal preparation has been recognized as an important reservoir of bioactive lead compounds. 2. Mass spectrometry has led to discovery of many active constituents from herbal preparation. 3. Exploration of candidate drug is greatly promoted by high-throughput MS platform.
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4. Evolving MS screening approach enables a revolution for drug discovery of herbal medicine.
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S0165-9936(17)30111-5
DOI:
10.1016/j.trac.2017.07.007
Reference:
TRAC 14955
To appear in:
Trends in Analytical Chemistry
Received Date: 27 March 2017 Revised Date:
1 July 2017
Accepted Date: 10 July 2017
Please cite this article as: A. Zhang, H. Sun, G. Yan, X. Wang, Recent developments and emerging trends of mass spectrometry for herbal ingredients analysis, Trends in Analytical Chemistry (2017), doi: 10.1016/j.trac.2017.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Recent developments and emerging trends of mass spectrometry for herbal ingredients analysis
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Aihua Zhang, Hui Sun, Guangli Yan, Xijun Wang* Sino-America Chinmedomics Technology Collaboration Center, National TCM Key Laboratory of Serum Pharmacochemistry, Chinmedomics Research Center of TCM State Administration, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin
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150040, China.
Address correspondence to: Prof. Xijun Wang
Sino-America Chinmedomics Technology Collaboration Center, National TCM Key Laboratory of Serum Pharmacochemistry, Chinmedomics Research Center of TCM State Administration, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China. Email: [email protected]
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Abstract:
Herbal preparation has recently increased health awareness and its efficacy is brought about by the multi-constituents. Therefore, the application of mass spectrometry (MS) in herbal preparation has been dramatically growing due to the improved detection capabilities. It offered high sensitivity, high-throughput and selectivity, has better accuracy, and can be utilized to quantitative, qualitative and imaging. High-throughput screening method integrated with MS platform is an excellent tool to analyse the multi-components of herbal preparation in the post-genomic era. For
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providing an up-to-date overview of MS application on the HM-derived compounds, the papers published in the latest years involving quantitative and qualitative analysis of chemical constituents and MS platform integrated with high-throughput screening method are summarized in this review. Examples of the application of MS in the HM
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sciences focusing on chemical analysis are highlighted, and new developments and future prospects are also highlighted. Keywords:
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Mass spectrometry; herbal preparation; chemical constituents; natural products; identification
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1. Introduction
The discovery of natural product artemisinin from the herb Artemisia annua that brought breakthroughs in the therapy of tropical parasitic diseases was awarded for Youyou Tu that received the Nobel Prize for Medicine 2015 [1]. It demonstrates the importance of herbal medicine (HM)-derived drugs. Today, increasing studies have focused on natural compounds extracted from herbal preparation [2,3]. The bioactive compounds from herbal medicine have continued to play an important role in drug discovery, and more than 50% drugs used in pharmacopoeia are derived
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from herbs [4-6]. The most well-known examples include taxanes (docetaxel, paclitaxel), vinca alkaloids (vinorelbine, vindesine, vinblastine, vincristine), podophyllotoxin and its derivative (teniposide and etoposide), anthracyclines (idarubicin, epirubicin, daunorubicin, doxorubicin), camptothecin and its derivatives (irinothecan and topothecan),
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and others [7-12]. Based on the therapeutic effects, thousands of herbal preparations have been practiced for many millennia and thus been widely accepted by Asian communities. There is a higher possibility of discovering a bioactive conpound from HM based on their therapeutic effects, rather than from other natural sources via random
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screening.
Currently, more and more attention has been focused on drug discovery from natural compounds of HM [13]. The HM are complex, and their components may act on multiple targets. Various techniques have allowed researchers to acquire more insights into these components are lacking. Hence, fast, sensitive and effective analytical tools and methods are needed to acquire a better understanding of the phytoconstituents of HM and to enhance its quality
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control. Fortunately, mass spectrometry (MS) can provide us with useful structural information for chemical constituents derived from HM [14-16]. MS can capture the candidate molecules, facilitate their identification of novel chemical structures. Recently, MS has been recognized as yielding huge potential for high-throughput discovery of
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new lead compounds from HM [17]. The effectiveness of the MS-based methods was demonstrated for the discovery of bioactive compounds and elucidation of the action mechanisms of herbal preparation [18-21]. These studies
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suggest that the MS approach provides a new research paradigm for translating HM from experience-based medicine to an evidence-based medicine. Many scientists have attempted to develop an appropriate approach rely upon MS for the screening effective compounds from HM, due to high-throughput MS characteristics [22-27]. In this context, the implementation of the MS platform integrated with high-throughput screening strategies is very essential for quantitative and qualitative analysis of herbal constituents. This critical review covers the use of MS with related techniques and methodologies for phytoconstituents discovery, identification, determination, and also highlights high-throughput screening method suitable for effective ingredients in medicinal plants illustrated by recent successful cases.
2. Natural products for disease treatment Herbal medicines are widely used for a long period, predominately as over the counter preparations. The main driver 3
for the use of herbal is the unmet needACCEPTED of patients. There MANUSCRIPT is another an impressive revival of seeking new drugs from natural compounds. HM is a valuable source of novel chemical structures and contains multiple active ingredients that have the possibility of be beneficial for disease prevention and treatment [28-32]. Currently, it is the primary form of health care in the developing countries, and also is widely used as a supplement in developed countries. HM is the most widely practiced form of herbalism worldwide and has always contributed extensively towards the development of modern medicine. To discover novel lead compounds, herbal ingredients, single herbs and formula in
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HM is important areas for disease therapy. Treatment effect of formula in HM that involves multi-targets and multipathways may be superior than that of the single agent targeting a single target [33-36]. The formulas consist of a combination of multi-constituents and have been widely used because of their effects protecting against many
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diseases [37,38]. However, due to the extreme complexity of chemical components and potential actions, a comprehensive understanding of HM using conventional phytochemical tools still faces many challenges, which have hindered the process of TCM modernization. To address this, research in this field requires a comprehensive
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approach to identify active ingredients. Establishing high throughput screening method is indispensable for the purpose. Traditional bioassays are time-consuming and are not able to easily identify the different constituents. Recently, MS is an ideal method to address these challenges and has demonstrated its merits for analyzing the known compounds and elucidation of unknown compounds in HM [39-43]. Recently, a number of studies describing the effective strategies for active constituents in HM have been reported and greatly expedited identification and
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characterization of the phytoconstituents [44-47]. With the progress of MS technology and method, the action mechanisms of HM will be further demonstrated, more and more herbs and formulas will be used as an effective
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therapy.
3. Evolving MS platform for HM: determining the need
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In the past decade, there has been growing interests in the usage of HM due to the increasing awareness of people in their health benefits [48]. HM is usually composed of multi-components responsible for their efficacies. Therefore, the systematic identification of the chemical components in HM is important in order to deciphering the action basis of the therapeutic effects. However, due to difficulties of isolation and preparation, conventional phytochemical tool is unrealistic and unpractical to studies on the high polarity, non-chromophores and low abundance compounds. It is a time-consuming and labor-intensive process, because of chemical diversity of HM. So, there is imperative to develop a sensitive and feasible method for qualitative analysis of the phytoconstituents in HM. Numerous efforts were made to identify the effective constituents from HM [49-52]. Various analytical techniques are used in HM which could be divided into two categories: MS and nuclear magnetic resonance (NMR). More attention has been paid to develop the chemical constituents analysis with MS [53-56]. These techniques have led to considerable development in screening phytoconstituents from HM. In addition, high resolution MS could rapidly identify the active compound, tandem MS 4
ACCEPTED MANUSCRIPT may combine the bioactive screening steps as one and providing more useful information for the HM study. Primarily, MS is used to sensitively and specifically detecting known constituents and identifying unknown constituents. MS-based screening assay could provide a powerful and practical approach for rapid screening from HM [57]. The combination of rapid and sensitive analytical tools with MS, the so-called “hyphenated techniques”, can play an increasingly important role in the phytopharmaceuticals. Particularly, these hyphenated techniques is an important tool used for high-throughput screening and rapid identification of compounds from HM [58]. For example,
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ultra-high pressure liquid chromatography (UPLC) can increase the speed of analysis, improving separation sensitivity, resolution and efficiency, and reduce the solvent consumption, compared to other analytical approaches. Commonly used MS detector types include single quadrupoles, triple quadrupoles, ion traps, orbitraps, time-of-flight
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(TOF). Applications of UPLC coupled with different detection tools for determining herbal constituents of HM have been recently reported. For example, Zhang QQ et al. had established a fast UPLC-QTOF/MS method to characterize multiple constituents in Danhong injection [59]. A total of 63 compounds, including 2C-glycosyl quinochalcones, 33
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phenolic acids, 6 flavonoid O-glycosides, 6 organic acids, 5 amino acids, 4 iridoid glycosides, and 3 nucleosides, were tentatively characterized. Dong P et al. had developed UHLC-QTOF/MS to quickly identify the chemical components and understand the chemical profiles of Zibu Piyin Recipe [60]. A total of 155 compounds in Zibu Piyin Recipe was tentatively identified using the optimized method. Zou D et al. established UPLC- Orbitrap-MS approach
HM prescription [61].
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for systematically screening and characterizing the chemical constituents of Wuzi-Yanzong-Wan which is a classical
4. Mass spectrometry identification in vivo ingredients
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Identification of the phytoconstituents in HM preparations is crucial to revealing the therapeutic basis and action mechanism. The traditional practice of isolation, purification, and biological activity screening in vitro is
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time-consuming and poorly efficiency. Identification of the bioactive ingredients from HM by traditional approach remains a challenge. Fortunately, the integration of mass spectrometry based technologies efforts with with integrative approach, has driven the development of a new drug discovery paradigm. It provides highly specific structural information related to ingredient and metabolite identity such as isotope distribution patterns, an ions accurate mass, and characteristic fragment ions used for structural elucidation [62-66]. The compounds absorbed into the blood had chances to bring about bioactivities [67]. However, the concentrations of some compounds after oral administration of HM, are quite low, and therefore increase the complexity of the detection in vivo. In recent years, the scientists have developed a lot of methods to clarify the chemical components for HM, such as serum pharmacochemistry, and fingerprint chromatography [68-70]. In views of this, the screening strategy of plasma pharmacochemistry was proposed and introduced that bioactive components can reveal their therapeutic effects only when they can be discovered in blood with suitable concentrations after administration of 5
MANUSCRIPT herbal preparation [71]. This strategy ACCEPTED is effective and straightforward and has been widely accepted to screen and investigating the bioactive components in HM. Serum pharmacochemistry approach has been used to profile the active constituents by the MS technique [72-76]. This approach is demonstrated to be effective tool for bioactive compound screening and identification in vivo ingredients and reported on some herbal preparations [77-81]. In a study, the plasma pharmacochemistry strategy integrating and MS analysis was used to screening the in vivo components of Daming capsule [82]. Six anthraquinones with fast and high absorption were screened as potentially
HM, providing new insights into the development and research of new drugs.
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5. High-throughput MS screening approach
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active compounds of Daming capsule. It facilitated the identification and screening of functional components from
Complex diseases are serious threats to human health. Recently, the drug discovery approach of “single drug and single target” was found to be limited against complex diseases [83]. New multicomponent drugs development is
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imperative, and a suitable solution establishment. HM is a sophisticated systems and has been recognized as a renewable resource for the discovery of novel drugs. The rapid screening method offers an efficient way to discover bioactive compounds from HM. To bridge the gap between HM system and modern molecular biology, MS will be considered one of the most helpful tools available. High-throughput MS has become fundamental tool to the development of innovative drug for complex diseases. Utilizing MS, researchers can reveal therapeutic effects
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generated from multi-ingredients, multi-targets of HM, develop innovative drugs. Ling Y et al had establish a rapid and sensitive MS method to rapidly determine the active ingredients in a well-known formula Cong-Ming-Tang for the amnesia treatment [84]. It allowed the identification of 55 compounds
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including 4 sucrose esters, 4 xanthone C-glycosides, 15 triterpene saponins, 11 oligosaccharide multi-esters, 2 lignans 15 triterpene acids and 4 phenylpropanoids. Sixteen compounds were unambiguously identified by comparing the MS
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data, and 38 compounds were tentatively characterized from Cong-Ming-Tang. A called screening method by combining MS for mitochondria-targeted bioactive constituents was developed for searching mitochondria-targeted compounds from Scutellariae Radix [85]. Nineteen bioactive compounds were identified by MS, of which 17 were new mitochondria-targeted compounds, and the bioactivity of 9 hit compounds was confirmed using in vitro test. A study using human neuroblastoma SH-SY5Y cells was to screen bioactive compounds of Radix Bupleuri and discover the anti-schizophrenic candidate drugs [86]. The components such as saikosaponin B1, saikosaponin B2, saikosaponin A, saikosaponin D and saikosaponin C were identified and detected by the MS method under the optimized conditions. A study has been undertaken to establish the hyphenated MS method of bioactivity-guided fractionation to identify the bioactive constituents of a well-known formula Xiao Chai Hu Decoction (XCHD) [87]. As a result, 79 compounds including flavonoids, saikosaponins, polysaccharides, licoricesaponins, ginsenosides and gingerols were detected, 69 of them were tentatively characterized. A segmented selected reaction monitoring MS 6
ACCEPTED MANUSCRIPT strategy were established to simultaneously monitoring 63 licorice metabolites in vivo, and obtained the pharmacokinetics profiles of 55 metabolites [88]. In a study, an efficient strategy based on bioassay-guided method with MS technology was established to accurately and rapidly screen active constituents in HM [89]. These results may be significant significance for in-depth understanding of components and drug discovery from medicinal herbs.
6. Application and practices of the combined MS strategy
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HM has complex chemical compositions, including the alkaloids, flavonoids, terpenoids, saponins and phenolic acids that demonstrated to have potential pharmacological properties [90]. Clarifying which constituents have therapeutic effects is of great importance for understanding their action mechanism. The exploration of chemical constituents
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from HM may provide candidates for high-throughput screenings of most promising drug candidates [91]. However, in contrast to the chemical synthetic drugs, compounds from HM are likely to have complex structures which slow down the identification process and contribute to some problems that were related to supply and manufacturing.
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Conventional approaches are generally inaccurate, not very specific, and lacking sensitivity, meaning that new promising drug candidates present in minor levels can easily be overlooked.
A study presented an integrated strategy that used UHPLC/LTQ-Orbitrap-MS for the rapid characterization and discovery of the bioactive molecules from Uncaria rhynchophylla (UR) [92]. Ultimately, a total of 92 alkaloids (32 alkaloid O-glycosides and 60 free alkaloids) were characterized, 56 of which are potential new alkaloids for UR. A
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new strategy of metabolite discovery and identification was established by HPLC-HRMS technique [93]. This technique was developed to discovering comprehensive metabolites from multiple bioactive constituents. Altogether, 115 metabolites of 5 flavonoid monomers (baohuoside I, epimedin C, icariin, epimedin A, epimedin B) were
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discovered and identified in vivo via this new strategy. A combined MS strategy using both phytochemical and biological approaches was used to screen the chemical constituents of Glycyrrhiza uralensis (licorice) [94]. A total of
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122 compounds were identified by MS from the roots and rhizomes of licorice. These constituents were then further screened using enzyme- and cell-based bioassay. The bioactive compounds such as isoprenylated phenolics were found for the first time. In a study, plasma pharmacochemistry method by LC-MS were performed to screen the active components in Daming capsule [82]. These integrated strategies would be powerful tools for combinatorial screening for lead-like drug candidate in discovery and development for HM. A novel methodology based on a dose-dependent targeted knockout (DDTK) technique were used to identify the chemical profiling of licorice [95]. MS incorporated with the DDTK technique were employed to identify the compounds. Among the detected 232 compounds, twenty-seven compounds were unequivocally identified and 165 compounds, including twenty-nine different compounds were tentatively characterized. It opens the door the further identification of compounds from complicated HM. Chinmedomics by integrating serum pharmacochemistry and metabolomics technology has been proposed by Wang XJ et al, was to discover effective constituents of ShenQiWan protecting against kidney-yang 7
ACCEPTED MANUSCRIPT deficiency syndrome [96]. With the serum pharmacochemistry and MS, a total of 56 compounds were tentatively characterized in vivo and 17 potential biomarkers in urine were analyzed via the metabolomics method (Figure 1). Correlation analysis between potential biomarkers in urine and constituents in vivo showed that 28 compounds had a close relationship with therapeutic effects. The combination of proposed novel methods with mass spectrometry techniques provide a powerful tool in the discovery of new and novel bioactive compounds.
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7. Conclusion and Perspectives
HM has attracted more and more attention since it can exhibit complementary therapeutic effects against diseases. It is urgent to investigate the phytoconstituents, establish the integrated evaluation system and discover the active
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constituents in the HM. In recent years, MS was considered as a useful tool for the identification of phytoconstituents. Within the pharmaceutical industry, there has been a tendency to increasing the throughput natural compounds screening. MS application has opened the possibility to provide more data in a time-efficient manner. In this review,
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we describe how conjunction of MS with related techniques and method could provide us with useful structural information for discovery and exploration of chemical constituents from HM, and also summarise some of the strategies that are drawn up in HM research. In this review, we wanted to introduce an integrated MS platform in qualitative and quantitative analysis of chemical constituents. The use of this method has reiterated the importance of MS in the HM, and numerous studies have demonstrated that utility of MS combined the differential screening
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strategies were established with the aim of identifying phytoconstituents from HM, and it will increase the success rate in the discovery project of natural medicine.
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Acknowledgments
This work was supported by grants from the Key Program of Natural Science Foundation of State (Grant No.
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81430093, 81373930, 81673586, 81302905), National Key Subject of Drug Innovation (Grant No. 2015ZX09101043-005, 2015ZX09101043-011), Natural Science Foundation of Heilongjiang Province of China (H2015038), Program for Youth Innovative Talents in Heilongjiang Province of China (UNPYSCT-2015118).
Competing financial interests
The authors declare no competing financial interests.
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Fig. 1 Schematic of the proposed integrated chinmedomics strategy for the discovery of novel bioactive molecules
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from herbal medicines.
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ACCEPTED MANUSCRIPT Highlights 1. Herbal preparation has been recognized as an important reservoir of bioactive lead compounds. 2. Mass spectrometry has led to discovery of many active constituents from herbal preparation. 3. Exploration of candidate drug is greatly promoted by high-throughput MS platform.
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4. Evolving MS screening approach enables a revolution for drug discovery of herbal medicine.
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