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Home , Ethnomedicine, Herbal, Herbal medicine, Kampo, Therapy, Traditional medicine

Review The Traditional and Modern Medicine from Natural Products

Haidan Yuan 1,2, Qianqian Ma 1, Li Ye 1 and Guangchun Piao 1,2,*

1 College of , Yanbian , Yanji 133002, ; [email protected] (H.Y.); [email protected] (Q.M.); [email protected] (L.Y.) 2 Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of , Yanbian University, Yanji 133002, China * Correspondence: [email protected]; Tel.: +86-433-243-6008

Academic Editor: Derek J. McPhee Received: 19 March 2016; Accepted: 25 April 2016; Published: 29 April 2016

Abstract: Natural products and traditional are of great importance. Such forms of medicine as traditional Chinese medicine, , , traditional Korean medicine, and Unani have been practiced in some areas of the and have blossomed into orderly-regulated systems of medicine. This study aims to review the literature on the relationship among natural products, traditional medicines, and modern medicine, and to explore the possible concepts and methodologies from natural products and traditional medicines to further develop discovery. The unique characteristics of theory, application, current role or status, and modern research of eight kinds of systems are summarized in this study. Although only a tiny fraction of the existing species have been scientifically researched for bioactivities since 1805, when the first pharmacologically-active compound was isolated from opium, natural products and traditional medicines have already made fruitful contributions for modern medicine. When used to develop new , natural products and traditional medicines have their incomparable advantages, such as abundant clinical experiences, and their unique diversity of chemical structures and biological activities.

Keywords: natural products; traditional medicines; ; traditional uses; chemodiversity

1. Introduction Since prehistoric times, humans have used natural products, such as , animals, microorganisms, and marine , in medicines to alleviate and treat . According to records, the human use of plants as medicines may be traced back at least 60,000 years [1,2]. The use of natural products as medicines must, of course, have presented a tremendous challenge to early humans. It is highly probable that when seeking , early humans often consumed poisonous plants, which led to vomiting, diarrhea, coma, or other toxic reactions—perhaps even death. However, in this way, early humans were able to develop knowledge about edible materials and natural medicines [3]. Subsequently, humans invented fire, learned how to make alcohol, developed religions, and made technological breakthroughs, and they learned how to develop new drugs. Traditional medicines (TMs) make use of natural products and are of great importance. Such forms of medicine as traditional Chinese medicine (TCM), Ayurveda, Kampo, traditional Korean medicine (TKM), and Unani employ natural products and have been practiced all over the world for hundreds or even thousands of years, and they have blossomed into orderly-regulated systems of medicine. In their various forms, they may have certain defects, but they are still a valuable repository of human knowledge [2,4].

Molecules 2016, 21, 559; doi:10.3390/molecules21050559 www.mdpi.com/journal/molecules Molecules 2016, 21, 559 2 of 18

In the case of China, Western medicine was introduced in the sixteenth century, but it did not undergo any development until the nineteenth century. Before that, TCM was the dominant form of medical care in the country [5]. Now TCM still plays an important role in China, and it is constantly being developed. TCM is based on 5000 years of medical practice and experience, and is rich in data from “clinical experiments” which guarantee its effectiveness and efficacy. It has developed techniques with respect to such areas as correct dosage, methods of preparing and processing materials, and the appropriate time to collect the various medicinal parts of plants. It is notable that there is increasing convergence between TCM and modern medicine. With the development of modern technology, it has become possible to determine the and mechanisms of action of many Chinese , and TCM has become comprehensible in terms of modern medicine [6–9]. With advances in the theoretical background, therapeutic principles, associated technologies, and understanding of the life , a clearer understanding of the active compounds of TCM has become possible [5]. At the beginning of the nineteenth century, the era of “modern” drugs began. In 1805, the first pharmacologically-active compound morphine was isolated by a young German pharmacist, Friedrich Sertürner, from the opium plant [10,11]. Subsequently, countless active compounds have been separated from natural products. Among them, some follow their traditional uses and the others do not. Later, the development of synthetic techniques led to a significant reduction in the importance of natural products, and there were concerns that the use of some natural products for medicinal purposes might be completely banned. However, natural products are important for the development of new drugs, and these products have been in constant use. Some type of medicines, such as anticancer, antihypertensive, and antimigraine , have benefited greatly from natural products [10,12]. The development of new drugs relying purely on modern technology appears to be reaching something of a limit. In developing new drugs, the has tended to adopt high-throughput synthesis and combinatorial -based drug development since the 1980s; however, the considerable efforts made in this direction have not resulted in the expected drug productivity. Some large pharmaceutical companies are facing great challenges to develop new products. Over the past dozen years, increasing attention has accordingly been paid to natural products in the search for novel drugs in combination with new technology, such as high-throughput selection [13,14]. Natural products, which have evolved over millions of years, have a unique chemical diversity, which results in diversity in their biological activities and drug-like properties. Those products have become one of the most important resources for developing new compounds and scaffolds. Natural products will undergo continual use toward meeting the urgent need to develop effective drugs, and they will play a leading role in the discovery of drugs for treating human diseases, especially critical diseases [15].

2. Natural Products Natural products have a wide range of diversity of multi-dimensional chemical structures; in the meantime, the utility of natural products as biological function modifiers has also won considerable attention. Subsequently, they have been successfully employed in the discovery of new drugs and have exerted a far-reaching impact on chemicobiology [16–18]. From the past century, the high structural diversity of natural products have been realized from the perspective of physical chemistry. Their efficacy is related to the complexity of their well-organized three-dimensional chemical and steric properties, which offer many advantages in terms of efficiency and selectivity of molecular targets. As a successful example of drug development from natural products, and its analogs are presently in wide use for the anti- treatment. This shows how research using natural products has made a significant contribution in drug development [19,20]. Among anticancer drugs approved in the time frame of about 1940–2002, approximately 54% were derived natural products or drugs inspired from knowledge related to such. For instance, the Vinca Molecules 2016, 21, 559 3 of 18 from , and the terpene paclitaxel from Taxus baccata, are among successful anticancer drugs originally derived from plants [12,21]. During the period between 1981 and 2002, the application of natural products in the development of new drugs—especially in the search for novel chemical structures—showed conspicuous success. In that 22-year time frame, drugs derived from natural products have been significant. That is especially true in the case of antihypertensives, where about 64% of newly-synthesized drugs have their origins in structures [12]. Considering their incomparable chemical diversity and novel mechanisms of action, natural products have continued to play a pivotal role in many drug development and research programs. With time, those natural products have undergone interesting and meaningful developments in their ability to interact with numerous, varied biological targets, and some have become the most important drugs in care system [14,22,23]. For example, plants, microorganisms, and animals manufacture small molecules, which have played a major role in drug discovery. Among 69 small- new drugs approved from 2005 to 2007 worldwide, 13 were natural products or originated from natural products, which underlines the importance of such products in drug research and development [12,13]. Over the past 50 years, there has been a great diversity of new drugs developed using high-throughput screening methods and combinatorial chemistry; however, natural products and their derived compounds have continued to be highly-important components in . Of the reckoned 250,000–500,000 existing plant species, only a tiny proportion has been scientifically researched for bioactivities [13]. Therefore, there is great potential for future discoveries from plants and other natural products which, thus, offer huge potential in deriving useful information about novel chemical structures and their new types of action related to new drug development.

3. Traditional Medicines TM is the oldest form of in the world and is used in the prevention, and treatment of physical and mental illnesses. Different societies historically developed various useful methods to combat a variety of health- and life-threatening diseases. TM is also variously known as complementary and alternative, or ethnic medicine, and it still plays a key role in many countries today [24,25]. The medicaments used in TM are mostly derived from natural products. In TM, “clinical trials” have been conducted since ancient times. In the case of TCM, considerable experience and advances have been accumulated and developed over the past thousands of years with respect to methods of preparation, selection of herbs, identification of medicinal materials, and the best time for obtaining various different plants. Appropriate processing and dose regulation are urgently needed in TCM to improve drug efficacy and reduce drug toxicity. Considerable amounts of data have been acquired through clinical experiments, and in this way TM has assisted in the development of modern drugs. Through its use of natural products, TM offers merits over other forms of medicine in such areas as the following: discovery of lead compounds and drug candidates; examining drug-like activity; and exploring physicochemical, biochemical, pharmacokinetic, and toxicological characteristics. If any form of TM is applied successfully, it may surprisingly assist in the development of new drugs, thereby resulting in many benefits, such as significant cost reductions. TCM is now an inseparable part of the Chinese public . In recent years, TCM has gradually gained considerable approval as a complementary or in Western countries. Chinese medicine, which is the most important component of TCM, is currently used in the health care of an estimated 1.5 billion people worldwide [26,27]. It should be noted that in TCM, several herbs and ingredients are combined according to strict rules to form prescriptions, which are referred to as formulas (fang ji in Chinese). Commonly, a classic formula is composed of four elements—the “monarch”, “minister”, “assistant”, and “servant”—according to their different roles in the formula, each of which consists of one to several drugs. Ideally, these drugs constitute an organic group to produce the desired and reduce adverse reactions [28]. Molecules 2016, 21, 559 4 of 18

Kampo is the TM of Japan. Between the fifth and sixth centuries, TCM was introduced to Japan from China; since then, TCM has been significantly altered and adapted by Japanese practitioners to meet their particular circumstances and gradually evolved into Kampo [29]. A recent study has found that some in Japan use Kampo medicines in their daily practice—sometimes as the preferred medication [29–31]. Together with radiotherapy or , some Japanese physicians frequently utilize Kampo medicines in treating . This indicates how modern Western medicine can be well integrated with TM [30,32]. As the use of Kampo continues to rise in conjunction with Western medicine, there is growing realization of the urgent need to study the interactions between these two types of medicines [28]. Unani is an ancient Greek holistic medical system with a history that can be traced back 2500 years [33]. Since the mid-1970s, when the WHO began to place a greater focus on TM, Unani has attracted considerable attention all over the world, especially in , where it has been integrated into the national health care system [34]. It was reckoned by WHO that a large quantity of people in the world still depend on TMs for health care [35]. The current status of TM differs in different countries. In 2012, the total value of the TCM industry was equivalent to around one-third of the total for China’s pharmaceutical industry [36]. It has been determined that 80% of the in makes use of TM—either alone or in conjunction with conventional medicine [37]. By contrast, traditional Aboriginal medicine in is in danger of vanishing owing to the prevalence of conventional medicine [38]. In the case of Israel with its ethnic diversity, modern medicine is prevailing, and TM is declining [39]. Many practitioners of Western medical think such TM systems as being short of reliability; however, they are adopted by the majority of people in the world [35]. It is possible to produce remarkable synergy and yield great benefits in developing reformed medicines and new drugs by connecting powerful modern scientific techniques and methods with the reasonable ethnobotanical and ethnomedical experiences of TM. Characteristics of several TM systems are summarized in Table1.

4. Drugs Developed from Traditional Medicines that Follow the Traditional Uses TM is too valuable to be ignored in the research and development of modern drugs. Though it has an enigmatic character, there are also wide contexts for its use in terms of non-Western medical technology or activities. In TM, a single or formula may contain many constituents, such as alkaloids, terpenoids, flavonoids, etc. Generally speaking, these chemicals function alone or in conjunction with one another to produce the desired pharmacological effect [35]. It is notable that a lot of plant-originated drugs in clinical medicine today were derived from TM [21]. In addition, it has been demonstrated that the many valuable drugs derived from plants were discovered through their application in TM [2]. Almost 20 years ago, a thorough investigation of the pharmacopoeias of developed and developing and the associated world scientific literature was conducted as part of the WHO’s TM Program. The aim of that study was to determine whether TM really had inspired modern drug discoveries and whether there was any correlation between the current use of various compounds and their application in TM. The study focused on various compounds used in drugs derived from plants in different countries, and it established that TM had indeed played a significant role in developing effective new drugs. That study focused on 122 compounds, 80% of which were found to be related to pharmaceutical effects in folk medicine, and it was determined that these compounds originated from 94 plant species [2]. Molecules 2016, 21, 559 5 of 18

Table 1. Characteristics of several important traditional medicine systems.

Name Origin and Developing Characteristics of Theory or Application Current Role or Status Modern Research

‚ Both TCM and conventional medicine exist at every ‚ TCM is based on Yinyang and gradation of the health-care ‚ The pharmacology of TCM Wuxing concepts. system, and both are covered has made great advancements. ‚ A TCM formula includes a group of under public and ‚ In recent decades, many TCM various drugs that function together private insurance. active compounds and Traditional Chinese medicine ‚ China congenially to achieve a ‚ There is a TCM division in compound-based therapeutics (TCM) [26,28,40–43] ‚ Thousands of years ago. synergistic effect. most ordinary hospitals and have been discovered. ‚ A classic formula is composed of four TCM services are supplied for ‚ Great efforts have been made elements: monarch, minister, assistant, both inpatients to reveal the underlying and servant according to their roles in and outpatients. molecular mechanisms the formula. ‚ TCM is attracting increasing of TCM. attention, interest, and acceptance around the world.

‚ Ayurveda uses natural elements to eradicate the main cause of the by reinstating balance. ‚ More than 400,000 Ayurveda ‚ Pharmacologically-active ‚ India ‚ The Ayurvedic philosophy is to live a practitioners are registered. compounds of Ayurvedic ‚ Ayurveda can be dated back healthy life to avoid the appearance of ‚ The Indian government has an medicine and their Ayurveda [35,44] to the pre-Vedic epochs imbalance and unnecessary pain. official body to ensure effectiveness in treatment has (4000 BC–1500 BC) Ayurveda’s educational ‚ In many Ayurvedic treatments, been increasingly recognized. multiple herbs are united in a special efforts, quality, and practice. quotient to create an ideal therapeutic effect and lessen the toxicity.

‚ It treats a person’s body, , and soul as a whole. ‚ Unani is accepted by India as ‚ Unani looks upon the as meeting the health-care needs ‚ India a single unit, which consists of four of people and has gained ‚ derived from basic elements which have four formal status. ‚ Many bioactive ingredients Greco- medicine dating disparate temperaments respectively. ‚ Unani has been acknowledged have been separated from Unani medicine [33,34,45,46] back 2500 years and ‚ A person’s temperament reflects their by the WHO as an alternative mangrove plants which are developed during the physical characteristics and health-care system. used in Unani medicine. Arab civilization. natural disposition. ‚ Unani is one of the most ‚ Disproportion in temperament makes important traditional the human body susceptible to medicine systems. many illnesses. Molecules 2016, 21, 559 6 of 18

Table 1. Cont.

Characteristics of Theory or Name Origin and Developing Nation Current Role or Status Modern Research Application

‚ Kampo was developed over the ‚ Kampo formulas are past 1400 years and has been produced by certificated drug organically unified with firms under strict quality Japanese original . management standards. ‚ Kampo treats every human ‚ Both the government and being as a complete and drug firms are deeply ‚ Japan self-controlled whole in which ‚ Kampo is incorporated into the involved in surveillance of all ‚ Kampo was introduced from body and mind health-care system in Japan. processes to ensure the quality Kampo (traditional China via the Korean impact mutually. ‚ All citizens can use of Kampo and safety of Japanese medicine) [30,47] peninsula in the 5th or ‚ Diseases are thought to originate herbal formulas approved by Kampo formulas. 6th century. from the disorders of psyche the government. ‚ There has also been a focus on and soma and are examining the efficacy of trusted to affect the soul and the Kampo formulas and body equally. exploring related mechanisms. ‚ Kampo places emphasis Kampo is regarded as on the sufferer as a whole very safe. instead of on the illness.

‚ SCM classifies persons into four ‚ Although the conventional Sasang types: Tae-Yang, ‚ The Lee Jema project to supply health-care organization is quite So-Yang, Tae-Eum, and So-Eum scientific proof of SCM began good in Korea, 86% of people according to his/her in 2006 and is supported by still employ SCM. Traditional Korean ‚ SCM is a division of Korean inborn features. the Korean government. traditional medicine. ‚ Traditional medicine doctors can medicine (TKM), Sasang ‚ SCM is holistic. ‚ It has gained many significant ‚ It was first introduced in the supply Korean SCM both in achievements involving constitutional medicine ‚ SCM is theoretically similar to mid-19th century. private and public hospitals. constitution-diagnostic means, (SCM) [42,48–50] . ‚ Both national medical insurance constitution-specific disease ‚ SCM supplies individualized and private insurance cover vulnerabilities, and and constitution-specific Korean SCM services. genetic research. treatments for various problems.

‚ Currently, there is only one national folk organization in operation. ‚ of Australia ‚ During 2010–2011, 32.1% of the believe that health problems chief, indigenous health-care Traditional Aboriginal ‚ Australia have three types of causes: organizations in Australia medicine [38,50] natural bodily causes, harmful provided some kind of spirits, or . traditional medicine services. ‚ Because of colonization, traditional Aboriginal medicine is in danger of becoming extinct. Molecules 2016, 21, 559 7 of 18

Table 1. Cont.

Characteristics of Theory or Name Origin and Developing Nation Current Role or Status Modern Research Application

‚ Eighty percent of African ‚ Traditional medicine doctors people use traditional treat patients holistically. medicine either by itself or ‚ They generally seek to with conventional medicine. recombine the mental and social ‚ Research on Hydnora africana, ‚ Up to 80% of Ghanaians and equipoise of sufferers according which is used as Ethiopians depend on to social relationships and rules. in Africa, has Traditional medicine in ‚ Africa traditional medicine for their ‚ The accessibility of traditional demonstrated the antioxidant Africa [25,37,38,51] main health-care demands. medicine is one of the most and antibacterial activities of ‚ ’s traditional medical important reasons for its natural products. system has been integrated popularity across Africa. into the national health-care ‚ Traditional medicine exemplifies system and, therefore, it is respect for the cultural heritage. comparatively well organized.

‚ Due to the special geographical ‚ Herbal therapy is a formal and environment of Russia, Russian independent department of herbal therapy has collected and ‚ Soviet/Russian researchers medicine in Russia; thus, adopted traditional medicine have focused mainly on the herbal medicinal products are methods that were introduced development of adaptogens ‚ Russia regarded as official remedies. from Europe and . derived from plants. Russian [52] ‚ 10th century ‚ A recent survey shows that ‚ The Russian Federation follows ‚ The collection of plants with 14% of the Russian people the State of the expectorant effects shows frequently use herbal USSR; 32 of 83 individual plant huge potential. remedies and 44% use monographs are found only in them occasionally. this Pharmacopoeia. Molecules 2016, 21, 559 8 of 18

The acceptability, convenience, and accessibility of TMs have been, and will be, helpful for new drug research [13]. As noted above, artemisinin and other antimalarial drugs are examples of modern drugs based on TMs. Early in China’s Jin Dynasty, Hong Ge (AD 284–384) recorded the efficacy and related details of L. in treating malaria in his book Zhou Hou Bei Ji Fang. That is the earliest record anywhere of treating malaria with Artemisia annua L., and it shows that Chinese physicians 1700 years ago had reached a sophisticated level of medical treatment [53,54]. Artemisinin is known as qinghaosu in Chinese, and its study has made significant progress, including the synthesis of new artemisinin analogs and derivatives, and research efforts into the biological activities and related mechanisms. As a result, artemisinin, as well as its effective derivatives, are extensively applied throughout the world as new-type anti-malarial drugs [55]. The discovery of artemisinin can be traced back to the 1960s, when tropical malaria was a serious problem during the Vietnam War. North Vietnam requested China to help tackle the malaria problem. The Chinese government approved a project for malaria control and drug research in 1967. The research group made its investigations and carried out a large-scale search of the literature on the subject. As part of the phytochemical and pharmacological research effort, a lot of Chinese herbal medicines were screened and investigated with respect to their toxicity or efficacy. Eventually artemisinin was derived from Artemisia annua L. in 1972 [53,55,56]. Artemisinin is quite different from previously-used antimalarial drugs, such as chloroquine, in that it has a novel structure, with a sesquiterpene lactone bearing a peroxy group, and it does not contain nitrogen heterocycles. Compared with previous antimalarial drugs, artemisinin has the merit of high efficiency, quick effect, and low toxicity. Artemisinin is effective in treating various forms of malaria, such as falciparum and cerebral malaria, which are resistant to chloroquine, and its mechanism of action is different from traditional antimalarial drugs. The discovery of artemisinin was a great success for TCM at a special period in China’s history, and it was achieved through a well-organized team of hundreds of researchers [56]. Since that breakthrough, scientists have conducted comprehensive research in such areas as pharmaceutical chemistry, organic synthetic chemistry, and chemical biology. Through etherification and esterification, they have produced a series of well-known new drugs, such as artemether and artesunate. Those drugs have improved efficacy and solubility, which are of benefit for patients receiving oral or intravenous administration and have overcome the high parasite recrudescence rate and low solubility of artemisinin [55–57]. Most importantly, one of these scientists, Youyou Tu, was just awarded the 2015 Nobel Medicine Prize for her significant devotion in discovering artemisinin. The discovery of artemisinin illustrates how TCM constitutes a great store of knowledge about natural products, such as Chinese herbs, and holds much future promise. The discovery of successful new drugs can proceed by profiting from this knowledge [56]. Some drugs or compounds isolated from Chinese herbal medicines which follow the ethnomedical uses are summarized in Table2. Molecules 2016, 21, 559 8 of 16 Molecules 2016,, 21,, 559 8 of 16 Molecules 2016Molecules, 21, 5592016 , 21, 559 8 of 16 9 of 18 Table 2. Some drugs or compounds isolated from Chinese herbal medicines which follow the traditional uses. Table 2.. Some drugs or compounds isolated from Chinese herbal medicines which follow the traditional uses. Table 2. Some drugs or compounds isolated from Chinese herbal medicines which follow the traditionalAncient uses. Chinese Literature Recording TableDrugs 2. orSome drugs or compounds isolated from Chinese herbal medicines which followAncient the traditional Chinese uses. Literature Recording Plant Origin Drugs or Chemical Structures Effects or Indications Chinese Herbal Medicines with Same Plant Origin Compounds Chemical Structures Effects or Indications ChineseAncient ChineseHerbal Medicines Literature withRecording Same CompoundsDrugs or Effects and the Published Time Plant Origin Chemical Structures Effects or Indications ChineseAncientEffects Herbal Chineseand the Medicines LiteraturePublished Recordingwith Time Same Chinese Herbal Plant Origin DrugsCompounds or Compounds Chemical Structures Effects or Indications Effects and the Published Time H Medicines with Same Effects and the Published Time H Effects and the Published Time H O O H O H O H Zhou Hou Bei Ji Fang OO Zhou Hou Bei Ji Fang Artemisia annua L. [53,55] Artemisinin O O Anti-malarial Zhou Hou Bei Ji Fang Artemisia annua L.. [53,55] Artemisinin O Anti-malarial (JinZhou Danasty, Hou Bei AD Ji 266Fang–420) Artemisia annua L. [53,55] Artemisinin O Anti-malarial (Jin Danasty, AD 266–420) ArtemisiaArtemisia annua annua L. [53,55]L. [53 ,55]Artemisinin Artemisinin O Anti-malarial Zhou(Jin Danasty, Hou Bei JiAD Fang 266 (Jin–420) Danasty, AD 266–420) O (Jin Danasty, AD 266–420) O O O

O O O O O CorydalisCorydalis yanhusuo yanhusuo O LeiLei Gong Gong Pao Pao Zhi Zhi Lun Lun TetrahydropalmatineTetrahydropalmatine O AnalgesicAnalgesic Lei Gong Pao Zhi Lun CorydalisCorydalis yanhusuo yanhusuo Tetrahydropalmatine O Lei Gong Pao Zhi Lun W.T.WangW.T.Wang [58,59] [58,59 ] TetrahydropalmatineTetrahydropalmatine O AnalgesicAnalgesic (NanchaoLei(Nanchao Gong Pao Song Song Zhi Dynasty,Lun Dynasty, (Nanchao AD AD 420–479) Song 420– Dynasty,479) AD 420–479) W.T.WangW.T.Wang [58,59 [58] ,59] O (Nanchao , AD 420–479) O O O Ligusticum chuanxiong Mmyocardial ischemia- Shen Nong Ben Cao Jing N Tetramethyl-pyrazine N LigusticumLigusticumHort. chuanxiong [60]chuanxiong N MMmyocardialreperfusionmyocardial ischemia injuryischemia - - (DonghanShenShen Nong NongDynasty, Ben Ben CaoAD Cao Jing25–220) Jing LigusticumLigusticum chuanxiong chuanxiong TTetramethyletramethyl-pyrazine-pyrazine MmyocardialMmyocardial ischemia-reperfusion ischemia- Shen Nong Ben Cao Jing Hort. [60] TetramethylTetramethyl-pyrazine-pyrazine N reperfusion injury Shen(Donghan Nong Ben Dynasty, Cao Jing (DonghanAD 25–220) Dynasty, AD 25–220) Hort. Hort.[60] [60] N reperfusioninjury injury (Donghan Dynasty, AD 25–220) N

Paeonia lactiflora Pall. Shen Nong Ben Cao Jing O Paeoniflorin O Analgesic [61,62] HO OH O (Donghan Dynasty, AD 25–220) HO OH HO OH H O Paeonia lactiflora Pall. H O Shen Nong Ben Cao Jing H O PaeoniaPaeonia lactiflora lactiflora Pall. Pall. Paeoniflorin HO O H Analgesic Shen Nong Ben Cao Jing Paeonia lactiflora Pall. PaeoniflorinPaeoniflorin HO O H AnalgesicAnalgesic ShenShen Nong Nong Ben Cao Ben Jing Cao (Donghan Jing Dynasty, AD 25–220) [61,62[61] ,62] Paeoniflorin HO O H Analgesic (Donghan Dynasty, AD 25–220) [61,62] OH (Donghan Dynasty, AD 25–220) [61,62] OH (Donghan Dynasty, AD 25–220) O OH OH O OH O OH O O O O O O H H Epimedium brevicornum H Shen Nong Ben Cao Jing Icariin Osteoporosis Maxim. [63,64] (Donghan Dynasty, AD 25–220)

O O OH O OH O OH EpimediumEpimedium brevicornum brevicornum HO O O O Shen Nong Ben Cao Jing Epimedium brevicornum HO O O Shen Nong Ben Cao Jing Epimedium brevicornum IcariinIcariin HO O O OsteoporosisOsteoporosis ShenShen Nong Nong Ben Cao Ben Jing Cao (Donghan Jing Dynasty, AD 25–220) Epimedium brevicornum Icariin HO O O O OH Osteoporosis Shen Nong Ben Cao Jing Maxim.Maxim. [63,64 [63], 64] Icariin O OH Osteoporosis (Donghan Dynasty, AD 25–220) Icariin O O OH Osteoporosis Maxim. [63,64] O OH (Donghan Dynasty, AD 25–220) Maxim. [63,64] HO O O (Donghan Dynasty, AD 25–220) HO O O HO O O OH O O OH HO OH OH O HO OH HO OH O HO OH Pueraria lobata HO HO Shen Nong Ben Cao Jing Puerarin HO (Willd.) Ohwi [65] (Donghan Dynasty, AD 25–220)

Molecules 2016, 21, 559 10 of 18

Table 2. Cont.

Molecules 2016, 21, 559 9 of 16 MoleculesMolecules 201 2016, 216, ,21 559, 559 Ancient Chinese Literature Recording9 of9 Chinese 16of 16 Herbal Plant Origin Drugs or Compounds Chemical Structures Effects or Indications Medicines with Same Effects and the Published Time OH OH OH OH OH OH OH OH

O O O OH OH PuerariaPueraria lobata lobata OH OH Shen Nong Ben Cao Jing PuerariaPueraria lobata lobata Puerarin HO O Diabetes ShenShen Nong Nong Ben Ben Cao Cao Jing Jing Puerarin HO O Diabetes (Willd.) Ohwi(Willd.) [65 Ohwi] PuerarinPuerarinPuerarin HO HO O O DDiabetesiabetesDiabetes (Donghan Shen Nong Dynasty, Ben Cao Jing AD (Donghan 25–220) Dynasty, AD 25–220) (Willd.)(Willd.) Ohwi Ohwi [[6565 []]65 ] (Donghan(Donghan Dynasty, Dynasty, AD AD 25 –25220)–220)

O O O OH OH OH OH

OH OH OH OH O O O OH OH OH OH OH OH OH O OH HO O OH O OH miltiorrhiza HO O OH O OH OH Cardiovascular and Shen Nong Ben Cao Jing Salvia miltiorrhiza HO HO O O OH OH O O O Cardiovascular and Shen Nong Ben Cao Jing SalviaSalvia miltiorrhizaSalvia miltiorrhiza miltiorrhiza Salvianolic acid B O CardiovascularCardiovascularCardiovascular and cerebrovascular and and ShenShen Nong Nong Ben Ben Cao Cao Jing Jing SalvianolicSalvianolic acid acid B B O O Shen Nong Ben Cao Jing (Donghan Dynasty, AD 25–220) Bunge [66,67] SalvianolicSalvianolic acid acid B B O cerebrovascular diseases (Donghan Dynasty, AD 25–220) Bunge [Bunge66,67] [66,67] O cerebrovasculardiseases diseases (Donghan Dynasty, AD 25–220) BungeBunge [66,67 [66,67] ] O O O O cerebrovascularcerebrovascular diseases diseases (Donghan(Donghan Dynasty, Dynasty, AD AD 25 –25220)–220) O O O O O O OH OH OH OH

HO HO OH HO HO OH OH OH

N N N N O O Uncaria rhynchophyllaUncaria O O Ming Yi Bie Lu UncariaUncaria rhynchophylla rhynchophylla Rhynchophy-lline H Antihypertensive MingMing Yi YiBie Bie Lu Lu rhynchophylla RhynchophyRhynchophy-lline-lline H AntihypertensiveAntihypertensive Ming Yi Bie Lu (Nanchao Liang Dynasty, AD 502–557) (Miq.) Jacks. [68] RhynchophyRhynchophy-lline-lline N O H H AntihypertensiveAntihypertensive (Nanchao Liang Dynasty, AD 502–557) (Miq.) Jacks. [68] NH O (Nanchao Liang Dynasty, AD 502–557) (Miq.) Jacks. [68 ] NH N O O (Nanchao Liang Dynasty, AD 502–557) (Miq.) Jacks.(Miq.) [68 Jacks.] [68] H H (Nanchao Liang Dynasty, AD 502–557) O O O O O O O O

H H H HO O O O SaussureaSaussurea lappa lappa O O O O Anti-gastric ulcer, Shen Nong Ben Cao Jing SaussureaSaussurea(Decne.) lappa lappa C.B. CostunolideCostunolide Anti-gastricAntiAnti-gastric ulcer,-gastricantispasmodic ulcer, ulcer, ShenShen NongShen Nong BenNong CaoBen Ben JingCao Cao (Donghan Jing Jing Dynasty, AD 25–220) (Decne.) C.B. Clarke [69] CostunolideCostunolide antispasmodic (Donghan Dynasty, AD 25–220) (Decne.)(Decne.) C.B. C.B. ClarkeClarke Clarke [6969 []]69 ] H antispasmodicantispasmodic (Donghan(Donghan Dynasty, Dynasty, AD AD 25 –25220)–220) H H

HO HO HO HO

HO HO Gastrodia dlata Bl. HO HO O OH Shen Nong Ben Cao Jing O OH Shen Nong Ben Cao Jing Gastrodia dlata Bl. [70,71] GGastrodinastrodin O O OH OH AntiAnti-convulsion,-convulsion, analgesic analgesic ShenShen NongShen Nong BenNong CaoBen Ben JingCao Cao (Donghan Jing Jing Dynasty, AD 25–220) GastrodiaGastrodia dlata dlata Bl.[ 70Bl. [70,71,71 [70,71] ] ] GastrodinGastrodin AntiAnti-convulsion,-convulsion, analgesic analgesic (Donghan Dynasty, AD 25–220) HO O (Donghan Dynasty, AD 25–220) HO O (Donghan(Donghan Dynasty, Dynasty, AD AD 25 –25220)–220) HO HO O O OH OH OH OH Molecules 2016, 21, 559 11 of 18

5. Drugs Developed from Natural Products In clinical practice in China in the 1960s, it was found that Schisandra chinensis (Turcz.) Baill.—a traditional Chinese herb—had obvious -reducing and hepatoprotective effects. Chinese scientists then began isolating the chemical constituents of S. chinensis. In the subsequent total chemical synthesis and pharmacodynamic study of schisandrin C (which is one of the compounds of S. chinensis), researchers found that the intermediate compound bifendate had a stronger pharmacological activity and that the cost of preparation was low. They discovered that it may be used to lower the enzyme content in the treatment of B [57]. Since the end of the 1980s, chemists and pharmacologists at the Chinese Academy of Medical Sciences have been closely cooperating in studying the structure and activity relationships of bifendate and its analogs. As part of their research, a series of novel derivatives were synthesized. After screening using a number of chemical and pharmaceutical liver injury models, it was found that the hepatoprotective activities of the derivatives were closely related to the locations of dimethylenedioxy in two benzene rings, the length of the side-chain carboxylic acid, and the heterocycle between the two benzene rings. Finally, a new compound, bicyclol—formulated as 4,4”-dimethoxy-5,6,51,61-bis(methylene-dioxy)-2-hydroxy-methyl-21-methoxycarbonyl biphenyl—was designed and synthesized. Bicyclol had greater in vivo absorption, and better bioavailability and biological activity, than bifendate owing to the introduction of the 6-hydroxymethyl group and 61-carbomethoxy in the side chain [72]. Pharmacological results of bicyclol showed antifibrotic and hepatoprotective effects against liver injury and liver fibrosis induced by CCl4 or other hepatotoxins in mice and rats; it also exhibited the antihepatitis virus effect in the 2.2.15 line and duck model with viral hepatitis [73,74]. In clinical trials, it was found that the increased levels of alanine aminotransferase and aspartate aminotransferase were dramatically decreased by bicyclol. It was also found that bicyclol prohibited hepatitis B virus replication in chronic hepatitis B patients [75]. Compared with previous anti-hepatitis drugs, bicyclol exhibited a more consolidated effect after the drug was discontinued; the rebound rate was low, with fewer adverse reactions and higher oral bioavailability [76]. Based on previous studies in such areas as synthesis, pharmacology, , pharmacokinetics, preparation, and quality control, researchers determined that the new antihepatitis drug bicyclol offered significant hepatoprotective effects, antihepatitis virus activity, and fewer adverse reactions [57]. Bicyclol has been approved for the treatment of chronic viral hepatitis in China since 2004 [73]. Bicyclol has independent intellectual property rights and belongs to Class 1 of China’s New Chemical Drug. The drug is one of the anti-inflammatory and hepatoprotective drugs recommended by the “Guidelines on Clinical Diagnosis and Treatment” in China, and it has been exported to many countries [57,76]. In the same decade in which Chinese scientists found that S. chinensis (Turcz.) Baill. had obvious enzyme-reducing and hepatoprotective effects, a program screening for cancer drugs from plants began in 1960 at the National Cancer Institute in the . Neither China nor the United States knew what the other was doing in this area. In that US project, 650 plant samples were gathered in three states. After the initial cytotoxicity tests were carried out using crude , Taxus brevifolia was chosen for further research. Taxol was isolated as a new compound from T. Brevifolia. Taxol has an unusual chemical structure and radically distinctive mechanism of action and was developed as a novel anticancer drug in subsequent decades. Nevertheless, the drug attracted little attention during the early stage of its development because of its poor solubility in , low yield from natural products, and other disadvantages, particularly by the medical society. The story of Taxol involved many events that nearly resulted in discontinuation of the research. Fortunately, it underwent extraction, isolation, and structural determination; its activity against solid tumors and its mechanism of action were established, and it became developed for clinical practice. Finally, Taxol was approved by the US Food and Drug Administration for treating ovarian cancer in 1992—21 years after the initial breakthrough paper recording its isolation and structural identification. Taxol has remained a basic drug for treating various Molecules 2016, 21, 559 12 of 18 forms of cancer, and is still being used to develop new synergistic groups of anticancer drugs [77–79]. MoleculesMoleculesMolecules 201 201 20166, ,21 621,, 21,559 559, 559 1111 of11 of 16 of16 16 SomeMoleculesMolecules drugs 201 or6,, 2121 compounds,, 559559 isolated or developed from natural products are summarized in Table11113 . ofof 1616 MoleculesMolecules 2016, 20121, 6559, 21 , 559 11 of 1611 of 16 TableTableTable 3 3. . Some 3Some. Some drugs drugs drugs or or orcompounds compounds compounds isolated isolated isolated or or ordeveloped developed developed from from from natural natural natural products. products. products. TableTable 3. 3Some. Some drugs drugs or or compounds compounds isolated isolated or or developed developed from from natural natural products. products. TableTable 3. Some 3. Some drugs drugs or compounds or compounds isolated isolated or developed or developed from from natural natural products. products. OriginOriginOrigin (Plant, (Plant, (Plant, etc. etc. etc.) ) ) DrugsDrugsDrugs or or Compoundsor Compounds Compounds ChemicalChemicalChemical Structures Structures Structures EffectsEffectsEffects or or Indicationor Indication OriginOrigin (Plant,(Plant, etc.etc.)) DrugsDrugs oror CompoundsCompounds ChemicalChemical StructuresStructures EffectsEffects oror IndicationIndication OriginOrigin (Plant, (Plant,etc. etc.)) DrugsDrugs or or Compounds Compounds ChemicalChemical StructuresO Structures Effects or IndicationEffects or Indication Origin (Plant, etc.) Drugs or Compounds Chemical StructuresO O Effects or Indication OO O O O O O OH O H O O O OH O O O O H OOH O H Schisandra chinensis Schisandrin C, bicyclol, OOO O OH O Hepatoprotective, Schisandra chinensis Schisandrin C, bicyclol, O Hepatoprotective, Schisandra chinensis Schisandrin C, bicyclol, O O Hepatoprotective, OO O (Turcz.)Schisandra Baill. chinensis [55,72–76 ] Schisandrinbifendate C, bicyclol, O O O antiHepatoprotective-hepatitis B virus, (Turcz.)Schisandra(Turcz.)Schisandra Baill. Baill. chinensis [55,72 [55,72 chinensis– 76–76] ] SchisandrinSchisandrinbifendatebifendate C, bicyclol, C, bicyclol, O OO antiHepatoprotectiveanti-hepatitis-Hepatoprotectivehepatitis B virusB virus, , Schisandra chinensis chinensis SchisandrinSchisandrin C, bicyclol, C, bicyclol, OO Hepatoprotective,Hepatoprotective, (Turcz.) Baill. [55,72–76] bifendate O O O anti-hepatitis B virus (Turcz.) Baill. [55,72–76] bifendate O O O O anti-hepatitis B virus (Turcz.)(Turcz.) Baill. Baill.[55,72 [55,72–76] –76] bifendatebifendate O O anti-hepatitisanti-hepatitisanti- Bhepatitis virus B virus B virus (Turcz.) Baill. [55,72–76] bifendate O O O O O O O OO O O bicyclolbicyclolbicyclol bicyclolbicyclolO bicyclolbicyclolbicyclol O O OO O O O O O O O OH OH OH OH O O OH O O OH H OH O O OH O H OH OH N H OH O H N N OH O O H H OH OH H NH Taxus brevifolia [77–80] Taxol, docetaxel HN H OO H Antitumor Taxus brevifolia [77–80] Taxol, docetaxel O N O OH Antitumor Taxus brevifolia [77–80] Taxol, docetaxel O N O O O H O H Antitumor O O HO H H O Taxus brevifolia [77–80] Taxol, docetaxel OH O O Antitumor Taxus brevifolia [77–80] Taxol, docetaxel O O OH O Antitumor TaxusTaxus brevifolia brevifolia [77[77–80– [7780] ]–80] Taxol,Taxol,T docetaxelaxol, docetaxel docetaxel O O OOH HH O AntitumorAntitumorAntitumor O O O O H O O O H OHO O OOH O O OOH O O OH OO O O O OO OO O O OO taxoltaxoltaxol O O taxoltaxolO OH taxolO Otaxol OHOH OO OOHH O O H OH O O O O OO O O AspergillusAspergillus terreus terreus [ 81[81] ] LovastatinLovastatin O HHyperlipoidemiayperlipoidemia Aspergillus terreus [81] Lovastatin O HO Hyperlipoidemia Aspergillus terreus [81] Lovastatin H H Hyperlipoidemia AspergillusAspergillusAspergillus terreus terreus terreus [81[81] ][81] Lovastatin LovastatinLovastatin OO HyperlipoidemiaHyperlipoidemiaHyperlipoidemia Aspergillus terreus [81] Lovastatin O HH O Hyperlipoidemia H H

O O O OO O N O O O O N N OO NN O O N O O N Camptotheca acuminata Camptothecin, irinotecan HOO Camptotheca acuminata Camptothecin, irinotecan H Camptotheca acuminata Camptothecin, irinotecan OHO N Antitumor OO N Antitumor CamptothecaDecne. acuminata [1] acuminata Camptothecin,Camptothecin,and topotecan irinotecan irinotecan O N Antitumor CamptothecaDecne. acuminata [1] Camptothecin,and topotecan irinotecan O HHOO CamptothecaDecne. [1] acuminata Camptothecin,and topotecan irinotecan H AntitumorAntitumor Camptotheca acuminata Camptothecin, irinotecan HO O NN Antitumor Decne.Decne. [1] [1 ] andand topotecan topotecan N Antitumor Decne.Decne. [1] [1] and topotecanand topotecan N Antitumor Decne. [1] and topotecan

camptothecincamptothecincamptothecincamptothecin camptothecin camptothecincamptothecin H HO H H OH HOHHO OHOH HH H O O HHOOH H OH OOHH O Gimkgo biloba L. [82] Ginkgolide B O O O OHHO HO O O OH OHO O Cerebral infarction GimkgoGimkgo biloba biloba L. L.[82 [82] ] GinkgolideGinkgolide B B H H CerebralCerebral infarction infarction Gimkgo biloba L. [82] Ginkgolide B OO OO H OO OO Cerebral infarction Gimkgo biloba L. [82] Ginkgolide B O O O OO O Cerebral infarction GimkgoGimkgo biloba biloba L. [82 L.] [82] GinkgolideGinkgolide B B O O O O O O CerebralCerebral infarction infarction Gimkgo biloba L. [82] Ginkgolide B O OO Cerebral infarction OO O O OH OH OO O OHOH O H H O O O O OOHH O HH OH H H OHOH OH OH HO OH HO HO OH OH OH H HOO HO HO HO O OH PolygonumPolygonumPolygonum multiflorum multiflorum multiflorum HO HO O O OH OH Polygonum multiflorum Stilbene glycoside HO OH O Vascular dementia Stilbene glycoside HO OH O OHH Vascular dementia Polygonum multiflorum SStilbenetilbene glycoside glycoside HHO OH O O VascularV dementiaascular dementia PolygonumThunb. multiflorum [83] HO HOO O OH OH PolygonumThunb.Thunb.Thunb. [ [8383 [multiflorum83] ] ] H HO Polygonum multiflorum SStilbenetilbene glycosideglycoside OOH VVascularascular dementiadementia Stilbene glycoside HO OH Vascular dementia Thunb.Thunb. [[8383]] Stilbene glycoside HOOH Vascular dementia Thunb.Thunb. [83] [83] HO HO

OH OH OH H OOH OH O OH O O O Ranunculus ternatus ternatus O RanunculusRanunculus ternatus ternatus O O TTernatolideernatolideTernatolide O Anti-tuberculosisAAntinti-tuberculosis-tuberculosis Ranunculushunb. [84,85 ternatus] Ternatolide O O OO Anti-tuberculosis Ranunculushunb.hunb. [ 84,85 84ternatus,85] ] O O RanunculusRanunculushunb. ternatus [84,85 ternatus] Ternatolide O O O Anti-tuberculosis hunb. [84,85] TernatolideTernatolide Anti-tuberculosisAnti-tuberculosis hunb. [84,85] OO hunb.hunb. [84,85 []84,85 ] O O O O O O O O OO OO O OO O CurcumaCurcuma longa longa L. L. [ 86[86] ] CCurcuminurcumin HHypolipidemicypolipidemic Curcuma longa L. [86] HO OH Hypolipidemic CurcumaCurcuma longalonga L.L. [[8686]] CCurcuminurcumin HO HO OH OH HHypolipidemicypolipidemic CurcumaCurcuma longa longaL. [86 L.] [86] CurcuminCurcumin HO O O OH HypolipidemicHypolipidemic HO O O O O OH HO HO OH OH OO OO O O O O Molecules 2016, 21, 559 11 of 16

Table 3. Some drugs or compounds isolated or developed from natural products.

Origin (Plant, etc.) Drugs or Compounds Chemical Structures Effects or Indication

O

O

OH O Schisandra chinensis Schisandrin C, bicyclol, O Hepatoprotective, O (Turcz.) Baill. [55,72–76] bifendate O anti-hepatitis B virus

O

O bicyclol

O

O O OH OH H N O H Taxus brevifolia [77–80] Taxol, docetaxel Antitumor O O H O O OH O O O taxol

O OH

O

Aspergillus terreus [81] Lovastatin O Hyperlipoidemia H

O

O N

Camptotheca acuminata Camptothecin, irinotecan O HO Antitumor Decne. [1] and topotecan N

camptothecin

H HO OH H Gimkgo biloba L. [82] Ginkgolide B O O O O Cerebral infarction O O O OH H

OH

HO

Polygonum multiflorum HO O OH Stilbene glycoside OH Vascular dementia Thunb. [83] HO Molecules 2016, 21, 559 13 of 18

OH

Table 3. Cont. O Ranunculus ternatus O Ternatolide Anti-tuberculosis hunb. [84,85] Origin (Plant, etc.) Drugs or Compounds Chemical StructuresO Effects or Indication

O O

CurcumaCurcuma longa longaL. L. [86 [86]] CurcuminCurcumin HypolipidemicHypolipidemic MoleculesMolecules 201 20166, ,21 21, ,559 559 HO OH 1212 of of 16 16 O O

HO HO O HO O HO O C O C

CH2 HO OH CH2 HO OH O HO O Ophiopogon japonicus O HO Anti-myocardial cell OphiopogonOphiopogon japonicus japonicus O C Anti-myocardialAnti-myocardial cell PPolysaccharideolysaccharidePolysaccharide MDG MDG MDG-1-1-1 C (L.f.) Ker-Gawl. [87] CH injury (L.f.)(L.f.) Ker-Gawl.Ker-Gawl. [87 [87] ] 2H cell injuryinjury OH C 2 OH O O O O O HO O O OH O OH O HO O OH O OH O

OH CH2 OH OH OH CH2 n OH OH OH n OH

O O O - O i P-r i Pr S S NH NH H H H H NH NH O ChromobacteriumChromobacterium O RomidepsinRomidepsin O AntitumorAntitumor Romidepsin O Antitumor violaceum [88[88] ] S S violaceum [88] S S H H - NH i P-r NH i Pr O O NH NH O O

6.6.6. Discussion Discussion Discussion HumanHumanHuman history historyhistory is alsoisis alsoalso the thethe history historyhistory of medicines ofof medicinesmedicines used usedused to treat toto treat andtreat preventandand preventprevent various variousvarious diseases. diseases.diseases. To counterToTo counter counter the danger the the danger danger from from from serious serious serious illnesses illnesses illnesses and and toand guarantee to to guarantee guarantee survival survival survival of theof of the the species, species, species, it isit it is necessaryis necessary necessary toto continuallyto continually continually produce produce produce better better better drugs. drugs. drugs. With With With time, time, time, the the the use use use of of of these these these natural natural natural products products products as as as TM TM TM increased. increased. increased. ModernModernModern medicine medicine medicine has ha ha benefitedss benefited benefited considerably considerably considerably from from from TM TM TM in in twoin two two areas: areas: areas: drugs drugs drugs with with with similar similar similar effects effects effects and and and drugsdrugsdrugs with with with different different different effects effects effects from from from those those those of TM. of of TM. FromTM. From From the historythe the history history of drug of of drug development,drug development, development, it is evident it it is is evident evident that manythatthat drugsmany many havedrugs drugs been have have derived been been derived derived as a result as as a a ofresult result inspiration of of inspiration inspiration from TM. from from TM. TM. TheTheThe application application application of, of of and, ,and and research research research into, into into natural, ,natural natural products products products are are are far far far from from from satisfactory. satisfactory. satisfactory. A A numberA number number of of of problemsprproblemsoblems need need need to to beto be be addressed addressed addressed in in thein the the future. future. future. For For For example, example, example, synergistic synergistic synergistic effects effects effects may may may exist exist exist among among among the the the compoundscompoundscompounds that that that occur occur occur in in naturalin natural natural products; products; products; however, however, however, the the the modes modes modes and and and mechanisms mechanisms mechanisms of of actionof action action are are are seldom seldom seldom veryveryvery clear. clear. clear. It is,It It is therefore,is, ,therefore therefore necessary, ,necessary necessary to to maketo make make full full full use use use of of suchof suc suc synergetichh synergetic synergetic effects effects effects toward toward toward improving improving improving the the the effectivenesseffectivenesseffectiveness of of drugs.of drugs. drugs. However, However, However, it it isit is alsois also also requisite requisite requisite that that that any any any adverse adverse adverse effects effects effects of of naturalof natural natural products products products be be be properlyproperlyproperly reduced reduced reduced to to meetto meet meet safety safety safety standards. standards. standards. WithWithWith the thethe riches richesriches of ofof modern modernmodern technology, technology,technology, such suchsuch as asas in inin synthesis, synthesis,synthesis, fermentation, fermentation,fermentation, pharmacology, pharmacology,pharmacology, pharmacodynamics—togetherpharmacodynamicspharmacodynamics——togethertogether with with with biological biological biological diversity, diversity, diversity, chemodiversity, chemodiversity chemodiversity and, ,and and great great great breakthroughs breakthroughs breakthroughs in in in evolutionaryevolutionaryevolutionary techniques techniques techniques or or concepts—combinedor concepts concepts——combinedcombined with with with a wealtha a wealth wealth of of knowledgeof knowledge knowledge about about about natural natural natural products, products, products, it willitit will will be be be possible possible possible to to establishto establish establish a largea a l argelarge compound compound compound library library library for for for drug drug drug screening screening screening [89 [ 89[].89 This]]. .This This will will will enhance enhance enhance the the the possibilitiespossibilitiespossibilities for for individualfor individualindividual treatment treatmenttreatment and and preventionand preventionprevention of disease. ofof disease.disease. Humankind HumankindHumankind needs needs toneeds learn toto more learnlearn from moremore naturalfromfrom natural productsnatural products products and traditional and and traditional traditional medicines. medicines medicines. . InIn orderIn order order to to furtherto further further promote promote promote the the the development development development of of modernof modern modern medical medical medical research research research on on on natural natural natural products, product productss, , humanshumanhuman havess havehave to to faceto faceface up upup to to variousto variousvarious difficulties difficultiesdifficulties and andand challenges. challenges.challenges. Valuable VValuablealuable information informationinformation on onon natural naturalnatural productsproductsproducts and and and TMs TMs TMs is is mixedis mixed mixed in in ain largea a large large number number number of of documents,of documents documents data,, ,data, data, and and and useless useless useless rumors. rumors. rumors. Furthermore, Furthermore Furthermore, , oneoneone plant plant plant or or formulaor formula formula of of naturalof natural natural products products products and and and TMs TMs TMs contains contains contains a largea a large large number number number of of chemicalof chemical chemical constituents, constituents, constituents, includingincludingincluding active, active,active, invalid, invalid,invalid, and andand possible possiblepossible synergistic synergisticsynergistic components. componentscomponents Therefore,. . Therefore,Therefore, great greatgreat effort efforteffort should shouldshould be bebe mademademade at at firstat first first to to removeto remove remove the the the dross dross dross and and and take take take the the the essence—precious essence essence——preciousprecious experience experience experience of of naturalof natural natural products products products and and and TMs.TMs.TMs. Furthermore, Furthermore,Furthermore, in ini manyn manymany cases, cases,cases, the thethe role rolerole of of singleof singlesingle compound compoundcompound from fromfrom natural naturalnatural products productsproducts and andand TMs TMsTMs is isis paidpaid muchmuch attentionattention to.to. However,However, asas aa mattermatter ofof fact,fact, oonene advantageadvantage ofof TMTM’s’s therapeuticstherapeutics isis thethe “synergism”“synergism”; ;that that is, is, often often multiple multiple components components in in TMs TMs play play a a synergistic synergistic role role which which is is greater greater than than thatthat of of the the individual individual drug. drug. In In the the meantime meantime, ,the the “1 “1 disease, disease, 1 1 target, target, 1 1 drug” drug” mode mode can cannotnot treat treat some some complexcomplex diseasesdiseases effectivelyeffectively, , suchsuch asas cardiovascularcardiovascular diseasedisease and and diabetes. diabetes. ThusThus, , thethe treatmenttreatment hashas seenseen a a shift shift to to the the “ “multimulti--drugdrugss and and multi multi--targettargetss”” mode mode for for combination combination therapies. therapies. Therefore, Therefore, in in the the future,future, m multidisciplinaryultidisciplinary collaborative collaborative research research, ,closely closely cooperated cooperated with with new new ideas, ideas, such such as as network network pharmacologypharmacology andand bbigig datadata, , willwill bebe possiblepossible toto explainexplain thethe synergsynergismism andand otherother mechanismmechanismss ofof naturalnatural products products and and TMs TMs from from which which more more and and better better new new drugs drugs and and treatment treatment will will be be discovered discovered andand inspired inspired. . Molecules 2016, 21, 559 14 of 18

paid much attention to. However, as a of fact, one advantage of TM’s therapeutics is the “synergism”; that is, often multiple components in TMs play a synergistic role which is greater than that of the individual drug. In the meantime, the “1 disease, 1 target, 1 drug” mode cannot treat some complex diseases effectively, such as cardiovascular disease and diabetes. Thus, the treatment has seen a shift to the “multi-drugs and multi-targets” mode for combination therapies. Therefore, in the future, multidisciplinary collaborative research, closely cooperated with new ideas, such as network pharmacology and big data, will be possible to explain the synergism and other mechanisms of natural products and TMs from which more and better new drugs and treatment will be discovered and inspired.

Acknowledgments: This review was supported in part by research grants (No. 81260669 and 81560698) from National Natural Science Foundation of China, respectively. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Shi, Q.W.; Li, L.G.; Huo, C.H.; Zhang, M.L.; Wang, Y.F. Study on natural medicinal chemistry and new drug development. Chin. Tradit. Herb. Drugs 2010, 41, 1583–1589. 2. Fabricant, D.S.; Farnsworth, N.R. The Value of Plants Used in Traditional Medicine for Drug Discovery. Environ. Health Perspect. 2001, 109, 69–75. [CrossRef][PubMed] 3. Gao, X.M.; Zhang, T.M.; Zhang, J.R.; Guo, J.S.; Zhong, G.S. Chinese ; China Press of traditional Chinese Medicine: Beijing, China, 2007. 4. Alves, R.R.; Rosa, I.M. Biodiversity, traditional medicine and : Where do they meet? J. Ethnobiol. Ethnomed. 2007, 3.[CrossRef][PubMed] 5. Dong, J.C. The Relationship between Traditional Chinese Medicine and Modern Medicine. Evid. Based Complment. Altern. Med. 2013, 2013.[CrossRef][PubMed] 6. Zhang, L.H.; Li, J. Current situation and developing trends of modernization of traditional Chinese Medicine. J. Zhejiang Univ. Med. Sci. 2011, 40, 349–353. 7. Chan, K.; Shaw, D.; Simmonds, M.S.; Leon, C.J.; Xu, Q.; Lu, A.; Sutherland, I.; Ignatova, S.; Zhu, Y.P.; Verpoorte, R.; et al. Good practice in reviewing and publishing studies on herbal medicine, with special emphasis on traditional Chinese medicine and Chinese materia medica. J. Ethnopharmacol. 2012, 140, 469–475. [CrossRef][PubMed] 8. Tu, P.F.; Guo, H.Z.; Guo, D.A. Researches on active constituents of natural and traditional medicine and development of new drugs. J. Peking Univ. Health Sci. 2002, 34, 513–518. 9. Zhang, L.; Yan, J.; Liu, X.; Ye, Z.; Yang, X.; Meyboom, R.; Chan, K.; Shaw, D.; Duez, P. practice and risk control of Traditional Chinese Medicine drugs in China: Current status and future perspective. J. Ethnopharmacol. 2012, 140, 519–525. [CrossRef][PubMed] 10. Joo, Y.E. Natural product-derived drugs for the treatment of inflammatory bowel diseases. Intest. Res. 2014, 12, 103–109. [CrossRef][PubMed] 11. Hamilton, G.R.; Baskett, T.F. In the arms of Morpheus the development of morphine for postoperative pain relief. Can. J. Anaesth. 2000, 47, 367–374. [CrossRef][PubMed] 12. Newman, D.J.; Cragg, G.M.; Snader, K.M. Natural Products as Sources of New Drugs over the Period 1981–2002. J. Nat. Prod. 2003, 66, 1022–1037. [CrossRef][PubMed] 13. Ngo, L.T.; Okogun, J.I.; Folk, W.R. natural product research and drug development and traditional medicines. Nat. Prod. Rep. 2013, 30, 584–592. [CrossRef][PubMed] 14. Zhu, F.; Ma, X.H.; Qin, C.; Tao, L.; Liu, X.; Shi, Z.; Zhang, C.L.; Tan, C.Y.; Chen, Y.Z.; Jiang, Y.Y. Drug discovery prospect from untapped species: Indications from approved natural product drugs. PLoS ONE 2012, 7, e39782. [CrossRef][PubMed] 15. Galm, U.; Shen, B. Natural product drug discovery: The times have never been better. Chem. Biol. 2007, 14, 1098–1104. [CrossRef][PubMed] 16. Hong, J.Y. Natural product diversity and its role in chemical biology and drug discovery. Curr. Opin. Chem. Biol. 2011, 15, 350–354. [CrossRef][PubMed] Molecules 2016, 21, 559 15 of 18

17. Rosén, J.; Gottfries, J.; Muresan, S.; Backlund, A.; Oprea, T.I. Novel chemical space exploration via natural products. J. Med. Chem. 2009, 52, 1953–1962. [CrossRef][PubMed] 18. Butler, M.S. Natural products to drugs: Natural product-derived compounds in clinical trials. Nat. Prod. Rep. 2008, 25, 475–516. [CrossRef][PubMed] 19. Muschietti, L.; Vila, R.; Filho, V.C.; Setzer, W. Tropical Protozoan Diseases: Natural Product Drug Discovery and Development. Evid. Based Complement. Altern. Med. 2013, 2013.[CrossRef][PubMed] 20. Cragg, G.M.; Newman, D.J. Natural products: A continuing source of novel drug . Biochim. Biophys. Acta 2013, 1830, 3670–3695. [CrossRef][PubMed] 21. Li-Weber, M. New therapeutic aspects of flavones: The anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat. Rev. 2009, 35, 57–68. [CrossRef][PubMed] 22. Winter, J.M.; Tang, Y. Synthetic biological approaches to natural product biosynthesis. Curr. Opin. Biotechnol. 2012, 23, 736–743. [CrossRef][PubMed] 23. Li, J.W.; Vederas, J.C. Drug discovery and natural products: End of an era or an endless frontier? Science 2009, 325, 161–165. [CrossRef][PubMed] 24. Abdullahi, A.A. Trends and challenges of traditional medicine in Africa. Afr. J. Tradit. Complement. Altern. Med. 2011, 8, 115–123. [CrossRef][PubMed] 25. World Health Organisation. General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine; World Health Organisation: Geneva, Switzerland, 2000. 26. , F.H.; Wang, Z.X.; Cai, P.P.; Zhao, L.; Gao, J.J.; Kokudo, N.; Li, A.Y.; Han, J.Q.; Tang, W. Traditional Chinese medicine and related active compounds: A review of their role on hepatitis B virus . Drug Discov. Ther. 2013, 7, 212–224. [CrossRef][PubMed] 27. Dobos, G.J.; Tan, L.; Cohen, M.H.; McIntyre, M.; Bauer, R.; Li, X.; Bensoussan, A. Are national quality standards for traditional Chinese herbal medicine sufficient? Current governmental regulations for traditional Chinese herbal medicine in certain Western countries and China as the Eastern origin country. Complement. Ther. Med. 2005, 13, 183–190. [CrossRef][PubMed] 28. Zhang, A.H.; Sun, H.; Qiu, S.; Wang, X.J. Advancing drug discovery and development from active constituents of yinchenhao tang, a famous traditional Chinese medicine formula. Evid. Based Complement. Altern. Med. 2013, 2013.[CrossRef][PubMed] 29. Watanabe, S.; Imanishi, J.; Satoh, M.; Ozasa, K. Unique place of Kampo (Japanese traditional medicine) in complementary and alternative medicine: A survey of doctors belonging to the regional medical association in Japan. Tohoku J. Exp. Med. 2001, 194, 55–63. [CrossRef][PubMed] 30. Yakubo, S.; Ito, M.; Ueda, Y.; Okamoto, H.; Kimura, Y.; Amano, Y.; Togo, T.; Adachi, H.; Mitsuma, T.; Watanabe, K. Pattern classification in kampo medicine. Evid. Based Complement. Altern. Med. 2014, 2014. [CrossRef][PubMed] 31. Mogami, S.; Hattori, T. Beneficial effects of rikkunshito, a Japanese kampo medicine, on gastrointestinal dysfunction and anorexia in combination with Western drug: A systematic review. Evid. Based Complement. Altern. Med. 2014, 2014.[CrossRef][PubMed] 32. Yu, F.; Takahashi, T.; Moriya, J.; Kawaura, K.; Yamakawa, J.; Kusaka, K.; Itoh, T.; Morimoto, S.; Yamaguchi, N.; Kanda, T. Traditional Chinese medicine and Kampo: A review from the distant past for the future. J. Int. Med. Res. 2006, 34, 231–239. [CrossRef][PubMed] 33. Lone, A.H.; Ahmad, T.; Anwar, M.; Sofi, G.; Imam, H.; Habib, S. Perception of health promotion in Unani herbal medicine. J. Herb. Med. 2012, 2.[CrossRef] 34. Jabin, F. A guiding tool in Unani Tibb for maintenance and preservation of health: A review study. Afr. J. Tradit. Complement. Altern. Med. 2011, 8, 140–143. [CrossRef][PubMed] 35. Parasuraman, S.; Thing, G.S.; Dhanaraj, S.A. Polyherbal formation: Concept of ayurveda. Pharmacogn. Rev. 2014, 8, 73–80. [CrossRef][PubMed] 36. Lu, M. Status and Trends of Chinese Traditional Medicine Industry. Chin. J. Pharm. Ind. 2013, 44, 214–216. 37. Boakye, M.K.; Pietersen, D.W.; Kotzé, A.; Dalton, D.L.; Jansen, R. Knowledge and uses of African pangolins as a source of traditional medicine in Ghana. PLoS ONE 2015, 10, e0117199. [CrossRef][PubMed] 38. Oliver, S.J. The role of traditional medicine practice in within Aboriginal Australia: A review of the literature. J. Ethnobiol. Ethnomed. 2013, 9.[CrossRef][PubMed] 39. Lev, E. Ethno-diversity within current ethno-pharmacology as part of Israeli traditional medicine–a review. J. Ethnobiol. Ethnomed. 2006.[CrossRef] Molecules 2016, 21, 559 16 of 18

40. Brief Introduction of Huang Di Nei Jing. Available online: http://www.cssn.cn/sjxz/xsjdk/zgjd/zb/yj/ hdnjw/201503/ t20 150328_1564689. shtml (accessed on 28 April 2015). 41. Lehmann, H. A Westerner’s question about traditional Chinese medicine: Are the Yinyang concept and the Wuxing concept of equal philosophical and medical rank? J. Chin. Integr. Med. 2012, 10, 237–248. [CrossRef] 42. World Health Organization. WHO Traditional Medicine Strategy: 2014–2023; World Health Organization: Geneva, Switzerland, 2013. 43. Xue, R.; Fang, Z.; Zhang, M.; Yi, Z.; Wen, C.; Shi, T. TCMID: Traditional Chinese Medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res. 2013.[CrossRef][PubMed] 44. Patwardhan, B. Bridging Ayurveda with evidence-based scientific approaches in medicine. EPMA J. 2014. [CrossRef][PubMed] 45. Hongal, S.; Torwane, N.A.; Pankaj, G.; Chandrashekhar, B.R.; Gouraha, A. Role of unani system of medicine in management of orofacial diseases: A review. J. Clin. Diagn. Res. 2014, 8, ZE12–ZE15. [PubMed] 46. Govindasamy, C.; Kannan, R. of mangrove plants in the system of Unani medicine. Asia Pac. J. Trop. Dis. 2012, 2, S38–S41. [CrossRef] 47. Okamoto, H.; Iyo, M.; Ueda, K.; Han, C.; Hirasaki, Y.; Namiki, T. Yokukan-san: A review of the evidence for use of this Kampo herbal formula in dementia and psychiatric conditions. Neuropsychiatr. Dis. Treat. 2014. [CrossRef][PubMed] 48. Kim, J.U.; Ku, B.; Kim, Y.M.; Do, J.H.; Jang, J.S.; Jang, E.; Jeon, Y.J.; Kim, K.H.; Kim, J.Y. The concept of sasang health index and constitution-based health assessment: An integrative model with computerized four diagnosis methods. Evid. Based Complement. Altern. Med. 2013.[CrossRef][PubMed] 49. Yoon, D.W.; Lee, S.K.; Yi, H.; Hong, J.H.; Soichiro, M.; Lee, S.W.; Kim, J.Y.; Shin, C. Total nasal resistance among Sasang constitutional types: A population-based study in Korea. BMC Complement. Altern. Med. 2013. [CrossRef][PubMed] 50. Kim, J.Y.; Noble, D. Recent progress and prospects in Sasang constitutional medicine: A traditional type of physiome-based treatment. Prog. Biophys. Mol. Biol. 2014, 116, 76–80. [CrossRef][PubMed] 51. Wintola, O.A.; Afolayan, A.J. The antibacterial, and antioxidants evaluation of the root extracts of Hydnora africana Thunb. used as antidysenteric in Eastern Cape Province, South Africa. BMC Complement. Altern. Med. 2015.[CrossRef] 52. Shikov, A.N.; Pozharitskaya, O.N.; Makarov, V.G.; Wagner, H.; Verpoorte, R.; Heinrich, M. of the Russian Pharmacopoeia; their history and applications. J. Ethnopharmacol. 2014, 154, 481–536. [CrossRef] [PubMed] 53. Zhao, S.X.; Ye, W.C.; Gu, J.H.; Liu, J.H.; Zhang, X.Q.; Yin, Z.Q.; Wang, H.; Zhang, L.H.; Guo, Y.Z.; Feng, J.X. Medicinal plant resources in Lingnan area and in Ge Hong zhou hou bei ji fang. Asia Pac. Tradit. Med. 2012, 8, 11–12. 54. Li, J.; Zhou, B. Biological actions of artemisinin: Insights from medicinal chemistry studies. Molecules 2010, 15, 1378–1397. [CrossRef][PubMed] 55. Li, Y. Qinghaosu (artemisinin): Chemistry and pharmacology. Acta Pharmacol. Sin. 2012, 33, 1141–1146. [CrossRef][PubMed] 56. Wu, Y.L. Artemisinin –the revelation of the history and reality. Chemical Progress. Chem. Prog. 2009, 21, 2365–2371. 57. Yang, Y.F.; Yang, B.C.; Jin, L.L. Retrospection, strategy, and practice on innovative drug research and development of Chinese materia medica. Chin. Tradit. Herb. Drugs 2009, 40, 1513–1519. 58. Xu, T.; Jin, X.L.; Cao, H.M. Research progress of pharmacological effects of tetrahydropalmatine. Chin. J. Clin. Pharm. 2001, 10, 58–60. 59. Jiang, H.B.; Wang, J.; Su, J.H.; Fang, M.M.; Yang, N.; Yang, J.W.; Wang, F.; Xiao, H.; Tang, J.R. Effect of tetrahydropalmatine on expression of Cav1.2 dorsal root ganglion neurons in mice with sciatic nerve chronic constriction injury.Chinese Pharmacological Bulletin. Chin. Pharm. Bull. 2015, 31, 1598–1603. 60. Qian, W.; Xiong, X.; Fang, Z.; Lu, H.; Wang, Z. Protective effect of tetramethylpyrazine on myocardial ischemia-reperfusion injury. Evid. Based Complement. Altern. Med. 2014, 2014.[CrossRef][PubMed] 61. Zhang, X.J.; Chen, H.L.; Li, Z.; Zhang, H.Q.; Xu, H.X.; Sung, J.J.; Bian, Z.X. Analgesic effect of paeoniflorin in rats with neonatal maternal separation-induced visceral hyperalgesia is mediated through adenosine A(1) receptor by inhibiting the extracellular signal-regulated kinase (ERK) pathway. Pharmacol. Biochem. Behav. 2009, 94, 88–97. [CrossRef][PubMed] Molecules 2016, 21, 559 17 of 18

62. Ge, Y.B.; Cheng, X.Z.; Yan, A.L.; Xu, J. Research progress of anti-tumor mechanism of paeoniflorin. Journal of Chinese Medicinal Materials. J. Chin. Med. Mater. 2015, 38, 636–639. 63. Zhao, P.W.; Niu, J.Z.; Lee, D.Y.; Wang, J.F.; Sun, Y.L.; Li, Y.D. Effect and mechanism of traditional Chinese medicine and their active constituents in postmenopausal osteoporosis. China Journal of Chinese Materia Medica. Chin. J. Chin. Mater. Med. 2012, 37, 1693–1698. 64. Wang, X.M. Progress of pharmacological research on icariin. Chin. J. Chin. Mater. Med. 2008, 33, 2727–2732. 65. Zhong, Y.; Zhang, X.; Cai, X.; Wang, K.; Chen, Y.; Deng, Y. Puerarin attenuated early diabetic kidney injury through down-regulation of matrix metalloproteinase 9 in streptozotocin-induced diabetic rats. PLoS ONE 2014, 9, e85690. [CrossRef][PubMed] 66. Ma, C.; Yao, Y.; Yue, Q.X.; Zhou, X.W.; Yang, P.Y.; Wu, W.Y.; Guan, S.H.; Jiang, B.H.; Yang, M.; Liu, X.; et al. Differential proteomic analysis of platelets suggested possible signal cascades network in platelets treated with salvianolic acid B. PLoS ONE 2011, 6, e14692. [CrossRef][PubMed] 67. Lou, Z.; Peng, J. The Advance in Research on the Cardiovascular Protective Effects of Lithospermate B and the underlying mechanisms. Chin. J. Arterioscler. 2013, 21, 855–858. 68. Zhang, L.X.; Sun, T.; Cao, Y.X. Effects of on lowering blood pressure and diastolic blood vessel. Pharm. Clin. Res. Chin. Mater. Med. 2010, 26, 39–41. 69. Wei, H.; Peng, Y.; Ma, G.X.; Xu, L.J.; Xiao, P.G. Advances in studies on active components of Saussurea lappa and their pharmacological actions. Chin. Tradit. Herb. Drugs 2012, 43, 613–620. 70. Gong, Q.H.; Shi, J.S.; Yang, D.L.; Huang, B.; Xie, X.L. Pharmacological action and its mechanism of gastrodin in central nervous system. Chin. J. New Drugs Clin. Rem. 2011, 30, 176–179. 71. Gong, D.H.; Zheng, W.H.; Luo, N.; Tang, G.C. Effects and the mechanism of gastrodin on chemotherapy- induced neuropathic pain through the expression of Ibal of spinal dorsal horn. Chin. J. Chin. Pharmacol. Ther. 2014, 19, 743–746. 72. Liu, G.T.; Zhang, C.Z.; Li, Y. Study of the anti-hepatitis new drug bicyclol. Med. Res. J. 2010, 39.[CrossRef] 73. Sun, H.; Yu, L.; Wei, H.; Liu, G. A novel antihepatitis drug, bicyclol, prevents liver carcinogenesis in diethylnitrosamine-initiated and phenobarbital-promoted mice tumor model. J. Biomed. Biotechnol. 2012, 2012.[CrossRef][PubMed] 74. Li, M.; Liu, G.T. Inhibition of Fas/FasL mRNA expression and TNF-α release in concanavalin A-induced liver injury in mice by bicyclol. World J. Gastroenterol. 2004, 10, 1775–1779. [CrossRef][PubMed] 75. Bao, X.Q.; Liu, G.T. Bicyclol: A novel antihepatitis drug with hepatic heat shock protein 27/70-inducing activity and cytoprotective effects in mice. Cell Stress Chaperones. Cell Stress Chaperones 2008, 13, 347–355. [CrossRef][PubMed] 76. Li, Y.T.; Du, L.P.; Mei, D. Progress in the study on the pharmacokinetics of Bicyclol. Med. Res. J. Med. Res. J. 2011, 40, 18–20. 77. Wani, M.C.; Horwitz, S.B. as a remarkable chemist: A personal story of the discovery and development of Taxol. Anticancer Drugs 2014, 25, 482–487. [CrossRef][PubMed] 78. Shi, W.Q.; Zhao, D.; Liu, S.Y. A review on studies and development of natural drug Taxol. Nat. Prod. Res. Dev. 1997, 9, 102–108. 79. Holmes, F.A.; Walters, R.S.; Theriault, R.L.; Forman, A.D.; Newton, L.K.; Raber, M.N.; Buzdar, A.U.; Frye, D.K.; Hortobagyi, G.N. Phase II trial of taxol, an active drug in the treatment of metastatic . J. Natl. Cancer Inst. 1991, 83, 1797–805. [CrossRef][PubMed] 80. Jing, L.L.; Jin, Y.; Zhang, S.Y.; Sun, X.L. Synthesis of anticancer drug docetaxel. Chin. J. Med. Chem. 2006, 16, 292–295. 81. Faseleh Jahromi, M.; Liang, J.B.; Ho, Y.W.; Mohamad, R.; Goh, Y.M.; Shokryazdan, P. Lovastatin in Aspergillus terreus: Fermented rice straw extracts interfeRes. with methane production and expression in Methanobrevibacter smithii. Chin. J. Biomed. Res. Int. 2013, 2013.[CrossRef] 82. Yang, P.F.; Chen, W.D. Research progress of pharmacological effects of gingolide B. J. Anhui TCM Univ. 2012, 31, 86–90. 83. Han, F.; Jing, Z.W.; Yu, Y.N.; Liu, Y.N.; Liu, J.; Wang, Z. Process on Experimental Studies of Active Ingredients of Traditional Chinese Medicine for Vascular Dementia. Chin. J. Exp. Tradit. Med. Form. 2012, 18, 273–276. 84. Li, S.Y.; Ji, X.Y.; Li, Z.R. The research progress of effective ingredients of traditional Chinese medicine against tuberculosis. Chin. J. Antibiot. 2013, 38, 725–729. Molecules 2016, 21, 559 18 of 18

85. Ji, X.Y.; Li, S.Y.; Meng, S.; Xiao, C.L.; You, X.F.; Li, Z.R. Synthesis and antimycobacterial activity of ternatolide. J. Chin. Pharm. Sci. 2012, 21, 265–268. [CrossRef] 86. Fu, X.H.; Lin, L.M. Pharmacological research progress of main effective components of Curcuma longa L. J. Hubei Univ. Chin. Med. 2015, 17, 109–110. 87. Yuan, C.L.; Sun, L.; Yuan, S.T.; Kou, J.P.; Yu, B.Y. Pharmacological activities and possible mechanism of effective components in Ophiopogonis radix. Chin. J. New Drug 2013, 22, 2496–2502. 88. VanderMolen, K.M.; McCulloch, W.; Pearce, C.J.; Oberlies, N.H. Romidepsin (Istodax®, NSC 630176, FR901228, FK228, Depsipeptide): A Natural Product Recently Approved for Cutaneous T-cell Lymphoma. J. Antibiot. 2011, 64, 525–531. [CrossRef][PubMed] 89. Yang, X.W. Historical changes in the development of natural medicinal chemistry. J. Peking Univ. Health Sci. 2004, 36, 9–11.

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