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Chinese Medicine

, 14:51 | Cite as

Endophytes from Ginkgo biloba and their secondary metabolites

  • Zhihui Yuan
  • Yun Tian
  • Fulin HeEmail author
  • Haiyan ZhouEmail author
Open Access
Review
  • 212 Downloads

Abstract

Ginkgo biloba is a medicinal plant which contains abundant endophytes and various secondary metabolites. According to the literary about the information of endophytics from Ginkgo biloba, Chaetomium, Aspergillus, Alternaria, Penicillium and Charobacter were isolated from the root, stem, leaf, seed and bark of G. biloba. The endophytics could produce lots of phytochemicals like flavonoids, terpenoids, and other compounds. These compounds have antibacteria, antioxidation, anticardiovascular, anticancer, antimicrobial and some novel functions. This paper set forth the development of active extracts isolated from endophytes of Ginkgo biloba and will help to improve the resources of Ginkgo biloba to be used in a broader field.

Keywords

Ginkgo biloba Chinese medical plant Endophytes Secondary metabolites 

Abbreviations

G. biloba

Ginkgo biloba

CD

electronic circular dichroism

Gb-rGO

gbE-reduced graphene oxide

NIHL

noise-induced hearing loss

ROS

reactive oxygen species

Background

Ginkgo biloba (G. biloba) is a deciduous tree belonging to the ginkgo genus, which is also known as Gongsunshu, etc. G. biloba is one of the most ancient plants on earth dating back more than 200 million years. Commonly Ginkgo biloba has been used for a medicinal plant and its seeds, leaves and fruits can be used for medicines with biological activities involving antibacteria, antioxidation, anticardiovascular and others. However, Ginkgo trees grow slowly and under natural conditions they need more than 20 years from planting to fruiting, which is a restricting point for its development; while its endophytics provide physiological metabolic pathways to produce numerous novel medicinal compounds which have become a hotspot [1].

The endophytics play important roles in the process of host plant growth and systematic evolution [1, 2]. During the whole life, endophytics protect their host from infectious diseases and also help to survive in adverse environment [3]. Since the unique relationships between the host plant and associated endophytes, endophytes in G. biloba have been recognized as important sources of a variety of novel secondary metabolites with anticancer, antimicrobial and other biological activities [4, 5].

Secondary metabolites are the chemical bank which provides a huge quantity of diverse commercial products for human medicines. First report about endophytics is that Stierle et al. isolated Taxomyces andreanae from phloem of Taxus brevifolia, which can produce taxol and related chemicals at the concentration of 24–50 ng/L [6]. From then on, more and more endophytics from pharmaceutical plants, such as Camptotheca acuminata [7], pine [8] and Taxus plants [9, 10, 11] were isolated. As to G. biloba, various endophytics including Chaetomium, Aspergillus, Alternaria, Penicillium and Charobacter were isolated from the root, stem, leaf, seed and bark of G. biloba. They produce lots of phytochemicals like flavonoids, terpenoids, and other compounds [12, 13]. 50% of these isolates showed antimicrobial activities against various pathogens. Some secondary metabolites such as 2-hexenal have been involved in the plant’s defense against pests. These bioactive metabolites are attractive to developing the commercial prodrugs and agricultural/industrial production. Most importantly, as a therapeutic drug, G. biloba has no side effects even after long periods of use and its phytopharmaceuticals are readily accessible throughout the world. For better using endophytic and secondary metabolites from ginkgo trees, we summarize the data previously reported.

Endophytes in Ginkgo biloba

The whole plant of G. biloba can be used as medicine. In its root, stem, leaf, seed and bark of Ginkgo biloba, various endophytes have been isolated and their biological function was investigated. The conventional procedure of endophytes isolation is to wash the roots, stems or leaves of ginkgo firstly with 75% alcohol for 3 min, rinse with sterile water 3–5 times, 0.1% mercury sterilized for 2 min, rinsed with sterile water 3–5 times, cut into 0.5 cm × 0.5 cm pieces. The cutting pieces were inoculated in PDA medium at 28 °C for 4 days. After purification, ginkgo endophytes were isolated.

For the endophytic procaryotes, on the total DNA as the template, 27F(AGAGTTTGATC-CTGGGTCAG)/1492R(GGTTACCTTGTTACGACTT) as a primer, 16S rDNA was amplified. For the endophytic eukarya, ITS5 (GAAG TAAAAG TCGTAACAAGG)/ITS4 (TCCTCCGC TTA TTGA TATGC) as a primer, ITS rDNA was amplified. According to the culturing and molecular analysis between different species, the endophytics residing in G. biloba belong to Chaetomium, Aspergillus, Alternaria, Penicillium, Charobacter, etc.

Endophytic procaryotes in Ginkgo biloba

From the previous reports, around 50 species of endophytic procaryotes were found including Bacillus subtilis, Lactobacillus sp., Fusobacterium sp., Gemella sp., Neisseria sp., Pseudomonas sp., Rothia sp., Veillonella sp., etc. Basing on 16S RNA sequence of endophytic procaryotes from previous literatures, the phylogenetic tree was constructed in Fig. 1. Amongst these procaryotes, the community structure or compositional differences at different taxonomic levels was presented in Fig. 2.
Fig. 1

The phylogenetic tree of endophytic procaryotes from soil, root and leaf of Ginkgo biloba. 50 most abundant OTUs are used for display. If a number appears before the species name, it represents the total number of sequences of this OTU. If it is a graph, the graph size represents the relative abundance (percentage), and the black dot on the branch represents the bootstrap confidence greater than 95%

Fig. 2

The community structure at different taxonomic levels. (1) The community structure at different phylums; (2) the community structure at different classes; (3) the community structure at different families; (4) the community structure at different genus. The percentage in parentheses indicates that only the group with the average abundance greater than this ratio is listed. All other groups are classified in others

Sphingomonadaceae are a family of the Alphaproteobacteria and most abundant in G. biloba. An important feature is the presence of sphingolipids in the outer membrane of the cell wall [14]. In this family, some species are phototrophic which may have high nutritional value. The phototrophic bacteria are rich in amino acids, folic acid and vitamins, especially vitamin B12, biotin and coenzyme Q. Some other species are known as the ability to degrade some aromatic compounds which has the interests for environmental remediation [11].

Other abundant species are family Hyphomicrobiaceae, Burkholderiaceae, Methylobacteriaceae, Enterobacteriaceae, Neisseriaceae and Micrococcaceae. The family Hyphomicrobiaceae is affiliated with Alphaproteobacteria and members of this family are distributed everywhere in soils, freshwater, and also under the marine. This family is highly diverse morphologically and physiologically. Most are aerobic chemoheterotrophs and a few can grow anaerobically by denitrification or mixed-acid fermentation.

The Methylobacteriaceae comprises a large family of Alphaproteobacteria and contains three genera including Methylobacterium, Microvirga, and Meganema. Methylobacterium species are ubiquitous in the natural environment. Some species induce plant leaf and root nodule formation, and can promote plant growth by production of auxins [15]. Most of Methylobacterium are methylotrophs and they can use methanol or other one-carbon compounds as energy sources to produce proteins [16]. Otherwise, in Methylobacterium, common fatty acids were contained especially ubiquinone Q-10, a popular dietary supplement.

Family Enterobacteriaceae contains a large number of genera that are biochemically and genetically related to one another. Many of them are pathogens, such as Salmonella, Shigella or Yersinia, because they produce endotoxins. Endotoxins reside in the cell wall and when the cell dies and the cell wall disintegrates, endotoxins are released [9].

Family Burkholderiaceae belongs to the order Burkholderiales within the class Betaproteobacteria. This family is characterized by the presence of ecologically extremely diverse organisms and contains truly environmental saprophytic organisms, phytopathogens, opportunistic pathogens, as well as primary pathogens for humans and animals.

Family Neisseriaceae and Micrococcaceae are widespread in soil, subterranean cave silts, sea, glacier silts, sewage, water sludge, aerial surfaces of plants, vegetables, and various animal species and are even more distantly related to the human pathogens.

Endophytic eukarya in Ginkgo biloba

The phylogenetic tree of endophytic eukarya (Fig. 3) was constructed basing on ITS sequence of roots and leaves of Ginkgo biloba from previous literatures. Amongst these endophytic eukarya, the community structure at different taxonomic levels was presented in Fig. 4.
Fig. 3

The phylogenetic tree of endophytic eukarya from soil, root and leaf of Ginkgo biloba. 50 most abundant OTUs are used for display. If a number appears before the species name, it represents the total number of sequences of this OTU. If it is a graph, the graph size represents the relative abundance (percentage), and the black dot on the branch represents the bootstrap confidence greater than 95%

Fig. 4

The community structure at different taxonomic levels. (1) The community structure at different phylums; (2) The community structure at different classes; (3) The community structure at different families; (4) the community structure at different genus. The percentage in parentheses indicates that only the group with the average abundance greater than this ratio is listed. All other groups are classified in others

Amongst eukarya, family Pleosporaceae belongs to sac fungi. The taxonomic relationship of this family to associated genera is still not determined. The classification of Pleosporaceae has been a challenge because of the lack of the importance of morphological characters and reference strains. From the present knowledge, the family Pleosporaceae includes numerous saprobic, opportunistic human and plant pathogenic taxa [17].

Phaeosphaeriaceae is a large and important family of fungi in the order Pleosporales. Species in this family have a cosmopolitan distribution, and are generally nectrotrophic or saprobic on a wide range of plants [18]. This family includes economically important plant pathogens and previously accommodated 35 sexual and asexual genera and comprised more than 300 species with a range of morphological characters [19].

The Xylariaceae are a family of mostly small ascomycetous fungi. It is one of the most commonly encountered groups of ascomycetes and is found throughout the temperate and tropical regions of the world. They are typically found on wood, seeds, fruits, or plant leaves, some even associated with insect nests. Most decay wood and many are plant pathogens. Phylogenetic analyses suggest that there are two main lineages in this family, Hypoxyloideae and Xylarioideae [20, 21].

Secondary metabolites of endophytics in Ginkgo biloba

A series of compounds were obtained by fermentation, extraction, and isolation from endophytics of G. biloba, amongst which 115 metabolites were found in the fermentation broth of Chaetomium fungi, 44 metabolites were found from Aspergillus, 43 metabolites found in the genus Xylaria. The amount from these three genera accounted for 72% of the secondary metabolites from endophytic procaryotes and 21% were isolated from Fusarium, Alternaria and Penicillium. The number of metabolites of each genus is shown in Fig. 5.
Fig. 5

a The metabolite quantity of some major endophytics in Ginkgo biloba; b the metabolite quantity of some minor endophytics in Ginkgo biloba

Many metabolic products from G. biloba have strong inhibitory effects on pathogenic bacteria Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa. The secondary metabolites of Ginkgo, such as flavonoids and ginkgolides, are drugs or prodrugs used in the treatment of peripheral arterial diseases, neurological disorders, sclerosis of cerebral arteries, and cerebral ageing.

Secondary metabolites of Chaetomium

Chaetomium is the largest type of endophytic fungus from G. biloba and its secondary metabolites are biologically diverse. Chaetomium globosum is one of main endophytics. A total of 115 metabolites were isolated from the fermentation broth of Chaetomium globosum (see Fig. 6 and Table 1). Among them, chaetoglobosin A, chaetoglobosin C, chaetoglobosin E, chaetoglobosin G, chaetoglobosin Vb, chaetomugilin A, chaetomugilin D and ergosterol peroxide (peroxyergosterol; 5α, 8α-peroxy-(22E, 24R)-ergot-6,22-diene-3β-ol), which has been reported in many literatures, may be a research hotspot. Among these compounds, chaetomugilin A, chaetomugilin D, chaetoglobosin A and chaetoglobosin C have strong cytotoxic activity [22].
Fig. 6

The quantity of different kinds of metabolites from Chaetomium

Table 1

Secondary metabolites of Chaetomium in Ginkgo biloba

No.

Metabolites

CAS number

Molecular structure

Endophytes

Application

References

1

(22E, 24R)-ergosta-7,22-diene-3β,5α,6β-triol/cerevisterol

516-37-0

Open image in new window

Chaetomium globosum

 

[33]

2

(22E, 24R)-ergosta-7,22-diene-3β,5α,6β,9α-tetraol

88191-06-4

Open image in new window

Chaetomium globosum

 

[44]

3

(7Z,11E)-7,11-Hexadecadien-1-yl acetate

53042-79-8

Open image in new window

Chaetomium globosum No. 16

Pesticide

[45]

4

(E,E)-2,4-Decadienal

25152-84-5

Open image in new window

Chaetomium globosum No. 16

Food_additive; fragrance

[45]

5

(Z)-9-Hexadecenoic acid, methyl ester

1120-25-8

Open image in new window

Chaetomium globosum No. 16

 

[45]

6

(Z,Z)-9,12-Octadecadienoic acid

60-33-3

Open image in new window

Chaetomium globosum No. 16

Biosynthesis of prostaglandins and cell membranes

[45]

7

1-(3-Acetyl-2,2-dimethylcyclopropyl)-2-methyl-1-propanone

77142-84-8

Open image in new window

Chaetomium globosum T16

 

[49]

8

1-(3-Methoxy-2-pyrazinyl)-2-methyl-1-propanone

98618-81-6

Open image in new window

Chaetomium globosum T16

 

[46]

9

1,3-Dioxolane, 2-methoxy

19693-75-5

Open image in new window

Chaetomium globosum T16

 

[46]

10

1-Eicosene

3452-07-1

Open image in new window

Chaetomium globosum No. 16

 

[45]

11

1-Trimethylsilyl methanol

3219-63-4

Open image in new window

Chaetomium globosum T16

 

[46]

12

2,3,4-Trimethyl-5,7-dihydroxy-2,3-dihydrobenzofuran

1824584-79-3

Open image in new window

Chaetomium globosum

 

[47]

13

2,4,5-Trimethyl-1,3-dioxolane

3299-32-9

Open image in new window

Chaetomium globosum T16

Flavors

[46]

14

2,4-Decadienal

2363-88-4

Open image in new window

Chaetomium globosum No.16

Food additive

[20, 21]

15

2′-O-Methyladenosine

2140-79-6

Open image in new window

Chaetomium globosum

Inhibition of vaccinia virus growth

[47]

16

2′-Deoxyadenosine

958-09-8

Open image in new window

Chaetomium globosum

Anti-tumor and antiviral nucleoside drugs (cladribine)

[44]

17

20-Dihydrochaetoglobosin A

149560-98-5

Open image in new window

Chaetomium globosum

 

[47]

18

21 Methoxy-Chaetoglobosin F

 

Open image in new window

Chaetomium globosum

 

[47]

18

2-Cyclohexyl-hex-5-en-2-ol

959261-17-7

Open image in new window

Chaetomium globosum T16

 

[46]

19

2-Ethyl-5-propylphenol

72386-20-0

Open image in new window

Chaetomium globosum T16

 

[46]

20

2-Methyl-5-propyl-2,4-dihydro-3H-pyrazol-3-one

31272-04-5

Open image in new window

Chaetomium globosum T16

 

[46]

21

2-Octyl-cyclopropaneoctanal

56196-06-6

Open image in new window

Chaetomium globosum No.16

 

[45]

22

3,4-Dihydroxyphenyl acetic acid

102-32-9

Open image in new window

Chaetomium globosum

A metabolite of dopamine, Cytoplasm, Encephalitis, Hypothyroidism, Alzheimer’s disease, Colorectal cancer

[47]

23

3-Methylorsellinic acid

4707-46-4

Open image in new window

Chaetomium globosum ZY-22

Neuroprotective Activity

[46]

24

4-Aminophenylacetic acid/p-aminophenylacetic acid/4-aminophenylacetic acid

1197-55-3

Open image in new window

Chaetomium globosum

Anti-inflammatory Inhibition colitis

[47]

25

4-Methyl-1-hepten-5-one

26118-97-8

Open image in new window

Chaetomium globosum

 

[46]

26

5-(hydroxymethyl)-1H-pyrrole-2-carbaldehyde

67350-50-9

Open image in new window

Chaetomium globosum

Hapten, produces advanced glycation end-products (AGEs)

[47]

27

5′-Epichaetovirdin A

1308671-17-1

Open image in new window

Chaetomium globosum No. 12

 

[45]

28

5′-Deoxy-5′-methylamino-adenosine

No cas no.

Open image in new window

Chaetomium globosum

 

[47]

29

9(11)-dehyoergosterol peroxide

86363-50-0

Open image in new window

Chaetomium globosum ZY-22

 

[44]

30

9,12-Octadecadien-1-ol

1577-52-2

Open image in new window

Chaetomium globosum No. 16

 

[45]

31

Acetaldehyde, diethyl acetal

105-57-7

Open image in new window

Chaetomium globosum T16

Used in fruit, rum and whisky flavour

[46]

32

Adenosine

58-61-7

Open image in new window

Chaetomium globosum ZY-22

Vasodilatory, anti-arrhythmic and analgesic activities adenosine is an adenosine receptor agonist

[46]

33

Allantoin

97-59-6

Open image in new window

Chaetomium globosum

Healing, soothing, and anti-irritating properties anti-acne products, sun care products, and clarifying lotions 

[48]

34

alpha-Methylstyrene

98-83-9

Open image in new window

Chaetomium globosum

Membrane adhesives and sealant chemicals

[48]

35

Anthranilic acid

118-92-3

Open image in new window

Chaetomium globosum MX-0510

A water-soluble vitamin

[33]

36

Benzeneacetic acid

103-82-2

Open image in new window

Chaetomium globosum No. 16

Used in the manufacture of penicillin and bendazol

[45]

37

Benzeneacetic acid, methyl ester

101-41-7

Open image in new window

Chaetomium globosum No. 16

Used in the manufacture of atropine

[45]

38

Benzeneethanol/phenylethyl alcohol

60-12-8

Open image in new window

Chaetomium globosum

Essence

[45]

39

Butyraldehyde, 4-phenyl

18328-11-5

Open image in new window

Chaetomium globosum T16

 

[46]

40

Cerebroside B

88642-46-0

Open image in new window

Chaetomium globosum ZY-22

 

[46]

41

Cerebroside C

98677-33-9

Open image in new window

Chaetomium globosum ZY-22

 

[46]

42

Chaetoglobosin A

50335-03-0

Open image in new window

Chaetomium globosum

 

[44, 49]

43

Chaetoglobosin B

50335-04-1

Open image in new window

Chaetomium globosum CDW7

 

[48]

44

Chaetoglobosin C

50645-76-6

Open image in new window

Chaetomium globosum

 

[26, 28]

45

Chaetoglobosin D

55945-73-8

Open image in new window

Chaetomium globosum

 

[49]

46

Chaetoglobosin E

55945-74-9

Open image in new window

Chaetomium globosum (CDW7)

 

[49]

47

Chaetoglobosin F

55945-75-0

Open image in new window

Chaetomium globosum (CDW7)

 

[47]

48

Chaetoglobosin Fa

1599426-06-8

Open image in new window

Chaetomium globosum

 

[47]

49

Chaetoglobosin Fex

149457-95-4

Open image in new window

Chaetomium globosum

 

[47]

50

Chaetoglobosin G

65773-98-0

Open image in new window

Chaetomium globosum (NM0066)

 

[47]

51

Chaetoglobosin R

777939-30-7

Open image in new window

Chaetomium globosum

 

[49]

52

Chaetoglobosin V

1399682-37-1

Open image in new window

Chaetomium globosum

 

[47]

53

Chaetoglobosin Vb

1399690-75-5

Open image in new window

Chaetomium globosum (CDW7)

 

[48]

54

Chaetoglobosin Y

1608108-89-9

Open image in new window

Chaetomium globosum

 

[48]

55

Chaetomugilide A

1418138-71-2

Open image in new window

Chaetomium globosum

 

[45, 47]

56

Chaetomugilide B

1433976-48-7

Open image in new window

Chaetomium globosum

 

[45]

57

Chaetomugilide C

1418138-70-1

Open image in new window

Chaetomium globosum

 

[45, 47]

58

Chaetomugilin A

1041640-66-7

Open image in new window

Chaetomium globosum

 

[45]

59

Chaetomugilin D

1098081-38-9

Open image in new window

Chaetomium globosum

 

[25]

60

Chaetomugilin I

1187848-00-5

Open image in new window

Chaetomium globosum

 

[25]

61

Chaetomugilin J

1187848-01-6

Open image in new window

Chaetomium globosum

 

[25]

62

Chaetomugilin O

1187848-06-1

Open image in new window

Chaetomium globosum

 

[25]

63

Chaetomugilin Q

1319729-85-5

Open image in new window

Chaetomium globosum

 

[25]

64

Chaetomugilin S

1399093-77-6

Open image in new window

Chaetomium globosum

 

[25]

65

Chaetoviridin C

128230-02-4

Open image in new window

Chaetomium globosum

 

[15]

66

Chaetoviridin D

128230-04-6

Open image in new window

Chaetomium globosum

 

[33]

67

Chaetoviridin E

1178875-15-4

Open image in new window

Chaetomium globosum

 

[33]

68

Cyclo-(Phe-Gly)

5037-75-2

Open image in new window

Chaetomium globosum

 

[33]

69

Cyclopentadecane

295-48-7

Open image in new window

Chaetomium globosum No.16

 

[45]

70

Dimethyl phthalate

131-11-3

Open image in new window

Chaetomium globosum No.16

Used in plastics, insect repellents, safety glass, and lacquer coatings

[45]

71

Epimwsokorwnone A

1073-96-7

Open image in new window

Chaetomium globosum

 

[33]

72

Ergosta-4 6,8,22-tetraen-3-one/ergosta-4,6,8,22-tetraen-3-one

194721-75-0

Open image in new window

Chaetomium globosum (ZY-22)

 

[33]

73

Ergosterol

57-87-4

Open image in new window

Chaetomium globosum

Formation of vitamin D2

[49]

74

Ergosterol peroxide (5α,8α-epi-dioxy-(22E,24R) -ergosta-6,22-dien-3β-ol)

2061-64-5

Open image in new window

Chaetomium globosum

An antineoplastic agent, an antimycobacterial drug and a trypanocidal drug

[33]

75

Ethanoic acid

64-19-7

Open image in new window

Chaetomium globosum T16

Food additive, and in petroleum production

[46]

76

Ethyl 13-methyl-tetradecanoate

64317-63-1

Open image in new window

Chaetomium globosum No. 16

 

[45]

77

Ethyl 2-heptenoate

2351-88-4

Open image in new window

Chaetomium globosum T16

 

[45]

78

Ethylidene acetate

542-10-9

Open image in new window

Chaetomium globosum T16

 

[45]

79

flavipin (1,2-benzenedicarboxaldehyde-3,4,5-trihydroxy-6-methyl)

483-53-4

Open image in new window

Chaetomium globosum CDW7

Antioxidant fungicides

[22]

80

Fumigaclavine B

6879-93-2

Open image in new window

Chaetomium globosum

 

[47]

81

Fumitremorgin C

118974-02-0

Open image in new window

Chaetomium globosum (NM0066)

A mycotoxin and a breast cancer resistance protein inhibitor

[33]

82

Gliotoxin

67-99-2

Open image in new window

Chaetomium globosum (NM0066)

A mycotoxin, an immunosuppressive agent, an protein farnesyltransferase inhibitor, a proteasome inhibitor and an antifungal agent

[33]

83

Globosterol

1193319-70-8

Open image in new window

Chaetomium globosum ZY-22

 

[44]

84

Glycerol formal

5464-28-8

Open image in new window

Chaetomium globosum T16

 

[46]

85

Hexadecane

544-76-3

Open image in new window

Chaetomium globosum

Used as a solvent and an ingredient in gasoline and diesel and jet fuels

[45]

86

Hexadecanoic acid, ethyl ester

628-97-7

Open image in new window

Chaetomium globosum No. 16

Used as softener, lubricant, food additive

[45]

87

Hexadecanoic acid, methyl ester

112-39-0

Open image in new window

Chaetomium globosum No. 16

Used as intermediate of emulsifier, wetting agent, stabilizer and plasticizer

[45]

88

Indole-3- carboxylic acid

771-50-6

Open image in new window

Chaetomium globosum ZY-22

Used for synthesis of to rise tron and antiviral drugs

[33]

89

Indole-3-acetic acid

87-51-4

Open image in new window

Chaetomium globosum

Plant growth stimulating hormone

[33]

90

Isopentyl alcohol, acetate

123-92-2

Open image in new window

Chaetomium globosum T16

Used as a solvent and preparation of a variety of flavor food flavor

[22]

91

Lactic acid

50-21-5

Open image in new window

Chaetomium globosum T16

Used to make some plasticizers, adhesives, pharmaceuticals and salts, used in the leather tanning industry and as a solvent

[46]

92

Lactic acid, 2-methyl-,ethyl ester

80-55-7

Open image in new window

Chaetomium globosum T16

 

[46]

93

Maltol

118-71-8

Open image in new window

Chaetomium globosum MX-0510

Food additive

[33]

94

Mannitol

87-78-5

Open image in new window

Chaetomium globosum

Used as an osmotic diuretic

[33]

95

Methyl 13-methyltetradecanoate

5129-59-9

Open image in new window

Chaetomium globosum No. 16

 

[45]

96

Methyl 9,12-heptadecadienoate

15620-59-4

Open image in new window

Chaetomium globosum No. 16

 

[45]

97

Methyl vinylcarbinol

598-32-3

Open image in new window

Chaetomium globosum

Food additive

[46]

98

Methylthiogliotoxin

74149-38-5

Open image in new window

Chaetomium globosum (NM0066)

 

[33]

99

o-Coumaric acid

583-17-5

Open image in new window

Chaetomium globosum ZY-22

An antioxidant and is believed to reduce the risk of stomach cancer by reducing the formation of carcinogenic nitrosamines

[33]

100

Octanoic acid, methyl ester

111-11-5

Open image in new window

Chaetomium globosum No. 16

Food additive

[45]

101

Pentadecane

629-62-9

Open image in new window

Chaetomium globosum No. 16

Used as a solvent and in some household pesticides

[45]

102

Pentadecanoic acid, methyl ester

7132-64-1

Open image in new window

Chaetomium globosum No. 16

Fuels and fuel additives

Intermediates, pesticide

[45]

103

p-Hydroxybenzoic acid

99-96-7

Open image in new window

Chaetomium globosum

Used as preservatives, fungicides

[33]

104

Pseurotin A

58523-30-1

Open image in new window

Chaetomium globosum (NM0066)

An azaspiro compound, an oxaspiro compound and a lactam

[33]

105

Quercetin

117-39-5

Open image in new window

Chaetomium globosum GCZX015

Combined with chemotherapeutic drugs, produces anti-inflammatory and anti-allergy effects

[33]

106

Squalene

111-02-4

Open image in new window

Chaetomium globosum (NM0066)

Investigated as an adjunctive cancer therapy, also used as cosmetics and dietary supplement

[33]

107

S-Tetrachloroethane

79-34-5

Open image in new window

Chaetomium globosum T16

Used to make paint, varnish and rust removers, as a solvent and as an ingredient in pesticides

[45]

108

Succinic acid

110-15-6

Open image in new window

Chaetomium globosum

A radiation protective agent, an anti-ulcer drug

[33]

109

Tetradecane

629-59-4

Open image in new window

Chaetomium globosum No.16

Used as a solvent and some pesticide sprays

[45]

110

Thymine

65-71-4

Open image in new window

Chaetomium globosum ZY-22

A pyrimidine nucleobase and a pyrimidone

[33]

111

Tridecane

629-50-5

Open image in new window

Chaetomium globosum No. 16

Used as a solvent and as an ingredient in gasoline and diesel and jet fuel

[45]

112

Triethylene glycol monomethyl ether acetate

3610-27-3

Open image in new window

Chaetomium globosum T16

 

[46]

113

Uracil

66-22-8

Open image in new window

Chaetomium globosum ZY-22

Use in the body to help synthesis of many enzymes, and the biosynthesis of polysaccharides and the transportation of sugars containing aldehydes

[49]

114

α-Guajene

3691-12-1

Open image in new window

Chaetomium globosum No. 16

 

[45]

Chaetomugilin A and D, both are a kind of azaphilone isolated from Chaetomium globosum and has been shown to exhibit inhibitory activity against the brine shrimp (Artemia salina) and Mucor miehei [22]. Chaetomugilide A isolated from Chaetomium globosum TY1 has strong activity against hepatoma cell HepG-2, and the IC50 value is only 1.7 μmol/L [23]. Chaetoglobosin A is a Chaetomium secretion with the anticancer activity in vitro [24] and it derivates into other bilobalide compounds MBJ-0038, MBJ-0039, and MBJ-0040 [25]. Chaetoglobosin E is a cytochalasan alkaloid found in Chaetomium globosum and Chaetomium subaffine. It is a cytochalasan alkaloid, a member of indoles, a macrocycle and a secondary alpha-hydroxy ketone. It has a role as a Chaetomium metabolite and an antineoplastic agent.

One new cytochalasan alkaloid, chaetoglobosin V(b), together with two structurally related known compounds, chaetoglobosin V and chaetoglobosin G, were isolated from the ethyl acetate extract of a culture of the endophytic fungus Chaetomium globosum, associated with the leaves of G. biloba tree. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR and mass spectrometry. The absolute conStruration of chaetoglobosin V(b) was established by means of electronic circular dichroism (CD) spectroscopy. The correlation between compounds was demonstrated by a biomimetic transformation of chaetoglobosin G under mild conditions in chaetoglobosins V and V(b). The isolated metabolites were tested against some phytopathogens [22].

The compound flavipin isolated from Chaetomium globosum CDW 7 has strong antioxidant activity [23]. Chaetomium globosum ZY-22 could produce two polyhydroxylated steroids [24] and two other important compounds bilobalide, ginkgolides are to be beneficial to human health [26]. Bilobalide has neuroprotective effects [27] as well as inducing the liver enzymes CYP3A1 and 1A2 which may be partially responsible for interactions between gingko and other herbal medicines or pharmaceutical drugs; while ginkgolide has been investigated for its potential to reducing migraine frequency [28]. Ergosterol peroxide (5α,8α-epidioxy-22E-ergosta-6,22-dien-3β-ol) is a steroid derivative. It has been reported to exhibit immune- suppressive, anti-inflammatory, antiviral, trypanocidal and antitumor activities in vitro [27].

Secondary metabolites of Aspergillus

Aspergillus is the dominant flora of endophytic fungi of G. biloba and was isolated from different parts of G. biloba which cultivated in various areas. A total of 44 metabolites were found in the fermentation broth of Aspergillus (see Table 2), among which 3-hydroxy-terphenyl, 4,5-dimethoxycandidusin A, prenylcandidusin C, and prenylterphenyllin were studied most popularly. For 4″-Deoxycandidusin A, 4″-deoxytripentin, 4′-deoxy-3-hydroxyrisperidone, aspergiloid A, coumarin A, and tribenzine, three articles reported about each compound, respectively. Among these metabolites, 3-hydroxy-terphenyl and 4″-deoxycandidusin A, 4″-deoxytripentin have strong inhibitory activity against neuraminidase [29]; 4′-deoxy-3-hydroxytripentin, 3-hydroxy-terphenyl, 4″-deoxycandidusin has moderate activity against human nasopharyngeal carcinoma cell KB, human gastric cancer cell SGC-7901, human colon cancer cell SW1116 and human lung cancer cell A549 [30].
Table 2

Secondary metabolites of Aspergilus in Ginkgo biloba

No.

Metabolites

CAS number

Molecular structure

Endophytes

Application

References

1

3-Hydroxyterphenyllin

66163-76-6

Open image in new window

Aspergillus sp.

Induces apoptosis and S phase arrest in human ovarian carcinoma cells

[28, 50]

2

4″-Deoxycandidusin A

1354549-88-4

Open image in new window

Aspergillus sp.

 

[51, 52]

3

4″-Deoxyterphenyllin

59904-04-0

Open image in new window

Aspergillus sp.

 

[50]

4

4,5-Dimethoxycandidusin A/3,4-dimethoxycandidusin A

1354549-89-5

Open image in new window

Aspergillus sp.

 

[50, 52]

5

4′-Deoxy- 3-hydroxyterphenyllin

1296205-84-9

Open image in new window

Aspergillus sp.

 

[50, 52]

6

4′’-Deoxy-5′-desmethyl-terphenyllin

1354549-87-3

Open image in new window

Aspergillus sp.

 

[50]

7

4′’-Deoxyprenylterphenyllin

959124-87-9

Open image in new window

Aspergillus sp. IFB-YXS

Potential anticancer lead molecules

[50]

8

4-Hydroxy-3-(3′-methyl-2′-butenyl) benzoic acid

1138-41-6

Open image in new window

Aspergillus sp. YXf3

Show potent inhibition of HLE

[50]

9

5′-Desmethylterphenyllin

1299485-87-2

Open image in new window

Aspergillus sp.

An alpha-glucosidase inhibitor

[50]

10

Alternariol

641-38-3

Open image in new window

Aspergillus sp. YXf3

An cholinesterase inhibitor and a mycotoxin

[52]

11

Alternariol monomethyl ether/alternariol-4-methyl ether

23452-05-3

Open image in new window

Aspergillus sp. YXf3

An antifungal agent

[52]

12

Aspergiloid A

1354549-91-9

Open image in new window

Aspergillus sp.

 

[50]

13

Aspergiloid B

1354549-92-0

Open image in new window

Aspergillus sp.

 

[50]

14

Aspergiloid C

1354549-93-1

Open image in new window

Aspergillus sp.

 

[50]

15

Aspergiloid D

1354549-94-2

Open image in new window

Aspergillus sp.

 

[50]

16

Aspergiloid E

1579256-33-9

Open image in new window

Aspergillus sp. YXf3

 

[52]

17

Aspergiloid F

1579256-35-1

Open image in new window

Aspergillus sp. YXf3

 

[52]

18

Aspergiloid G

1579256-37-3

Open image in new window

Aspergillus sp. YXf3

 

[52]

19

Aspergiloid H

1579256-39-5

Open image in new window

Aspergillus sp. YXf3

 

[52]

20

Aspergiloid I

1887750-59-5

Open image in new window

Aspergillus sp. YXf3

Anti-cancer and inhibition of plant pathogens

[50]

21

Candidusin A

81474-59-1

Open image in new window

Aspergillus sp.

 

[50]

22

Candidusin C/4″-methoxycandidusin A

267007-58-9

Open image in new window

Aspergillus sp.

 

[50]

23

Chlorflavonin

23363-64-6

Open image in new window

Aspergillus sp. (strain no. YXf3)

An antifungal agent

[50]

24

Chlorflavonin A

1443055-96-6

Open image in new window

Aspergillus sp. (strain no. YXf3)

An antifungal agent

[50]

25

Cyclo-(L-Leu-L-Trp)

15136-34-2

Open image in new window

Aspergillus sp. YXf3

 

[50]

26

Ginkgolide B

15291-77-7

Open image in new window

Aspergillus.fumigatus var. fumigatus FG 05

Ginkgolide B protects human umbilical vein endothelial cells against xenobiotic injuries via PXR activation

[52]

27

Ginkgolide C

15291-76-6

Open image in new window

Aspergillus

 

[32]

28

Prenylcandidusin B

1297472-19-5

Open image in new window

Aspergillus sp. IFB-YXS

An antineoplastic agent

[53]

29

Prenylcandidusin C

1297472-20-8

Open image in new window

Aspergillus sp.

An antineoplastic agent

[53]

30

Prenylterphenyllin

959124-85-7

Open image in new window

Aspergillus sp.

Exhibits cytotoxic activity, an antineoplastic agent

[53]

31

Prenylterphenyllin B

1297472-16-2

Open image in new window

Aspergillus sp. IFB-YXS

Exhibits cytotoxic activity, an antineoplastic agent

[53]

32

Sphaeropsidin A

38991-80-9

Open image in new window

Aspergillus sp. YXf3

larvicidal and biting deterrents against Aedes aegypti

[50]

33

Sphaeropsidin B

39022-38-3

Open image in new window

Aspergillus sp. YXf3

 

[50]

34

Terphenolide

1354549-90-8

Open image in new window

Aspergillus sp.

 

[50]

35

Terphenyllin

52452-60-5

Open image in new window

Aspergillus sp.

A mycotoxin

[50]

36

Terreinol

669073-67-0

Open image in new window

Aspergillus sp. YXf3

 

[31]

37

Xanthoascin

61391-08-0

Open image in new window

Aspergillus sp. IFB-YXS

 

[53]

38

Prenylterphenyllin D

2079979-59-0

Open image in new window

Aspergillus sp. IFB-YXS

Antibacterial activities, anti-phytopathogenic activities

[31]

39

Prenylterphenyllin E

2079979-60-3

Open image in new window

Aspergillus sp. IFB-YXS

Antibacterial activities, anti-phytopathogenic activities

[31]

40

2′-O-Methylprenylterphenyllin

2079979-61-4

Open image in new window

Aspergillus sp. IFB-YXS

Antibacterial activities, anti-phytopathogenic activities

[31]

41

4-O-Methylprenylterphenyllin

2079979-62-5

Open image in new window

Aspergillus sp. IFB-YXS

 

[31]

42

[1,1′:4′,1′’-Terphenyl]-4,4′’-diol, 2′,3′,5′-trimethoxy-(9CI)

59914-89-5

Open image in new window

Aspergillus sp. IFB-YXS

 

[31]

43

[1,1′:4′,1′’-Terphenyl]-2′,4′’-diol,3′,4,6′-trimethoxy-(9CI)

59903-93-4

Open image in new window

Aspergillus sp. IFB-YXS

 

[31]

44

[1,1′:4′,1′’-Terphenyl]-2′,4-diol,3′,4′’,6′-trimethoxy-(9CI)

59903-92-3

Open image in new window

Aspergillus sp. IFB-YXS

 

[31]

Secondary metabolites of Alternaria

Alternaria is a very common fungus. It is an important pathogen for plants, human and animal diseases. It is a biological resource with great application potential as well. According to the existing literatures, 17 metabolites were isolated from the fermentation products of Alternaria (see Table 3). Alterperylenol inhibits human telomerase activity. Alterperylenol can inhibit telomerase activity (IC50 = 30 μM), but altertoxin I (dihydroalterperylenol), a structurally related compound, did not affect activity at 1 mM. Moreover, alterperylenol and altertoxin I show phytotoxic and antifungal activity [31].
Table 3

Secondary metabolites of Alternaria in Ginkgo biloba

No.

Metabolites

CAS number

Molecular structure

Endophytes

Application

References

1

(22E,24R)-ergosta-7,22-diene-3β,5α,6β-triol/cerevisterol

516-37-0

Open image in new window

Alternaria tenuissima SY-P-07

 

[29]

2

(2R,3R)-3,5,7,3′,5′-pentahydroxyflavane

87592-94-7

Open image in new window

Alternaria tenuissima SY-P-07

 

[29]

3

3β,5α,9α-Trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one

88191-14-4

Open image in new window

Alternaria tenuissima SY-P-07

 

[29]

4

6-Epi-stemphytriol

1262797-65-8

Open image in new window

Alternaria tenuissima SY-P-07

 

[29]

5

7-Epi-8-hydroxyaltertoxin I

1262797-64-7

Open image in new window

Alternaria tenuissima SY-P-07

 

[29]

6

Alternariol

641-38-3

Open image in new window

Alternaria No. 28

An cholinesterase inhibitor

[29]

7

Alternariol monomethyl ether/alternariol-4-methyl ether

23452-05-3

Open image in new window

Alternaria No. 28

An antifungal agent

[29]

8

Alterperylenol

88899-62-1

Open image in new window

Alternaria tenuissima

 

[45]

9

Altertoxin I (dihydroalterperylenol)

56258-32-3

Open image in new window

Alternaria sp.

 

[29]

10

Ergosta-4,6,8,22-tetraen-3-one/ergosta-4,6,8,22-tetraen-3-one

194721-75-0

Open image in new window

Alternaria No. 28

 

[29]

11

Ergosterol

57-87-4

Open image in new window

Alternaria sp.

Formation of vitamin D2

[29]

12

Flazin

100041-05-2

Open image in new window

Alternaria tenuissima SY-P-07

 

[47]

13

Solanapyrone G

220924-51-6

Open image in new window

Alternaria tenuissima SY-P-07

 

[47]

14

Stemphyperylenol

102694-33-7

Open image in new window

Alternaria tenuissima SY-P-07

An antifungal agent

[47]

15

Tenuazonic acid

610-88-8

Open image in new window

Alternaria No. 28

An antibiotic with antiviral and antineoplastic, also as a mycotoxin

[29]

16

Vivotoxin II

1261267-71-3

Open image in new window

Alternaria No. 28

 

[29]

In these metabolites, botulinum toxin and botulinum toxin II have strong cytotoxic activity. When the concentration is 10 μg/mL, the mortality rate of brine shrimp is 68.9% and 73.6%, respectively [32]. Alternaria No. 28 could produce cytotoxic metabolites which have inhibitory potential against some different protein kinases [7].

Secondary metabolites of Penicillium

Penicillium is widely distributed in nature and generally has a strong biological activity. According to the existing literatures, 17 secondary metabolites were found from the fermentation products of Penicillium sp. in G. biloba (Table 4), and some metabolites were biologically active. The compound arcacic acid is isolated from the fermentation broth of Penicillium commune, which has antibacterial activity and has inhibition activities on 12 kinds of plant pathogens, especially has strong inhibitory activity against Bacillus licheniformis and Sclerotinia sclerotiorum, and the IC50 values are only 39.28 mg/L and 60.62 mg/L [33].
Table 4

Secondary metabolite of Penicillium in Ginkgo biloba

No.

Metabolites

CAS number

Molecular structure

Endophytes

Application

References

1

2′-Deoxyuridine/uracil deoxyriboside

951-78-0

Open image in new window

Penicillium sp. YY-25

Antimetabolite

[29]

2

3-Methylorsellinic acid

4707-46-4

Open image in new window

Penicillium No. 97

Antibacterial activity

[29]

3

3-Methylpiperazine-2,5-dione

6062-46-0

Open image in new window

Penicillium sp. YY-24

 

[29]

4

Adenine

73-24-5

Open image in new window

Penicillium sp. YY-22

Dietary supplement

[29]

5

Adenosine

58-61-7

Open image in new window

Penicillium sp. YY-20

Analgesic, antiarrhythmic

[29]

6

Anthranilamide

88-68-6

Open image in new window

Penicillium No. 97

Fluorescent dyes

[54]

7

Anthranilic acid

118-92-3

Open image in new window

Penicillium No. 97

Anticonvulsants

[55]

8

Cyclopaldic acid

477-99-6

Open image in new window

Penicillium commune (TMSF169)

 

[56]

9

Ferulic acid

1135-24-6

Open image in new window

Penicillium No. 97

Free radical scavengers, anti-inflammatory agents, antihypertensive agents, anticoagulants

[55]

10

Fructigenine A

144606-96-2

Open image in new window

Penicillium No. 97

Inhibits the growth of leukemia cells

[55]

11

Indole-3-acetic acid

87-51-4

Open image in new window

Penicillium No. 97

Used for preventing, destroying or mitigating pests

[55]

12

Methyl β-d-ribofuranoside

7473-45-2

Open image in new window

Penicillium sp. YY-21

Used to synthesize novel alpha-amino acid esters against herpes simplex virus 1 (hsv-1) and hepatitis b virus

[29]

13

Orsellinic acid

480-64-8

Open image in new window

Penicillium No. 97

 

[29]

14

p-Hydroxybenzoic acid

99-96-7

Open image in new window

Penicillium No. 97

 

[55]

15

β-sitosterol

83-46-5

Open image in new window

Penicillium No. 97

Hypolipidemic agents

[55]

16

Quercetin glycoside (orange pigment)

3520-72-7

Open image in new window

Penicillium sp.

 

[34]

The compounds adenosine, deoxyadenosine and adenine which were isolated from the fermentation product of Penicillium sp. YY-20 have a strong scavenging capacity for DPPH free radical [34]. Wu isolated Penicillium cataractum SYPF 7131 from 58 endophytic fungi obtained from the leaves, stems and roots of G. biloba. This strain displayed the strongest antibacterial activity [35].

Secondary metabolites of Xylaria

43 kinds of compounds were isolated from the fermentation products of Xylaria in Ginkgo biloba (Table 5), in which the compound 7-amino-4-methylcoumarin was isolated from the fermentation product of Xylaria sp. YX-28 [36]. It has antibacterial activity and also has strong inhibitory activity against 13 kinds of human susceptible pathogens, which is significantly higher than the positive controls ampicillin, gentamicin and tetracycline.
Table 5

Secondary metabolite of Xylaria in Ginkgo biloba

No.

Metabolites

CAS number

Molecular structure

Endophytes

Application

References

1

7-Amino-4-methylcoumarin

26093-31-2

Open image in new window

Xylaria sp. YX-28

A fluorescent dye used to stain biological specimens

[57]

2

Pentadecane

629-62-9

Open image in new window

Xylaria sp. YX-28

Treatment of plantar keratosis with medicinal plant in diabetic patients

[57]

3

Quercetin

117-39-5

Open image in new window

Xylaria Colletotrichum

Chemotherapy induced oral mucositis; treatment of erosive and atrophic oral lichen planus; chronic obstructive pulmonary disease; gastroesophageal reflux disease

[57]

4

Tetradecane

629-59-4

Open image in new window

Xylaria sp.YX-28

 

[57]

5

Tridecane

629-50-5

Open image in new window

Xylaria sp. YX-28

 

[57]

6

Dibutyl phthalate

84-74-2

Open image in new window

Xylaria sp. YX-28

Against the larval trombiculid mite; preventing scrub typhus of topical application in troops

[57]

7

1,3-Diphenyl-2-pyrazoline

2538-52-5

Open image in new window

Xylaria sp. YX-28

 

[57]

8

1-Acetyl-1,2,3,4-tetrahydropyridine

19615-27-1

Open image in new window

Xylaria sp. YX-28

 

[57]

9

Z,Z-7,11-Hexadecadien-1-ol

53963-06-7

Open image in new window

Xylaria sp. YX-28

 

[57]

10

Isosorbide

652-67-5

Open image in new window

Xylaria sp. YX-28

Prevention of angina pectoris due to coronary artery disease; short-term reduction of intraocular pressure

[57]

11

Dimethoxy-phenol

91-10-1

Open image in new window

Xylaria sp.YX-28

Food Flavoring Agents

[57]

12

1-hydroxymethyl-1,2,3,4,-tetrahydro-naphthalen-2-ol

872824-43-6

Open image in new window

Xylaria sp. YX-28

 

[57]

13

(1,4-Dimethylpent-2-enyl)benzene

951288-80-5

Open image in new window

Xylaria sp. YX-28

 

[57]

14

2,4-Bis(1,1-dimethylethyl)phenol

96-76-4

Open image in new window

Xylaria sp. YX-28

 

[57]

15

3-Phenyl-4-methyl-isoxazol-5(4)-one

875244-90-9

Open image in new window

Xylaria sp. YX-28

 

[57]

16

3,4-Dihydro-8-hydroxy-3-methyl-isocoumarin

1200-93-7

Open image in new window

Xylaria sp. YX-28

 

[57]

17

[l(3-butenylthio)-2-nitroethyl]-benzene

128869-50-1

Open image in new window

Xylaria sp. YX-28

 

[57]

18

Pentadecanoic acid, methyl ester

7132-64-1

Open image in new window

Xylaria sp. YX-28

pesticide

[57]

19

14-Octadecenal

56554-89-3

Open image in new window

Xylaria sp. YX-28

 

[57]

20

E-11,13-Dimethyl-12-tetradecen-1-ol acetate

400037-00-5

Open image in new window

Xylaria sp. YX-28

 

[57]

21

Hexadecanoic acid, methyl ester

112-39-0

Open image in new window

Xylaria sp. YX-28

Food flavoring agents

[57]

22

n-Hexadecanoic acid

57-10-3

Open image in new window

Xylaria sp. YX-28

Inhibits HIV-1 infection; a potential candidate for specifically attack multiple myeloma cells

[57]

23

2-Undecenal

2463-77-6

Open image in new window

Xylaria sp. YX-28

 

[57]

24

Hexadecanoic acid, 14-methyl-methyl ester

2490-49-5

Open image in new window

Xylaria sp. YX-28

 

[57]

25

9,12-Octadecadienoic acid(Z,Z)-methyl ester

112-63-0

Open image in new window

Xylaria sp. YX-28

Flavoring agent or adjuvant

[57]

26

9-Octadecenoic acid (Z)-,methyl ester

112-62-9

Open image in new window

Xylaria sp. YX-28

Solvents

[57]

27

3,7,11-trimethyl-2,6,10-Dodecatrien-1-ol

4602-84-0

Open image in new window

Xylaria sp. YX-28

Inhibits proliferation and induces apoptosis of tumour-derived but not non-transformed cell lines

[57]

28

9,12-Octadecadienoic acid (Z,Z)

2197-37-7

Open image in new window

Xylaria sp. YX-28

Treats the prevention of preeclampsia;

[57]

29

9-Octadecenamide (Z)

3322-62-1

Open image in new window

Xylaria sp. YX-28

Induce drowsiness or sleep or to reduce psychological excitement or anxiety

[57]

30

Pentadecanoic acid,2-hydroxymethy l ester

98863-01-5

Open image in new window

Xylaria sp. YX-28

Emulsifier

[57]

31

Ferruginol

514-62-5

Open image in new window

Xylaria sp. YX-28

An antineoplastic agent; antibacterial agent; protective agent

[57]

32

9,12-Octadecadienoic acid(Z,Z)-,2-hydroxy-1-(hydroxy methyl)ethyl ester

544-35-4

Open image in new window

Xylaria sp. YX-28

Flavoring agents

[57]

33

Hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl)ethyl ester

23470-00-0

Open image in new window

Xylaria sp. YX-28

Lipid maps classification

[57]

34

Bis(2-ethylhexyl)phthalate

117-81-7

Open image in new window

Xylaria sp.YX-28

 

[57]

35

5,6,8,9,10,11-Hexahydrobenz[A]anthracene

67064-61-3

Open image in new window

Xylaria sp. YX-28

 

[57]

36

1,2,3,4-Tetrahydro-Triphenylene

5981-10-2

Open image in new window

Xylaria sp. YX-28

 

[57]

Secondary metabolites of Fusarium

Fusarium is one of the dominant bacteria, which can be isolated from different parts of Ginkgo cultivated in various areas. According to the literatures, 25 kinds of compounds were isolated from the fermentation products of Fusarium (Table 6). Since Fusarium of G. biloba can produce ginkgolides B, it can be used as a new source of ginkgolides B [37]. Some studies have shown that Fusarium oxysporum GF521 can produce rutin and kaempferol, and the total flavonoids production of endophytic fungi is 21.10 ± 1.30 mg/L, which indicates that Fusarium genus also have a high ability of producing flavonoids [37].
Table 6

Secondary metabolite of Fusarium in Ginkgo biloba

No.

Metabolites

CAS number

Molecular structure

Endophytes

Application

References

1

Adenosine

58-61-7

Open image in new window

Fusarium solani GBT07 GBT07

Terminate paroxysmal supraventricular tachycardia; terminating stable and narrow-complex supraventricular tachycardias; adjunct to thallous chloride TI 201 myocardial perfusion scintigraphy and vagal maneuvers and clinical assessment

[11]

2

Benzeneethanol/Phenylethyl alcohol

60-12-8

Open image in new window

Fusarium sp. G1024

Anti-infective agents, local; disinfectants; preservatives, pharmaceutical

[11]

3

Enniatin B

917-13-5

Open image in new window

Fusarium sp.

 

[58]

4

Ginkgolide B

15291-77-7

Open image in new window

Fusarium oxysporum

 

[59, 60]

5

Hexadecane

544-76-3

Open image in new window

Fusarium sp. G1024

 

[11]

6

Kaempferide

491-54-3

Open image in new window

Fusarium solani

An antihypertensive agent

[61]

7

Kaempferol

520-18-3

Open image in new window

Fusarium oxysporum

A possible cancer treatment; antibacterial agent

[61]

8

Quercetin

117-39-5

Open image in new window

Fusarium oxysporum

 

[57]

9

Rutin

153-18-4

Open image in new window

Fusarium oxysporum

A role as an antioxidant; antiallergic; anti-inflammatory; antiproliferative; and anticarcinogenic properties

[61]

10

Soyasapogenol B

595-15-3

Open image in new window

Fusarium oxysporum Schlecht GB-1(3)

 

[61]

11

Tetradecane

629-59-4

Open image in new window

Fusarium sp. G1024

 

[11]

12

β-Sitosterol

83-46-5

Open image in new window

Fusarium oxysporum Schlecht GB-1(3)

As anticholesteremic drug; antioxidant; treats hyperlipidemia.

[61]

13

Isorhamnetin

480-19-3

Open image in new window

Fusarium sp

Warning; (tyrosinase inhibitor; an anticoagulant)

[62]

14

Decane

124-18-5

Open image in new window

Fusarium sp. G1024

 

[11]

15

2-Ethyl-1-hexanol

104-76-7

Open image in new window

Fusarium sp. G1024

 

[11]

16

2-Butanol,3,3′-oxybis-4-ethylphenol

123-07-9

Open image in new window

Fusarium sp. G1024

Flavoring Agents

[11]

17

Dodecane

112-40-3

Open image in new window

Fusarium sp. G1024

Increase the risk of neoplasms in humans or animals

[11]

18

1,2-benzisothiazole

272-16-2

Open image in new window

Fusarium sp. G1024

 

[11]

19

4-Ethyl-2-methoxyphenol

2785-89-9

Open image in new window

Fusarium sp. G1024

Flavoring agents

[11]

20

p-Nitroacetophenone

100-19-6

Open image in new window

Fusarium sp. G1024

Potentiate the effectiveness of radiation therapy in destroying unwanted cells

[11]

21

2,3,5,6-Tetramethyl-p-benzoquinone

527-17-3

Open image in new window

Fusarium sp. G1024

product quinones duroquinone

[11]

22

Eicosane

112-95-8

Open image in new window

Fusarium sp. G1024

Flavoring Agents.

[11]

23

1,2-Benzenedicarboxylic acid bis(2-methylpropyl)ester

88-99-3

Open image in new window

Fusarium sp. G1024

 

[11]

24

Dibutyl phthalate

84-74-2

Open image in new window

Fusarium sp. G1024

Against the larval trombiculid mite; preventing scrub typhus of topical application in troops

[11]

Secondary metabolites of other genus

53 compounds were isolated from the fermentation products of other genus in G. biloba (Table 7), some of which can also produce other valuable compounds. From the endophytic Muscodor albus GBA, 19 kinds of volatile components can be separated [24], which normally have a strong ecological effect. Some volatile components can inhibit the pathogenic microorganisms and enhance the disease resistance of plants. Bacillus amyloliquefaciens can produce 8 kinds of compounds [35, 37] which have some biological activities. Two compounds, apigenin-8-C-glucoside and 2-(Hydroxymethylthio) ethanol, were isolated from Colletotrichum sp. NTB-2., in which apigenin-8-C-glucoside has strong inhibitory activity against Bacillus subtilis, Salmonella typhimurium and Pseudomonas cepacia [38]. Moreover, Colletotrichum sp. could produce flavones which exhibited potent anti-cancer, anti-HIV [39] and antioxidant activities [40].
Table 7

Secondary metabolite of other endophytics in Ginkgo biloba

No.

Metabolites

CAS number

Molecular structure

Endophytes

Application

References

1

2-(Hydroxymethylthio)ethanol

876503-58-1

Open image in new window

Colletotrichum sp. NTB-2

Platelet aggregation inhibitor, an alpha-glucosidase inhibitor, an antineoplastic agent

[63]

2

Apigenin-8-C-β-d-glucopyranoside

3681-93-4

Open image in new window

Colletotrichum sp.

 

[63, 64]

3

6-Ethoxyl-2,4-amide lactone

 

Open image in new window

Bacillus amyloliquefaciens CGMCC 5569

 

[64]

4

6-Hydroxylbutyl-2,4-amide lactone

 

Open image in new window

Bacillus amyloliquefaciens CGMCC 5569

 

[64]

5

6-Hydroxypropyl-2,4-amide lactone

 

Open image in new window

Bacillus amyloliquefaciens CGMCC 5569

 

[64]

6

Biuret

108-19-0

Open image in new window

Bacillus amyloliquefaciens CGMCC 5569

Used for preventing, destroying or mitigating pests

[64]

7

Ginkgolide B

15291-77-7

Open image in new window

Oospora wallr. G10

Fibrinolytic agents

[65]

8

2′-Deoxyuridine/uracil deoxyriboside

951-78-0

Open image in new window

Unidentified

Antimetabolites

[65]

9

3-Methylpiperazine-2,5-dione

6062-46-0

Open image in new window

Unidentified

 

[65]

10

Adenine

73-24-5

Open image in new window

Unidentified

 

[65]

11

Adenine deoxyriboside

 

Open image in new window

Unidentified

 

[65]

12

Adenosine

58-61-7

Open image in new window

Unidentified

Used as an initial treatment for the termination of paroxysmal Supraventricular tachycardia

[65]

13

Quercetin

117-39-5

Open image in new window

Stemphylium sp.

Act inomyces

Antioxidants

[37, 66]

Nodulisporium hyalosporum

Schizophyllum commune Fr.

 

[67]

Fusella Sacc

Alternaria sp

Sphacelia sp.

Anpelomyces humuli

 

[37]

Phoma glomerate

 

[30, 61]

Trichothecium

 

[53]

Mucor circinelloides

 

[40]

Sphaeropsis sp. B301

 

[68]

14

Kaempferol

520-18-3

Open image in new window

Fusella Sacc

Alternaria sp.

Gibberella sp.

Sphacelia sp.

Dematium Pers

As a selective estrogen receptor modulator

[66]

Trichothecium

 

[53]

Sphaeropsis sp.

 

[68]

15

Cerebroside B

88642-46-0

Open image in new window

Phyllosticta sp. TP78, (GenBank ID: KC445736)

An antimicrobial compound

[20, 21]

16

Cerebroside C

98677-33-9

Open image in new window

Phyllosticta sp. TP78 (GenBank ID: KC445736)

Increases tolerance to chilling injury and alters lipid composition in wheat roots

[20, 21]

17

Enniatin B1

19914-20-6

Open image in new window

Tuberculariaceae F1-3

Fusarium mycotoxins

[69]

18

Enniatin D

19893-21-1

Open image in new window

Tuberculariaceae sp. F1-3

Inhibition of Botrytis cinerea spore germination

[69]

19

Benzeneethanol/Phenylethyl alcohol

60-12-8

Open image in new window

Muscodor albus strain GBA

Anti-bacterial agents and antioxidants. Anti-Infective Agents

[69]

20

Ginkgolide C

15291-76-6

Open image in new window

Gloeosporium; Tolura; Phacodium

Reduced lipid accumulation and suppresses adipogenesis

[32]

21

Kaempferide

491-54-3

Open image in new window

Phoma glomerata

Reverse bacterial resistance to amoxicillin in AREC

[61]

Anpelomyces humuli

 

[61]

22

Rutin

153-18-4

Open image in new window

Mucor circinelloides GF521

Used therapeutically to decrease capillary fragility

[61]

Nodulisporium hyalosporum

 

[67]

23

Sporothriolide

154799-92-5

Open image in new window

Nodulisporium sp. A21

Used to treat the infection caused by candida albicans and cryptococcus neoformans

[55]

24

Isorhamnetin

480-19-3

Open image in new window

Stemphylium sp.

Alternaria sp

Gibberella sp.

Trichothecium

prevents endothelial dysfunction, superoxide production, Isorhamnetin appears to be a potent drug against esophageal cancer

[62]

sphaeropsis

 

[68]

Plantactinospora sp. NEAU-gxj3

 

[20, 21]

25

Antibiotic U-62162

82516-67-4

Open image in new window

Plantactinospora sp. NEAU-gxj3

Inhibited the growth of Gram-positive bacteria

[20, 21]

26

Salternamide C

1662688-81-4

Open image in new window

sphaeropsis

 

[68]

27

Abscisic acid

21293-29-8

Open image in new window

Phoma betae

Plant Growth Regulator

[69]

28

Taxol

33069-62-4

Open image in new window

Phomopsis sp. 2 strain

BKH 30 (BSL No. 72)

An antineoplastic agent, tubulin modulators

[70]

Muscodor albus strain GBA

 

[69]

29

Acetic acid, methyl ester

79-20-9

Open image in new window

Muscodor albus strain GBA

 

[69]

30

2-Butanone

78-93-3

Open image in new window

Muscodor albus strain GBA

Polar aprotic solvent

[69]

31

Acetic acid, 2-methylpropyl ester

110-19-0

Open image in new window

Muscodor albus strain GBA

An antifungal agent

[71]

32

1-Propanol, 2-methyl

78-83-1

Open image in new window

Muscodor albus strain GBA

Possesses nicotine-like synaptotropic actions on the nervous systems

[71]

33

1-Butanol, 3-methyl-,acetate

123-92-2

Open image in new window

Muscodor albus strain GBA

 

[71]

34

Cyclohexane,1-methyl-4-methylene

2808-80-2

Open image in new window

Muscodor albus strain GBA

 

[69]

35

2,3-Dimethyl-3-isopropyl-cyclopentene

73331-73-4

Open image in new window

Muscodor albus strain GBA

 

[69]

36

1-Butanol, 3-methyl

123-51-3

Open image in new window

Muscodor albus strain GBA

 

[69]

37

Pyrrolidine

123-75-1

Open image in new window

Muscodor albus strain GBA

 

[72]

38

Germacrene B

15423-57-1

Open image in new window

Muscodor albus strain GBA

 

[72]

39

α-Sinensal

17909-77-2

Open image in new window

Muscodor albus strain GBA

 

[69]

40

Propanoic acid, 2-methyl

79-31-2

Open image in new window

Muscodor albus strain GBA

 

[73]

41

Trans-caryophyllene

87-44-5

Open image in new window

Muscodor albus strain GBA

Anti-inflammatory agents

[73]

42

4-Piperidinone, 1-methyl

1445-73-4

Open image in new window

Muscodor albus strain GBA

 

[73]

43

Acetic acid, 2-phenylethyl ester

103-45-7

Open image in new window

Muscodor albus strain GBA

 

[73]

44

(+)-Vitrene

90250-82-1

Open image in new window

Muscodor albus strain GBA

 

[73]

In recent years, some new ginkgo endophytes and secondary metabolites have been discovered. Guo et al. [20, 21] discovered a new amide compound from Plantactinospora sp. NEAU-gxj3, Cao et al. [22] found the metabolite sporothriolide from the Nodulisporium of G. biloba, which has anti-phytopathogenic activity.

Application of secondary metabolites from Ginkgo biloba

Following the discovery by Schwabe of Germany that Ginkgo biloba contains active ingredients—ginkgo flavonoids and ginkgolides for the prevention and treatment of cardiovascular, cerebrovascular and neurological diseases, the researches about ginkgo has become more popular. Germany and France were the first countries in the world to develop ginkgo leaf products. In the mid-1970s, they first developed Ginkgo biloba leaves for the treatment of cardiovascular diseases. Since then, there are more than 50 kinds of ginkgo products on the market.

In the application, Ginkgo can be used with the extracts. Some examples, a substance EGb 761 extracted from Ginkgo biloba has shown to be effective against Noise-induced hearing loss (NIHL) in an animal model. This substance is assumed to protect the cochlea from hair cell loss after intensive noise exposure by reducing reactive oxygen species (ROS). Further effects of EGb 761 on the cellular and systemic levels of the nervous system make it a promising candidate not only for protection against NIHL but also for its secondary comorbidities like tinnitus [41]; One Ginkgo biloba extract (GbE) was used as a nontoxic natural reducing and stabilizing agent for preparing cytocompatible graphene. The as-prepared GbE-reduced graphene oxide (Gb-rGO) showed significant biocompatibility with cancer cells. Addition of GbE makes rGO producing procedure cost-effective and green. This method could be used for various biomedical applications, such as tissue engineering, drug delivery, biosensing, and molecular imaging [42].

Some application has been using a part of the plant. Another example, Ginkgo tea is a kind of health food produced from Ginkgo biloba leaves. Two kinds of glycosidase were used to improve the flavor of Ginkgo tea, and three kinds of bioactivities were selected to investigate the health care function of the tea infusion [43].

The Ginkgo preparation mainly includes capsules, tablets, granules, tea bags. Capsules and tablets are most popular in the formulation of the product. Recently, new preparation like shampoo, facial cleanser and hair moisturizer have been introduced in cosmetics applications. Most of the ginkgo products on the market are registered as health foods and a few are registered as over-the-counter drugs.

In many existing products, especially in the medicines, 24% of total flavonoids and 6% of ginkgolides are the basic quality requirements for Ginkgo biloba extracts. Some famous manufacturers proposed higher standards. They appended ginkgolides A, B, C, J and biloba lactone as the quality indicators and generally required the content of ginkgolides A, B, C, J greater than 2.5%, the content of biloba lactone greater than 2.6%.

On the basis of data about the endophytes and secondary metabolites in G. biloba, the catalogue is diverse in terms of structural complexity and lots of them have promising biological activities, which have the potential to be a source of new pharmaceutical agents which have a constant, critical need to combat cancers, viral infections, infectious diseases, and autoimmune disorders. There is also a growing need to fight insect-borne diseases of both animals and plants as climatological changes provide conditions conducive to more intensive outbreaks of these events. The fight against any disease is a dynamic equilibrium between advances in chemotherapy and natural selection in infectious or invasive agents. If the scientific community is to maintain parity in this never-ending struggle, then new sources of novel, bioactive chemotherapeutic agents must be found.

It appears that the mechanism by which endophytes produce secondary metabolites that mimic those produced by their host plants is far from clear. Even though efforts to unravel the pathway genes in the endophytes, it has failed to detect critical genes corresponding to those existing in plants, our understanding of the mechanisms associated with the development of different diseases increases, our ability to use this knowledge to select for ever more potent and selective compounds should increase commensurately. Endophytes of G. biloba will continue to provide a fertile arena for these quests.

Prospects

With human aging process is accelerating, it has been common pursuit for a healthy and high-quality living. Since Ginkgo biloba preparations have a worldwide reputation as natural medicines and healthy products, Ginkgo development and the prospects are attractive. In the United States, Ginkgo biloba extracts have been on the list of imported drugs. Ginkgo products on the market are almost all products of American companies, and few products have been seen in Europe. At present, the European market is basically occupied by French and German products. Most of the Ginkgo extracts on the US market are produced by Japan and South Korea, a small portion is purchased from China.

Although comparing with the developed countries, China market is not competitive and too weak to take the risks, the potential of China’s Ginkgo development is still worth looking forward to. China is the birthplace and main producing area of the world’s Ginkgo. Many excellent Ginkgo germplasm resources are valuable treasures for China. With the sharp increase in Ginkgo resources and products output in China, the market has become more concerned at present (Fig. 7). At present, the Ginkgo products in China have low added-value and quality. In the development of ginkgo industry in China, it is necessary to increase the quality standardization and to improve the scientific research efforts and the production technology of Ginkgo preparations. It deserves to initiate new and technological products on flavonoids, bilobalide, polyisoprene, etc. Especially some new application in other industries should be explored, such as supplying in cytocompatible graphene preparation.
Fig. 7

The production of Ginkgo extracts in China and its proportion in the world market. a The production of Ginkgo extracts in China from 2015 to 2019; b the proportion of China Ginkgo products in the world market from 2014 to 2018

Chinese people have a tradition to have Ginkgo preparation as healthy products. China’s population accounts for about a quarter of the world’s total population. Therefore, the Ginkgo products in China should have more concerns on the domestic market and at the same time expand the international market with high-quality and featured products.

Notes

Acknowledgements

Not applicable.

Authors’ contributions

ZY and YT drafted the manuscript and prepared tables and figures. FH and HZ contributed to revisions of the manuscript. All authors read and approved the final manuscript.

Funding

The work reported in the paper has been supported by the National Natural Science Foundation of China (No. 31741109), the Hunan Provincial Natural Science Foundation of China (Nos. 2018JJ2145, 2018JJ2146) and the Scientific Research Project of Hunan University of Science and Technology (17XKY002, 17XKY011, 17XKY012).

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. 1.College of Bioscience and BiotechnologyHunan Agricultural UniversityChangshaChina
  2. 2.Hunan Provincial Engineering Research Center for Ginkgo BilobaYongzhouChina
  3. 3.College of Chemistry and BioengineeringHunan University of Science and EngineeringYongzhouChina

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