The Traditional Medicine and Modern Medicine from 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, artemisinin and its analogs are presently in extensive use for anti-malaria treatment. This shows how research using natural products has made a significant contribution to drug development [19,20]. Among anticancer drugs approved in the time frame of about 1940–2002, approximately 54% were derived natural products or medicines inspired by knowledge related to such. For instance, the Vinca alkaloids from Catharanthus roseus, and the terpene paclitaxel from Taxus baccata, are among successful anticancer drugs initially 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 outstanding success. In that 22-year time frame, medicines derived from natural products have been significant. That is especially true in the case of antihypertensives, where about 64% for newly-synthesized medicines have their origins in natural product 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 exciting and meaningful developments in their ability to interact with numerous, varied biological targets, and some have become the most critical drugs in the health care system [14,22,23]. For example, plants, microorganisms, and animals manufacture small molecules, which have played a significant role in drug discovery. Among 69 small-molecule 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 pharmacopeias. Of the reckoned 250,000–500,000 existing plant species, only a tiny proportion has been scientifically researched for bioactivities [13]. Therefore, there is an excellent potential for future discoveries from plants and other natural products, which, thus, offer tremendous potential in deriving useful information about novel chemical structures and their new types of activities related to new drug development.    

TM is the oldest form of health care in the world and is used in the prevention and treatment of physical and mental illnesses. Different societies historically developed various useful healing 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 crucial 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 concerning methods of preparation, selection of herbs, identification of medicinal materials, and the best time for obtaining 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 integral part of the Chinese public health system. In recent years, TCM has gradually gained considerable approval as complementary or alternative medicine in Western countries. Chinese herbal medicine, which is the essential 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 method 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 therapeutic effect and reduce adverse reactions [28].  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 physicians in Japan use Kampo medicines in their daily practice—sometimes as the preferred medication [29–31]. Together with radiotherapy or chemotherapy, some Japanese physicians frequently utilize Kampo drugs in treating cancer patients. 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 a growing realization of the urgent need to study the interactions between these two types of drugs [28]. Unani is an ancient Greek holistic medical system with a history that can be traced back to 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 India, where it has been integrated into the national health care system [34]. It was reckoned by WHO that a large number 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 population in Africa makes use of TM—either alone or in conjunction with conventional medicine [37]. By contrast, traditional Aboriginal medicine in Australia 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 science 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 significant benefits in developing reformed medicines and new drugs by connecting powerful modern scientific techniques and methods with the conscious ethnobotanical and ethnomedical experiences of TM. The characteristics of several TM systems are summarized in Table 1.    

 TM is too valuable to be ignored in the research and development of modern drugs. Though it has an enigmatic character, there are also wibroadontexts for its use in terms of non-Western medical technology or activities. In TM, a single herb or formula may contain many phytochemical 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]. Notably, a lot of plant-originated drugs in clinical medicine today were derived from TM [21]. Besides, 

it has been demonstrated that the many expensive medications derived from plants were discovered through their application in TM [2]. Almost 20 years ago, a thorough investigation of the pharmacopeias of developed and developing nations and the associated world scientific literature was conducted as part of the WHO’s TM Program. That study aimed to determine whether TM 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 multiple 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] 

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 medicines based on TMs. Early in China’s Jin Dynasty, Doctor Hong Ge (AD 284–384) recorded the efficacy and related details of Artemisia annua 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 useful 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 severe 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 concerning 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 an excellent success for TCM at an extraordinary 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 2015 Nobel Medicine Prize for her significant devotion to discovering artemisinin. The discovery of artemisinin illustrates how TCM constitutes a vast store of knowledge about natural products, such as Chinese herbs, and holds much future promise. The development of successful new drugs can proceed by profiting from this knowledge [56]. Some medicines or compounds isolated from Chinese herbal drugs that follow the ethnomedical uses are summarized in Table 2.       

In clinical practice in China in the 1960s, it was found that Schisandra Chinensis (Turcz.) Baill.—a traditional Chinese herb—had obvious enzyme-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 Schisandra 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 might be used to lower the enzyme content in the treatment of the hepatitis B virus [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 several 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 anti-hepatitis virus effect in the 2.2.15 cell line and duck model with viral hepatitis [73,74]. In clinical trials, it was found that the increased levels of serum 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, toxicology, pharmacokinetics, preparation, and quality control, researchers determined that the new anti-hepatitis drug bicyclol offered significant hepatoprotective effects, anti-hepatitis 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 medications recommended by the “Guidelines on Liver Disease 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 United States. 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 extracts, 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 unique 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 water, the low yield from natural products, and other disadvantages, particularly by the medical society. The story of Taxol involved many events that nearly resulted in the 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 necessary drug for treating various forms of cancer and is still being used to develop new synergistic groups of anticancer drugs [77–79]. Some drugs or compounds isolated or developed from natural products are summarized in Table 3   

Human history is also the history of medicines used to treat and prevent various diseases. To counter the danger from severe illnesses and to guarantee the survival of the species, it is necessary to produce better drugs continually. With time, the use of these natural products as TM increased. Modern medicine has benefited considerably from TM in two areas: drugs with similar effects and drugs with different effects from those of TM. From the history of drug development, it is evident that many medications have been derived as a result of inspiration from TM. The application of, and research into, natural products are far from satisfactory. Many problems need to be addressed in the future. For example, synergistic effects may exist among the compounds that occur in natural products; however, the modes and mechanisms of action are seldom self-explanatory. It is, therefore, necessary to make full use of such synergetic effects toward improving the effectiveness of drugs. However, it is also requisite that any adverse effects of natural products be adequately reduced to meet safety standards. With the riches of modern technology, such as in synthesis, fermentation, pharmacology, pharmacodynamics—together with biological diversity, chemodiversity, and significant breakthroughs in evolutionary techniques or concepts—combined with a wealth of knowledge about natural products, it will be possible to establish an extensive compound library for drug screening [89]. This will enhance the possibilities for individual treatment and prevention of disease. Humankind needs to learn more from natural products and traditional medicines. To further promote the development of modern medical research on natural products, humans have to face up to various difficulties and challenges. Valuable information on natural products and TMs is mixed in a large number of documents, data, and useless rumors. Furthermore, one plant or formula of natural products and TMs contains a large number of chemical constituents, including active, invalid, and possible synergistic components. Therefore, considerable effort should be made at first to remove the raw material and take the essence—valuable experience of natural products and TMs. Furthermore, in many cases, the role of a single compound from natural products and TMs are paid much attention to. However, one advantage of TM’s therapeutics is paid much attention to. However, one advantage of TM’s therapeutics is the “synergism”; that is, often, multiple components in TMs play a synergistic role, which is higher than that of the individual drug. In the meantime, the “1 disease, one target, one 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.