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Chinese Marine Materia Medica Resources: Status and Potential

Chinese marine materia medica (CMMM) is a vital part of traditional Chinese medicine (TCM). Compared with terrestrial TCM, CMMM, derived from specific marine habitats, possesses peculiar chemical components with unique structures reflecting as potent pharmacological activities, distinct drug properties and functions. Nowadays, CMMM appears to be especially effective in treating such difficult diseases as cancers, diabetes, cardio-cerebrovascular diseases, immunodeficiency diseases and senile dementia, and therefore has become an important medicinal resource for the research and development of new drugs. In recent years, such development has attracted wide attention in the field of medicine. In this study, the CMMM resources in China were systematically investigated and evaluated. It was found that the historic experiences of Chinese people using CMMM have continuously accumulated over a period of more than 3600 years, and that the achievements of the research on modern CMMM are especially outstanding. By June 2015, 725 kinds of CMMMs from Chinese coastal sea areas have been identified and recorded, covering 1552 organisms and minerals. More than 3100 traditional prescriptions containing CMMMs have been imparted and inherited. However, the number of CMMMs is less than the 8188 terrestrial TCMs, from more than 12,100 medicinal terrestrial plants, animals and minerals. In the future, the research and development of CMMM should focus on the channel entries (TCM drug properties), compatibility, effective ingredients, acting mechanisms, drug metabolism and quality standard. This study reveals the high potential of CMMM development.


Introduction
Traditional Chinese medicine (TCM), with its unique theories of Chinese medication and medical practices, plays an essential role in the entire history of world medicine, and has made notable contributions to the health of Chinese nationals and people of the world for thousands of years. As an important part of TCM, Chinese marine materia medica (CMMM), based upon oceanic medical  According to ShanHaiChing [13], marine organisms were recorded in Xia and Shang dynasties (approximately1600 B.C.), concerning eight kinds of CMMMs, such as Takifugu, Heterodontus, and Prognichthys et Cheilopogon et Exocoetus. By Qin and Han dynasties (about 1800 years ago), more knowledge of marine medicines was acquired. Especially, Shennong Bencaojing (Shennong's Classic of Materia Medica) [14]-an ancient book of Chinese herbology-mentioned 13 kinds of CMMMs, including Sargassum, Chelonia Testudinis, Sepiae Endoconcha, Meretricis et Cyclinae Concha, and Eriocheir et Gaetice. Thanks to the herbological development in Tang and Song dynasties, CMMM had achieved a remarkable progress in the Ming and Qing dynasties. Tang Ben Cao (Tang Materia Medica) [15], an imperial publication of the Tang dynasty (618-907), recorded 25  In addition to the CMMM, the ancient books above also recorded thousands of formulas (prescriptions and dietary therapy formulas) with the CMMMs as principal drugs. During the latter half of the 20th century, new CMMMs have been consecutively discovered along with the rapid development of TCM and modern marine drugs. In recent decades, it was found that there are a large number of marine drug formulas with CMMMs commonly applied in Chinese coastal areas, including proved formulas, secret prescriptions and folk formulas. These prescriptions and formulas have been dug out by long time investigation and practice, and their clinical effects have been verified in modern clinical use by traditional Chinese medicine physicians. As a result, these proved and effective recipes have been recorded in modern medical books, for instance, Chinese Materia Medica [18], and Chinese Marine Materia Medica [1]. The latest Chinese Marine Materia Medica [1], for example, comprises 613 CMMMs and 3100 formulas with the compatibility of CMMMs as principal drugs, providing a unique resource base for the research and development of modern CMMM drugs.

Investigation of CMMM Resources in China
The CMMM resources were investigated by field inspection and literature survey. The field investigation focused on four main areas, including the tropical coral reef ecosystem, the tropical and subtropical mangrove ecosystem, the estuary and intertidal zone ecosystem, and the aquatic ecosystem surrounding islands. The tropical coral reef ecosystem with extremely prolific biodiversity has become a vital biological source of marine natural products and modern marine drugs. The tropical and subtropical mangrove ecosystem features abundant of medicinal mangrove forests as well as epiorganisms or symbionts. The estuary and intertidal zone ecosystem, a coastal zone connecting with land and fresh waters, is the most convenient place for people to obtain and utilize medicinal marine organisms, while the aquatic ecosystem surrounding islands is less influenced by human activities, and thus the biocommunity maintains a native ecological state. Our investigation and statistical analysis indicated that CMMM resources are distributed within all Chinese seas, including the Bohai Sea, the Yellow Sea, the East China Sea, and the South China Sea, covering coastal areas and wetlands in 58 counties under the jurisdiction of 14 provinces, cities and special administrative regions (i.e., Liaoning, Hebei, Tianjin, Shandong, Jiangsu, Shanghai, Zhejiang, Fujian, Taiwan, Guangdong, Hong Kong, Macao, Hainan, and Guangxi). Some marine medicinal species only exist in China, and some of them are labeled as world rare species. By June 2015, a total of 725 CMMMs have been recorded and studied in terms of modern pharmacology and chemistry, involving 1552 species of medicinal organisms and minerals ( Table 1). The category of medicinal marine organisms falls into 17 biological taxa, consisting of one phylum of cyanobacteria; four phyla of algae; two phyla of salt marsh vascular plants, mangroves and seashore associated embryophytes; and 10 phyla of animals. For the medicinal cyanobacteria, 13 species are included. There are four phyla of algae including red algae, brown algae, diatom and green algae and two phyla of plants from coastal wetlands including Pteridophyta and Angiospermae. China has 171 species of medicinal seaweeds, accounting for 11.1% of the total medicinal marine organisms, including 94 species of red seaweed and 45 species of brown seaweed. There are 80 species of medicinal wetland plants, and 23 of them are medicinal mangrove plants growing in mangrove ecosystem at land-sea junctures [19]. Among the 10 phyla of medicinal marine animals, there are seven phyla of medicinal marine invertebrates including Porifera, Coelenterata, Annelida, Sipuncula, Mollusca, Arthropoda, and Echinodermata, as well as Urochordata, Cephalochordata and Chordata. Medicinal invertebrates account for 45.1% of the total medicinal marine organisms, with Mollusca being ranked first, including up to 428 species. In addition, there are 574 species of medicinal Chordata, up to 37.4% of the total medicinal marine organisms. It should be noted that 16 medicinal endemic species have been identified in Chinese seas (Table 2), and 76 poisonous species in medicinal species have been recorded. Especially, there are 33 gorgonians and soft corals that belong to the hot species for the studies of modern marine drugs showing a great prospect in medicinal applications [20]. These medicinal marine organisms are distributed in the vast area of Chinese seas, showing an incremental trend of the species numbers from the north to the south of Chinese coastal areas. The resources of some marine medicinal organisms are prolific, ensuring sufficient medicinal supplies for drug development, such as Laminariae Thallus, Porphyrae Thallus, Haliotidis Musculus, Haliotidis Concha, and Margarita. The endangered species, such as Syngnathus, Hippocampus, and Takifugu, come to a total number of 92 species. Most of the traditional Chinese medicine materials have been produced using artificial aquaculture as well as from wild collection. For example, the original species of medicinal Hippocampus (seahorses), Laminariae, Ostreae, and Margarita, have been artificially bred in large scale for drug use [21]. In total -725 1552

Research and Application of CMMM
Commodity market investigation indicated that among the 725 kinds of CMMMs, 50 kinds are in common medicinal use, including 34 marine animal drugs, 13 marine plant drugs, and three marine mineral drugs (Table 3), all of which are derived from oceanic environments and widely used by the residents in the coastal areas of China. Most of the CMMMs are traditional medicines with unique functions for special use [34][35][36][37][38][39][40] [41], which comprise nine animal MMMs (Arcae Concha, Haliotidis Concha, Ostreae Concha, Margaritifera Concha, Meretricis Concha, Hippocampus, Syngnathus, Sepiae Endoconcha, and Margarita) and three botanic MMMs (Sargassum, Laminariae Thallus, and Glehniae Radix) ( Figure 2). The Medicament portions of CMMMs often contain the whole alga, the shell, meat, and bone of animals with different drug properties to produce unique efficacies. Compared to the typical "terrestrial TCM", CMMM (marine TCM) is characterized with peculiar drug properties and channel entries. Most frequently-used CMMM drugs are generally cold but seldom warm in nature; and their flavors tend to be salty or sweet [42]. Studies have shown that salty-cold (such as Sargassum and Laminariae Thallus), salty-warm (Hippocampus and Syngnathus), sweet-neutral (Apostichopus et Stichopus et Thelenota and Chlamydis et Mimachlamydis et Argopectinis Adduotor) are representative in the natures and flavors of CMMMs, with salty flavor up to more than 90% of the total flavors. In terms of medicinal effects, the most representative efficacies of CMMMs include softening hard mass and removing stasis (Sargassum, Laminariae Thallus, Ostreae Concha, and Meretricis Concha), removing heat to cool blood, neutralizing poison and eliminating purpura (Porphyrae Thallus, Gelidium, and Gracilaria), invigorating kidney and strengthening essence (Hippocampus, Syngnathus, and Callorhini et Phocae Nephros), and calming liver and suppressing Yang (Haliotidis Concha and Margaritifera Concha) [1,43]. Therefore, the medicinal use of CMMM is wide, especially in the effective treatment of serious, difficult, and complex diseases, such as cancers, cardiovascular and cerebrovascular diseases and diabetes mellitus. With the development of life science and technologies, the contemporary research on CMMM is in gradual progress. Among the 725 CMMMs, the categories that have been studied for processing, compatible application,          In recent decades, the efficacies of CMMMs have been verified continuously by modern clinic research. For example, Laminariae is a very common CMMM used in China. Its functions mainly focused on dissolving phlegm, relieving cough and asthma, softening hard mass and eliminating stagnation, and promoting diuresis and dredging stranguria. The Capsule of Laminariae Thallus powder was used for treating hypertensive patients of I-II period. The systolic pressure and diastolic pressure of the patients were effectively reduced when they took 12 g Laminariae Thallus powder every day. The Capsule of Laminariae Thallus powder was found to enhance the function of conventional antihypertensive drugs when co-administrated [37]. Arcae Concha is also a common CMMM possessing the efficiency of dissolving phlegm, breaking stagnate and relieving pain. It has been reported that the superfine powder of Arcae Concha was applied exteriorly for different levels of chilblain, and all 35 patients recovered after 2-6 times [38].
In most cases, the CMMMs are usually used with other TCMs by compatibility rule in traditional Chinese prescriptions. Ulcer Styptic Powder, a compound recipe consisting of Sepiae Endoconcha and Bletillae Rhizoma with a ratio of 2:1, was applied to treat 100 patients of hematemesis or hematochezia induced by duodenal ulcer. The patients took Ulcer Styptic Powder, 2-4 g or 4-6 g per time, and 3-4 times one day. The results indicated that 97 patients stopped bleeding or recovered from hematemesis or hematochezia [39]. Rhei Radix et Rhizoma and Ostreae Concha Decoction was prepared with 30 g calcine Ostreae Concha, 30 g fresh Rhei Radix et Rhizoma, and other TCM materials. This decoction was used to treat 38 uremia patients by high retention-enema of rectum with 200 mL one day. A 10-day treatment course was designed, and the treatment period was 1-3 courses depending on the patient situation. The results revealed that this prescription was effective for 33 cases, of which 17 cases exhibited excellent effects [40].
Specifically, the studies on the effective components of CMMMs have also been executed by modern technology in recent decades. From most CMMMs, the main chemical components have been identified and analyzed and their pharmacological activities have been tested and evaluated. A series of effective constituents have been extracted and developed as modern component drugs. The most famous example is the research and development of the Laminariae, a traditional CMMM from brown alga. Chemical component analysis indicated that Laminariae contains abundant laminarin including algin, fucoidan and laminaran, as well as other ingredients, such as mannitol, iodine and inorganic elements. Laminariae is a rich source of algin, mannitol and iodine. Several In recent decades, the efficacies of CMMMs have been verified continuously by modern clinic research. For example, Laminariae is a very common CMMM used in China. Its functions mainly focused on dissolving phlegm, relieving cough and asthma, softening hard mass and eliminating stagnation, and promoting diuresis and dredging stranguria. The Capsule of Laminariae Thallus powder was used for treating hypertensive patients of I-II period. The systolic pressure and diastolic pressure of the patients were effectively reduced when they took 12 g Laminariae Thallus powder every day. The Capsule of Laminariae Thallus powder was found to enhance the function of conventional antihypertensive drugs when co-administrated [37]. Arcae Concha is also a common CMMM possessing the efficiency of dissolving phlegm, breaking stagnate and relieving pain. It has been reported that the superfine powder of Arcae Concha was applied exteriorly for different levels of chilblain, and all 35 patients recovered after 2-6 times [38].
In most cases, the CMMMs are usually used with other TCMs by compatibility rule in traditional Chinese prescriptions. Ulcer Styptic Powder, a compound recipe consisting of Sepiae Endoconcha and Bletillae Rhizoma with a ratio of 2:1, was applied to treat 100 patients of hematemesis or hematochezia induced by duodenal ulcer. The patients took Ulcer Styptic Powder, 2-4 g or 4-6 g per time, and 3-4 times one day. The results indicated that 97 patients stopped bleeding or recovered from hematemesis or hematochezia [39]. Rhei Radix et Rhizoma and Ostreae Concha Decoction was prepared with 30 g calcine Ostreae Concha, 30 g fresh Rhei Radix et Rhizoma, and other TCM materials. This decoction was used to treat 38 uremia patients by high retention-enema of rectum with 200 mL one day. A 10-day treatment course was designed, and the treatment period was 1-3 courses depending on the patient situation. The results revealed that this prescription was effective for 33 cases, of which 17 cases exhibited excellent effects [40].     Haliotis discus hannai Ino The coastal areas of Liaoning and Shandong Peninsula, China.

Haliotis asinina Linnaeus
The South China Sea, China; The coastal areas of Japan, Philippines, Malaysia, and Australia.

Haliotis ovina Gmelin
The East China Sea, the South China Sea, China.

Haliotis laevigata Donovan
The southwest sea area of Australia.

Haliotis ruber Leach
The coastal areas of Australia; aquiculture in the coastal areas of Guangdong, and Hainan, China. 18

Haliotidis Musculus
Sweet and salty in flavor, mild-natured Nourishing Yin and clearing heat, replenishing vital essence to improve eyesight, nourishing blood and liver, regulating menstruation and lactogenesis, moisturizing dryness and stimulating appetite, benefiting intestines and dredging stranguria. Mainly treating consumptive fever and hectic fever due to Yin-deficiency, cough, glaucoma and cataracta, Irregular menstruation, metrorrhagia and morbid leukorrhea, hypogalactia after delivery, stranguria and turbid discharge, kidney asthenia, frequent urination, dry stool.

Haliotis diversicolor Reeve
The East China Sea, and the South China Sea, China; the tropical sea areas of the Indian Ocean and the Pacific Ocean.

Haliotis discus hannai Ino
The coastal areas of Liaoning and Shandong Peninsula, China.

Haliotis asinina Linnaeus
The South China Sea, China; The coastal areas of Japan, Philippines, Malaysia, and Australia.

Haliotis ovina Gmelin
The East China Sea, the South China Sea, China.

Haliotis laevigata Donovan
The southwest sea area of Australia.

Haliotis ruber Leach
The coastal areas of Australia; aquiculture in the coastal areas of Guangdong, and Hainan, China.  The northern part of the Yellow Sea, China; The sea areas of far-eastern Russia, Japan, and Korean Peninsula.

Tegillarca granosa (Linnaeus)
The coastal areas of China; the sea areas from Indian to the western part of the Pacific Ocean.

Scapharca kagoshimensis (Tokunaga)
The Bohai Sea, the Yellow Sea, the East China Sea, China; the coastal areas of Japan, and Korean Peninsula.

Mytili et Pernae Musculus
Sweet and salty in flavor, warm-natured Invigorating the liver and kidney, nourishing Yin and calming wind, nourishing blood and regulating menstruation, boosting essence and marrow, softening hard mass and eliminating stagnation, stop bleeding and diarrhea. Mainly treating consumptive disease and emaciation, dizziness, night sweat, impotence and prospermia, lumbago due to kidney-asthenia, anemia, chronic dysentery, hematemesis, uterine bleeding, morbid leukorrhea, thyroid swelling.

Mytilus galloprovincialis Lamarck
The Yellow Sea, the Bohai Sea, China; sea areas of the Northern Hemisphere, and Oceania.

Mytilus coruscus Gould
The Yellow Sea, the Bohai Sea and the East China Sea, China; the coastal areas of Japan and Korean Peninsula.

Perna viridis (Linnaeus)
The coastal areas from Taiwan Strait to Hainan, China; the Southeast Asia and the Indian Ocean.

Trichomya hirsutus (Lamarck)
The sea areas from Nanji Island in Zhejiang to Hainan, China; Japan, Southeast Asia, India, and Australia.

Septifer bilocularis (Linnaeus)
The South China Sea, China; the sea areas from the southern part of Japan to Australia; the Indian Ocean.

Septifer excisus (Wiegmann)
The sea area from Nanji Island in Zhejiang to Hainan, China; Japan, and Vietnam; the Indian Ocean. 24 Margarita Sweet and salty in flavor, cold-natured Calming heart and nerves, clearing liver and improving vision, calming wind and arresting convulsion, nourishing the skin, detoxifying and promoting granulation. Mainly treating pavor and palpitation, insomnia and irritability, infantile convulsions and epilepsy, conjunctival congestion and nephelium, aphtha.

Pearl formed by stimulating in mantle of shell
Pinctada fucata martensii (Dunker) The coastal areas of Guangdong, Guangxi, Hainan, and Taiwan, China; the southern part of Japan.

Pinctada margaritifera (Linnaeus)
The sea areas of Guangdong, Guangxi and Taiwan, and Xisha Islands, China; from the Indian Ocean to the western part of the Pacific Ocean.
Pinctada maxima (Jameson) The sea areas of Taiwan, Hainan, Leizhou Peninsula and Xisha Islands, China; the western part of the Pacific Ocean.

Meretricis Concha
Bitter and salty in flavor, slightly cold-natured Clearing lung and eliminating phlegm, softening hard mass and eliminating stagnation, inducing diuresis to alleviate edema, relieving hyperacidity and analgesia, restraining sore and eliminating dampness.

Cyclina sinensis (Gmelin)
The coastal areas of China; Japan, Korean Peninsula, and the western part of the Pacific Ocean.

Dosinia japonica (Reeve)
The coastal areas China; the far-eastern Russia, Korean Peninsula, Japan, and Vietnam.

Sepiella japonica Sasaki
The Chinese Seas; the Indian Ocean and the western part of the Pacific Ocean.

Sepia esculenta Hoyle
The Chinese Seas; the Philippines Islands.

30
Octopus Sweet and salty in flavor, mild-natured Nourishing and strengthening body, reinforcing qi and nourishing blood, suppressing dysmenorrhea and promoting lactation, detoxifying and promoting granulation. Mainly treating qi and blood weakness, blood deficiency and blocked menstruation, lactation deficiency after delivery, carbuncle-abscess and swelling-toxicum, chronic sore.

Octopus vulgaris Cuvier
The East China Sea, and the South China Sea, China; wide distribution in all of the oceans.
Octopus ovulum (Sasaki) The East China Sea and the South China Sea, China; the southern sea area of Japan.

Eriocheir sinensis H. Milne Edwards
The coastal area of China; the west coastal area of Korean Peninsula.

Eriocheir japonica De Haan
The coastal areas of Fujian, Taiwan, and Guangdong, China; the east coast of Korean Peninsula, and Japan.

Gaetice depressus (De Haan)
The Yellow Sea, the East China Sea, and the South China Sea, China; Korean Peninsula, and Japan.

Hemigrapsus penicillatus (De Haan)
The coastal areas of China; Korean Peninsula, and Japan.

Sweet and salty in flavor, mild-natured
Nourishing the kidney and strengthening the essence, strengthening Yang and cure impotence, nourishing blood and promoting the secretion of saliva, regulating menstruation and nourishing the fetus, moisturizing dryness and smoothening intestines, hemostasis, reinforcing consumptive disease. Mainly treating kidney asthenia and damage of essence, impotence, emission, consumptive disease, deficiency of essence and blood, Yin deficiency and fatigue thin, lung asthenia and chronic cough, irritating dry cough, weakness after delivery or disease.

Whole body
Apostichopus japonicus (Selenka) The Yellow Sea, and the Bohai Sea, China; Japan, and Korean Peninsula.

Stichopus horrens Selenka
The sea areas of Hainan, Taiwan, and Xisha Islands, China; Madagascar, New Caledonia, Philippines, and Indonesia.

Stichopus chloronotus Brandt
The sea areas of Hainan, Xisha Islands, Zhongsha Islands, and Nansha Islands, China; the Indian Ocean to the western part of the Pacific Ocean.
Thelenota ananas (Jaeger) The sea areas of Taiwan, Xisha Islands, and Nansha Islands, China; East Africa, and Madagascar. Anthenea pentagonula (Lamarck) The coastal areas of Guangdong, and Fujian, China.

Rosaster symbolicus (Sladen)
The eastern sea area of Hainan Island, China; Arafura Sea, Ban Tak Sea, and Philippines Sea.

Whole body
Asterina pectinifera (Müller et Troschel) The Bohai Sea, and the Yellow Sea, China; the far-eastern sea area of Russia, Japan, and Korean Peninsula.

Asterina limboonkengi G. A. Smith
The coastal areas of Guangdong, and Fujian, China.

Asterina batheri Goto
The offshore area of Yantai, China; the coastal area from Honshu to Kyushu, Japan.

36
Asterias Salty flavor, mild-natured Harmonizing stomach and relieving pain, clearing heat and detoxifying, Calming the liver and relieving convulsion, softening hard mass and eliminating stagnation. Mainly treating stomachache and acid regurgitation, gastric ulcer and duodenal ulcer, diarrhea, epilepsy, crewels, otitis media.

Asterias rollestoni Bell
The Yellow Sea, and the Bohai Sea, China; the far-eastern sea area of Russia, and the coastal area of Japan.

Asterias amurensis Lütken
The Yellow Sea, and the Bohai Sea, China; the coastal areas of Asia in the northern Pacific Ocean.

Aphelasterias changfengYingi Baranova et Wu
The Bohai Sea, and the northern part of Yellow Sea, China.

Asterias argonauta Djakonov
The Bohai Sea, China; the southern part of Japan Sea, and Korean Peninsula.

Asterias versicolor Sladen
The Bohai Sea, and the northern part of the Yellow Sea, China; Japan Sea and the southern seacoast of Japan.

Calcareous bone shell
Hemicentrotus pulcherrimus (A. Agassiz) The Bohai Sea, the Yellow Sea, and the East Sea, China; Japan.
Strongylocentrotus nudus (A. Agassiz) The coastal areas of Liaoning Peninsula and the northern part of Shandong Peninsula, China; Japan, Russia.
Anthocidaris crassispina (A. Agassiz) The coastal areas of Zhejiang, Fujian, Guangdong, Taiwan and Hainan, China; the southern part of Japan Sea.

Temnopleurus toreumaticus (Leske)
The Chinese Seas; the Indian Ocean to the western part of the Pacific Ocean.

Temnopleurus hardwickii (Gray)
The northern coastal areas of Fujian, China; Japan, and Korean Peninsula.

38
Syngnathus Sweet and salty in flavor, warm-natured Invigorating the kidney and strengthening Yang, Removing stasis and swelling, relaxing and activating the tendons, relieving pain, hemostasis, expediting child delivery, antifatigue, anti-aging, anti-tumor. Mainly treating impotence, infertility, emission, infertility due to cold uterus, dystocia, kidney asthenia and asthma, rheumatism and paralysis pain, intestine obstruction and accumulation, crewels and goiter, traumatic injury, scrofula, carbuncle and furunculosis.
Whole body or whole body removed skin and viscera

Syngnathus acus Linnaeus
The coastal areas of Shandong, China; the southern part of Korean Peninsula, and Japan.

Syngnathoides biaculeatus (Bloch)
The East China Sea, and the South China Sea, China; Japan, Philippines, and Indonesia.

Solegnathus hardwickii (Gray)
The East China Sea, and the South China Sea, China; the coastal areas of Japan, India, New Zealand and Africa.

39
Hippocampus Sweet and salty in flavor, warm-natured Invigorating the kidney and strengthening Yang, boosting essence, relieving cough and asthma, promoting blood circulation to remove meridian obstruction, removing stasis and subsiding swelling, induced abortion. Mainly treating deficiency of the kidney asthenia and damage of essence, impotence and infertility, infertility due to cold uterus, dyspnea due to deficiency, chronic asthma, enuresis, deficient dysphoria and insomnia, intestine obstruction and accumulation, abdominal mass, stasis and stomachache, traumatic injury, bleeding wound, carbuncle and furuncle, swelling-toxicum, dystocia, scrofula and thyroid swelling.

Hippocampus trimaculatus Leach
The East China Sea, and the South China Sea, China.

Hippocampus kelloggi Jordan et Snyder
The East China Sea, and the South China Sea, China; Japan, and Vietnam.

Hippocampus histrix Kaup
The East China Sea and the South China Sea, China; Japan, Vietnam, Indonesia, and Philippines.

Hippocampus kuda Bleeker
The East China Sea, and the South China Sea, China; Japan, Philippines, Malaysia, and Indonesia.

Hippocampus japonicus Kaup
The coastal areas of China, mainly in Liaoning, Hebei, Shandong, and Zhejiang, China; Korean Peninsula, and Japan.  Sweet and salty in flavor, mild-natured Dispelling wind and eliminating dampness, promoting blood circulation to remove meridian obstruction, nourishing qi and blood, strengthening tendon and bone, relieving swelling and pain, detoxifying and stopping dysentery, relieving cough and asthma, eliminating dampness and alleviating itching, nourishing skin. Mainly treating rheumatism and paralysis pain, numbness of hands and feet, soreness in waist and knee, hemiplegia, rheumatoid arthritis, rheumatic arthritis, tetanus, convulsive epilepsy, scrofula, dysentery, bronchitis, leprosy and malignant sore, furuncle, skin itch, chronic eczema, mange, sore of mixed hemorrhoids.

Hydrophis cyanocinuctus Daudin
The China Sea; the sea areas from the Persian Gulf, passing through Indian Peninsula to Japan and Australia.
Hydrophis caerulescens (Shaw) The coastal areas of Shandong, Guangdong, and Taiwan, China; the sea areas from the Indian Ocean, passing through the South China Sea to Indonesia and the northern sea area of Australia.
Hydrophis fasciatus (Schneider) The coastal area of Zhejiang, Fujian, and Taiwan, China; Japan Islands.

Hydrophis melanocephalus Gray
The coastal areas of Zhejiang, Fujian, and Taiwan, China; Japan Islands.
Hydrophis ornatus (Gray) The coastal areas of Shandong, Guangdong, Guangxi, Hainan, and Taiwan, China; the sea areas from the Persian Gulf, passing through Indian Peninsula to Australia.

Hydrophis gracilis (Shaw)
The coastal areas of Fujian, Guangdong, Guangxi, and Hainan, China; the sea areas from the Persian Gulf, passing through Indian Peninsula, Australia To Papua New Guinea.
Lapemis curtus (Shaw) The coastal areas of Shandong, Fujian, Taiwan, Hong Kong, Hainan, and Guangxi, China. Specifically, the studies on the effective components of CMMMs have also been executed by modern technology in recent decades. From most CMMMs, the main chemical components have been identified and analyzed and their pharmacological activities have been tested and evaluated. A series of effective constituents have been extracted and developed as modern component drugs. The most famous example is the research and development of the Laminariae, a traditional CMMM from brown alga. Chemical component analysis indicated that Laminariae contains abundant laminarin including algin, fucoidan and laminaran, as well as other ingredients, such as mannitol, iodine and inorganic elements. Laminariae is a rich source of algin, mannitol and iodine. Several modern drugs have been developed from Laminariae. Particularly, based on the main component algin, Alginic Sodium Diester (PSS ® ) was developed into the market in 1985 as a marine polysaccharide sulfated drug with anti-hyperlipidemia function [44,45]. Up to date, Alginic Sodium Diester has been widely applied in clinic [46]. Mannitol Nicotinate is another marine drug with angiectasis and anti-hyperlipidemia effects developed based on mannitol extracted from Laminariae [47]. In addition, Longmu Zhuanggu Granules ® , an OTC calcium replenisher against rachitis and osteomalacia, is also a widely used marine prescription with calcium extracted from Ostreae Concha [48].
Currently, 20 single CMMM preparations and 200 compound CMMM preparations have been developed into the market. Nevertheless, it should be noted that the majority of the 3100 ancient marine herbal formulas and proved formulas as recorded in Chinese Marine Materia Medica have not been developed by modern technology. It may be predicted that the potential resources of CMMMs that have not yet been identified or utilized will be discovered and studied in the coming decades. These resources will no doubt become a prolific source for development of CMMMs under the guidance of Chinese traditional medicine theory, as well as a strategy resource to exploit modern marine drugs by high technology [12,49].

Investigation of CMMMs
With IRB approval and informed consent, CMMMs were investigated mainly in the TCM national markets of China, including Anguo TCM Market in Hebei, Bozhou TCM Market in Anhui, Qingping TCM Market in Guangdong, and Yulin TCM Market in Guangxi. The investigation was also conducted in coastal drug markets and marine product markets. Diverse ways and methods [9][10][11] were applied for the investigation, including samples and information collection, questionnaire surveys, interviewing pharmacists, and inspecting medicinal material factories. The questionnaire surveys covered CMMM assortments, original organisms, production areas, resource status, medicament portions, processing methods, storage conditions, storage duration, quality grades, prices, usages, outputs, sales volumes, and retailers (see Supplementary Information). In the factories, the productions of CMMMs were inspected, including CMMM assortments, original organisms, habitats, resource status, processing methods, storage conditions, outputs, and quality grades.
The literature survey was conducted by searching ancient medical literature and modern databases. The ancient medical literature looked up covered 500 pieces of traditional Chinese Medicine text concerning CMMMs. Ten databases were used as the main origin of medicinal information, including Traditional Chinese Medical Database System, Scientific Database of China Plant Species, Scientific Database of China Animal Species, Medline, Marinlit, ScienceDirect, SpringerLink, Wiley Online Library, ACS Publication, and RSC Publication. The data and information were collected and extracted from over 20,000 pieces of modern literature, including CMMM assortments, original organisms, chemical components, pharmacological activities, toxicity, clinical application, production areas, resource status, medicament portions, processing methods, storage conditions, storage duration, quality grades, prices, usages, outputs, and sales volumes.
The investigation was focused on the common endemic CMMMs in China. The original data were collected, summarized and analyzed. The inaccurate or invalid data were removed, and the valid data were transformed to charts using Excel and SPSS. The CMMM status was assessed based on the above data and information.

Investigation of Original Organisms of CMMMs
The fieldwork and historical document survey were carried out to investigate the original organisms of CMMMs and the distribution of marine medical species in China. A specific field investigation on marine medicinal bioresources was conducted in the South China Sea, the East China Sea, the Yellow Sea, and the Bohai Sea. The main areas for field investigation were selected based on the features of the Chinese oceanic geographical environment, marine ecosystem and marine medicinal bioresources, including tropical coral reef ecosystem, tropical and subtropical mangrove ecosystem, estuary and intertidal zone ecosystem, and aquatic ecosystem surrounding islands. The tropical coral reef ecosystem areas covered the South China Sea and those coastal waters near Hainan, Guangdong and Guangxi provinces. Specifically, the medicinal marine organisms were collected in the sea areas around Hainan Island (near Sanya, Lingshui, Wanning, Wenchang, Qionghai, Lingao, and Danzhou), Leizhou Peninsula (near Xuwen), Naozhou Island, Weizhou Island, and Xisha Islands. The key investigation areas in estuary and intertidal zone ecosystem included roundabout Hainan Island, coastal areas of Guangdong, Guangxi, Zhejiang, and Shandong, Bohai gulf, and estuaries of Zhujiang River, Yangtze River, and Yellow River.
The key investigation areas of the aquatic ecosystem surrounding islands included the sea areas around Weizhou Island, Naozhou Island, Nanao Island, Nanji Island, Zhoushan Islands, Lingshan Island and Miaodao Islands. The collection methods for the marine organisms included trawling sampling (horizontal trawling, slant trawling, and vertical trawling), bottom characteristics sampling, and SCUBA diving sampling [50,51]. From March 2006 to June 2015, field investigation was conducted on 15 voyages, involving 400 sites in 170 cross-sections around the Chinese Seas. In total, 18,445 biological samples were collected from various marine habitats. All of the collected samples were identified for their biological species. The extracts of all the samples were evaluated for their bioactivities by bioassay approaches with pharmaceutical screening models. Up to 5767 species were identified, among which 1552 species were clarified as the medicinal species.

Identification of Original Species of CMMMs
Medicinal coral species were identified by Hui Huang and Xiubao Li from South China Sea Institute, Chinese Academy of Sciences, China; medicinal sponge species were identified by Nicole J. de Voogd from Netherlands Centre for Biodiversity Naturalis, The Netherlands; medicinal mangrove species were identified by Cairong Zhong from Dongzhaigang National Mangrove Natural Reserve, China; medicinal algae were identified by Shuben Qian from Ocean University of China, and Bangmei Xia from Institute of Oceanology, Chinese Academy of Sciences, China; medicinal coastal wetland plants were identified by Fengqin Zhou from Shandong Traditional Chinese Medicine University, China; and medicinal fish, shellfish, and other invertebrates were identified by Yunfei Wu, Xiaoqi Zeng, Shichun Sun and Zhenjiang Ye from Ocean University of China, and Daohai Chen from Zhanjiang Normal University.

Investigation of Folk Application of CMMMs
The folk interviews included personal interview, telephone interview, conversazione, and consulting to fishers and folk doctors. The folk recipes, nostrums and informal prescriptions using CMMMs were collected and uncovered from Chinese coastal areas, mainly in coastal villages and small towns. The folk investigation and interview routes were along the Chinese southeast coastlines passing through the residential communities, involving Liaoning, Hebei, Shandong, Zhejiang, Guangdong, Guangxi, and Hainan provinces.

Conclusions
In present study, CMMM resources in China were investigated by systematical evaluation and statistical analysis. It was found that there are totally 725 kinds of CMMMs, covering 1552 original medicinal marine plants, animals and minerals. More than 3100 prescriptions containing CMMMs have been used with compatibility. CMMM, possessing distinct drug properties and functions, has been proven to be especially effective for treating chronic, complex and difficult diseases. It has now become an important medicinal resource for the research and development of drugs. From a perspective of historical origin of CMMM research and application, we know that CMMM, which has become an integral part of TCM treasury, plays a unique role in the history of TCM development. It is imperative to comprehend its essence from modern views, interpret its mystery with modern science, and dig into its potential using modern technology. Many CMMMs have been proven their medical usage as recorded in ancient TCM literature and also turned out to be effective after long-term clinical practices. Nevertheless, compared with the terrestrial TCM, from an overall view, the level of CMMM development is relatively low. The knowledge of CMMM as a special TCM resource is insufficient, while the research and development of its modern application is still in the infancy. Therefore, in future research and development of CMMMs, the key approaches to study should be the nature of the drugs, channel entries, compatible applications, efficient substances, action mechanisms, drug metabolism and quality standards. The development of marine compound preparations and component drugs under the guidance of TCM theories using CMMMs and their formulas could be expected.