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Antidiabetic and Antioxidant Activities of Bioactive Compounds from Endophytes

  • Rosa Martha Perez GutierrezEmail author
  • Adriana Neira González
Reference work entry
Part of the Reference Series in Phytochemistry book series (RSP)

Abstract

The aim of the present chapter is to appraise the phytochemical and pharmacological potential of the endophytes. This chapter will further highlight the future research prospects of the study of endophytes with antioxidant and antidiabetic activities. Informations on endophytes were obtained from related publications using electronic scientific databases. Based on previous reports, it could be said that the endophytes have emerged as excellent source of compounds which could be used for the treatment of skin diseases and microbial infections and as anticancer and anti-inflammatory agents. The studies provide new knowledge on the isolation and characterization of novel bioactives especially in the discovery of novel therapeutic drugs with antioxidant and antidiabetic properties. however, current research on the pharmacological properties of all the endophyte species including bioassay-guided isolation of phytoconstituents and their mechanism of action, pharmacokinetics, bioavailability, efficacy, and safety should be carried out in the future to add more value to this study.

Keywords

Endophytes Medicinal plants Marine plants Antioxidants Antidiabetic 

Abbreviations

ABTS

2,2-Azinobis(3-ethylbenzothiazoline-6-sulfonic acid)

AGEs

Advanced glycation end products

AgNPs

Silver nanoparticles

ALP

Alkaline phosphatase

ALT

Alanine aminotransferase

AMPK

AMP-activated protein kinase

AST

Aspartate aminotransferase

CAT

Catalase

CE6

Not identified

CE9

Not identified

CEC12

Cochliobolus sp.

CED3

Diaporthe sp.

CED4

Diaporthe sp.

CED7

Diaporthe sp.

CEDp11

Diaporthe phaseolorum

CEDp2

Diaporthe phaseolorum

CEP1

Phomopsis sp.

CEP10

Phomopsis sp.

CEP4

Phomopsis sp.

CES13

Sordariomycetes sp.

CES8

Sordariomycetes sp.

CVD

Cardiovascular diseases

DAPG

2,4-Diacetylphloroglucinol

DPPH

1,1-Diphenyl-2-picrylhydrazyl

EtOAc

Ethyl acetate

FRAP

Ferric reducing ability of plasma

FTIR

Fourier-transform infrared spectroscopy

GC-MS

Gas chromatography mass spectrometry

GPx

Glutathione peroxidase

ITS

Internal transcribed spacer

MDA

Malondialdehyde

NCB

Gene sequencing

PMS-NADH

Phenazine methosulfate-nicotinamide adenine dinucleotide

ROS

Reactive oxygen species

SOD

Superoxide dismutase

T2D

Type 2 diabetes mellitus

TEM

Transmission electron microscopy

UV-Vis

Ultraviolet-visible spectroscopy

VOLF4

Aspergillus sp.

VOLF5

Peniophora sp.

VOR5

Fusarium nematophilum

XRD

X-ray diffraction

1 Introduction

Non-insulin-dependent diabetes also called type 2 diabetes is characterized by insulin resistance in tissues including the skeletal muscle and liver and fat tissues and impaired insulin secretion in the pancreas. Diabetes has been associated with a high incidence of complications which are initiated by glycation of proteins which commonly occur in chronic hyperglycemia. A series of subsequent molecular rearrangements and oxidations generate complex compounds of which the most reactive and unstable compounds are known as advanced glycation end products (AGEs) [1]. These modifications can alter the structure and function of proteins and promote cross-linking between them leading to pathological conditions [2]. With the increase of obesity in the population owing to poor lifestyle, consumption of high-calorie diets, and lack of exercise, the incidence of type 2 diabetes has increased considerably over the last decades. It has been estimated that currently around 385 million people are living with type 2 diabetes (T2D), and it is predicted to rise to 595 million by 2035 [3]. In the present scenario, medical treatment does not work for 50% of diabetic patients generating complications which reduce the overall life quality and produce mortality [4]. Chronic hyperglycemia is considered as the main cause of dysregulation of the metabolic signal transduction pathway generating reactive oxygen species (ROS). Excess ROS overfreights the antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) causing an imbalance between antioxidant defense and free radical production generating oxidative stress [5]. Oxidative stress plays an important role in β-cell dysfunction and in pathogenesis of insulin resistance [6] as disruption of cellular homeostasis leads to dysregulation of cell metabolism.

Oxidative stress causes functional and structural alterations in the cellular proteins, nucleic acid, and lipids inviting several complications in patients with diabetes [7]. Antioxidant enzymes such as GPx, SOD, and CAT act as free radical scavengers and form innocuous products donating electrons to ROS inactivating free radicals, thereby protecting cells against oxidative damage [8]. However, in diabetes these antioxidant enzymes are degraded [9]. Chronic hyperglycemia affects antioxidant defense system followed by injury of cellular organelles, development of insulin resistance, and increased level of lipid peroxidation [10]. Malondialdehyde (MDA) is the product of lipid peroxidation used as an indicator of cellular damage [11]. The liver is also damaged severely in diabetes, and therefore, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) are widely used as indicators of liver functions [12].

Hundreds of plants have been used to treat diabetes mainly due to their hypoglycemic effect. Furthermore, numerous studies have reported the isolation and characterization of more than 200 compounds from medicinal plants [13, 14]. The benefits of such plants for treating diabetes are widely known, and they are regarded as alternatives to pharmaceuticals [15], e.g., Magnolia grandiflora contains honokiol as an active constituent which activates AMP-activated protein kinase (AMPK) [16]. AMPK is considered as a cellular energy sensor which helps regulate the energy balance and caloric intake and participates in the regulation of glycolysis, in the entry of glucose, in the oxidation of lipids, in the synthesis of fatty acids and cholesterol, and in gluconeogenesis . It has been considered as a white enzyme in the possible treatment of some diseases such as obesity, diabetes, and hepatic steatosis [17]. Metformin is an important oral antidiabetic drug which lowers blood glucose level and suppresses hepatic gluconeogenesis by activating AMPK in the skeletal muscle [18] and the liver [19].

The German scientist Heinrich Anton de Bary in 1866 used the term endophytes for all microorganisms that inhabit the tissues of healthy plants without showing symptoms of an identifiable disease in the host. Endophytes are bacterial, fungal, or actinomycete microorganisms which colonize healthy plant tissues. The relationship between host plant and the endophyte can be considered as symbiotic to near pathogenic [20] which is however poorly understood. In drug discovery, endophytes are major contributors in the production of compounds with diverse biological activities and novel chemical structures [21].

It has been estimated that there are approximately a million fungal endophytes living inside plant tissues without causing damage to hosts. In the last decades, they have been considered as important microbial resources [22] producing a large number of bioactive compounds. Starting from 2002, endophytic strains have generated nearly half of the newly discovered metabolites derived from fungi. Such metabolites show anti-inflammatory, antioxidant, antihypertensive, antidiabetic, anticancer, antifungal, immunomodulatory, and antibacterial activities [23].

Particularly tropical and subtropical plants are rich in diversity of endophytic microorganisms [24]. The biodiversity of endophytes is influenced by several factors such as the sampling site, the age of the tissue, and the associated vegetation [25]. The plant/microorganism association in many cases is influenced by the bioactive compounds produced by the microorganisms [26]. The compounds benefit the host plant in many cases by providing protection against infections and in others being crucial for their survival [27, 28]. Medicinal plants are producers of important bioactive compounds being a target for isolation of endophytic fungi [29, 30, 31]. Since endophytes are an important resource of bioactive compounds, it could be expected that they might have a solution for the treatment of diabetes. Thus, there is a need to study endophytes for the development of effective yet safe drugs.

In the last decades, marine organisms have attracted attention for their immense potential in producing widely diverse bioactives or secondary metabolites [32]. Among these, the study of fungi has become a foreground in the search for new marine compounds specially after the discovery of penicillin [33]. Around 70,000 fungal species and 1500 species of marine-derived fungi from coastal ecosystems have been described worldwide [34]. Gareth Jones (1998) [35] conclude that as 70% of the earth comprises water bodies, there would be at least 72,000 species of marine fungi, indicating that the discovery of new bioactives is still underway. In addition, filamentous marine fungi is getting more attention of the pharmaceutical community for production of a wide variety of compounds that are pharmacologically active and structurally unique [36]. In this chapter, we have organized the research findings in this field with our prime focus on antioxidant and antidiabetic properties of the endophytes. By bringing the possible perspectives and trends for further studies of the endophytes in the limelight, this review could help in carrying out future research in this field.

2 Research Methodology

Relevant information on pharmacology of endophytes and isolation of their phytoconstituents were compiled based on scientific literature available from online databases such as Scopus, PubMed, Google Scholar, Scirus, ScienceDirect, SciELO, Web of Science, MEDLINE, SpringerLink, BioMed Central (BMC), and SciFinder. Informations derived from these databases were obtained using the keyword “endophytes.” Furthermore, relevant scientific publications from different categories were also taken into consideration.

3 Antioxidative Potential of Endophytes

Oxidative stress is produced by an imbalance between the overproduction of reactive oxygen species and cellular antioxidant defenses resulting in the injury of macromolecules as proteins and lipids. Oxidative stress is mainly responsible for the pathogenesis of chronic diseases such as diabetes, cancer, and CVD [37] which leads to a global health problem causing disability and death of millions of people [38]. Numerous investigations indicate that a high consumption of vegetables and fruits rich in phenolic compounds significantly decrease the risk and/or incidence of cancer, diabetes, and CVD [39]. Diabetics have high concentrations of AGEs which have prooxidant effects and participate in the production of chronic complications in the diabetic patients [40]. Thus the treatment for increasing the effect of antioxidants and inhibiting the generation of AGES prevents complications in diabetes.

3.1 Endophytes from Medicinal Plants with Antioxidant Activities

3.1.1 Achyranthes aspera

Seventy-three isolates were obtained from the leaves of Achyranthes aspera as endophytic bacteria. Among them, AL2-14B showed higher DPPH radical scavenging activity with IC50 value of 6.41 ± 0.11 mg/mL compared to the control plant with IC50 value of 8.11 ± 0.24 mg/mL. In β-carotene-linoleic acid assay, AL2-14B inoculated plants showed a range of 15.77–78.85, and β-carotene-linoleic acid assay of extract obtained from inoculated plant was found to be slightly higher than the control plant. In A. aspera leaves inoculated with AL2-14B, the reducing antioxidant power assay showed higher value than that of the control plant. The values ranged in the inoculated plant from 0.452 to 1.122 [41].

3.1.2 Aegle marmelos

One hundred sixty-nine strains of endophytes were obtained from 5 trees of Aegle marmelos of which 67 were pigmented endophytic fungi. The isolates were classified into Deuteromycota , Basidiomycota, and Ascomycota. In DPPH assay, the endophytes FC39BY, FC8ABr, FC2AP, FC75ABr, and FC30AGr showed 50% inhibition at a concentration of 174 μg/μL, 62 μg/μL, 43 μg/μL, 200 μg/μL, and 161 μg/μL, respectively. Among the extracts, FC8ABr and FC2AP showed a significantly higher antioxidant activity. In addition, FC2AP was found to have a higher reductive power than other endophytes [42].

3.1.3 Caralluma acutangula, Moringa peregrina, and Rhazya stricta

Twenty-one fungal endophytes, viz., Cladosporium sp. (one strain), Bipolaris sp. (one strain), Alternaria sp. (two strains), and Phoma sp. (six strains), were identified from various organs of medicinal plants like Moringa peregrina, Rhazya stricta, and Caralluma acutangula based on 18S rDNA sequencing and phylogenetic analysis. Bipolaris sp. exhibited significantly higher radical scavenging activity in DPPH, ABTS, and NADH/PMS assays and exerted a greater anti-lipid peroxidation effect than the other isolates. Bipolaris sp. even displays higher phenolic and flavonoid content [43].

3.1.4 Centella asiatica Used in the Biosynthesis of AgNPs

An endophytic fungus isolated from the medicinal plant Centella asiatica was used in the biosynthesis of silver nanoparticles (AgNPs). These nanoparticles were characterized using UV-Vis and FTIR spectrum, TEM analysis, particle size analysis, and zeta potential. The endophytic fungus was identified as Aspergillus versicolor ENT7 based on 18S rRNA gene sequencing (NCBI). Antioxidant activity of the AgNPs was evaluated by DPPH radical scavenging assay. AgNPs at a concentration of 100 μg/mL produce a radical scavenging activity of 60.04% compared to ascorbic acid (68.52%) used as standard at the same concentration [44].

3.1.5 Costus spiralis

Costus spiralis is a Brazilian Amazon plant known for its medicinal properties. Thirteen strains of fungal endophytes were obtained from C. spiralis and identified as Phomopsis sp. (CEP1), Diaporthe phaseolorum (CEDp2), Diaporthe sp. (CED3), Diaporthe sp. (CED4), Phomopsis sp. (CEP4), not identified (CE6), Diaporthe sp. (CED7), Sordariomycetes sp. (CES8), not identified (CE9), Phomopsis sp. (CEP10), Diaporthe phaseolorum (CEDp11), Cochliobolus sp. (CEC12), and Sordariomycetes sp. (CES13). The antioxidant activities were measured using DPPH and FRAP assays. CEP1, CEDp11, CES13, CE6, and CEC12 showed highest antioxidant activities and were hence subjected to liquid-liquid fractionation with dichloromethane. The result suggested that coumarins were responsible for the antioxidant effect [45].

3.1.6 Emblica officinalis

Eleven endophytes were obtained from Emblica officinalis . These endophytes have been identified as homologues of Diaporthe sp., Xylaria sp., Epacris sp., and Phomopsis sp. Ethanolic extract of endophytic fungi showed significant activity in reducing power assay in the following order – Phomopsis sp. > Xylaria sp. > Diaporthe sp. > Epacris sp. – but they were less active than ascorbic acid used as standard. However, in DPPH assay, the scavenging activity was in the order Phomopsis sp. > Diaporthe sp. > Xylaria sp. > Epacris sp. where Phomopsis sp. showed the highest radical scavenging activity, Diaporthe sp. and Xylaria sp. showed moderate antioxidant effects, and Epacris sp. showed the lowest activity [46].

3.1.7 Eugenia jambolana

Ethyl acetate extracts of 21 different endophytic fungi associated with Eugenia jambolana Lam. contain terpenes and phenols as the main constituents responsible for producing antioxidant activity. The antioxidant activity of these extracts was evaluated using DPPH radical scavenging, reducing power and hydrogen peroxide scavenging assays. Among the isolated endophytes, the strains Aspergillus niger, Aspergillus peyronelii, Aspergillus sp., and Chaetomium sp. showed the highest antioxidant activity ranging from 50% to 80% compared to ascorbic acid used as a standard [47].

3.1.8 Fritillaria unibracteata

Fifty-nine strains of fungal endophytes were isolated from Fritillaria unibracteata var. wabuensis. The isolates were identified as 17 different taxa with abundant biodiversity. The most important taxa were Fusarium redolens (11 isolated) and Fusarium tricinctum (10 isolated), followed by Clonostachys rosea (8 isolated) as teleomorph, ochroleuca, and Bionectria and Plectosphaerella cucumerina (5 isolated). All the filtrates of fungal endophytes showed antioxidant effect in both FRAP and DPPH assays, and the values ranged from 84.60 ± 1.56 to 1104.44 ± 25.17 and from 6.88 ± 0.14% to 107.32 ± 8.91%, respectively. Findings indicated that 62.0% of 30 isolates showed a value of more than 550 μM in FRAP activity. However, in two isolates (6WBY2 and 6WBK3) of the Fusarium genus and an unidentified endophyte WBS026, FRAP activities were greater than 1000 μM. 39.2% of 20 isolates exerted more than 50% DPPH radical scavenging. WBS027 isolated from the genus Bionectria , 7WBY2 from Fusarium, and an unidentified isolate WBS013 showed DPPH radical scavenging inhibition close to 100% inhibition [48].

3.1.9 Guazuma tomentosa

An endophytic Phyllosticta sp. of the fungi mycelium was isolated from Guazuma tomentosa H.B and K (Sterculiaceae) endophytic, and its filtrate was extracted in ethanol. The antioxidant activity was measured from ethanolic extract of the fungus in vitro using scavenging ABTS and DPPH radicals. The ethanolic extract of Phyllosticta sp . showed significant antioxidant activity against both ABTS and DPPH radicals with the EC50 value of 580.02 ± 0.57 μg/mL and 2030.25 ± 0.81 μg/mL, respectively [49].

3.1.10 Gymnema sylvestre Used in the Biosynthesis of AgNPs

The endophytic fungi Pestalotiopsis microspora of phylum Ascomycetes was isolated from the leaves of Gymnema sylvestre and identified on the basis of the phenotypic characters. Biosynthesis of AgNPs was carried out with the fungal isolate of P. microspora, and then these nanoparticles were characterized using UV-Vis spectrum, FTIR spectrum, TEM analysis, XRD analysis, particle size analysis, and zeta potential analysis. Antioxidant activity of the biosynthesized AgNPs was measured by DPPH free radical scavenging assay using ascorbic acid as standard. Biosynthesis of AgNPs and fungal culture aqueous filtrate were found to be 76.95 ± 2.96 μg/mL and 182.89 ± 3.43 μg/mL, respectively. The biosynthesis AgNPs also showed a significantly high scavenging activity against H2O2 radicals at a concentration of 100 μg/mL (51.14% ± 1.78%), while the fungal filtrate showed scavenging activity of 31.28% ± 1.63% [50]. Further, P. microspora yields several bioactive compounds of biomedical and pharmaceutical importance [50, 51]. Bioactives like hydroxyl pestalopyrone, pestalopyrone, and ambuic acid are effective against human pathogens, and others like hydroxyl jesterone and jesterone are effective against plant pathogens [52].

3.1.11 Kandis gajah

The endophytic fungi Acremonium sp., Chrysonilia sitophila, and Penicillium sp. were isolated from Kandis gajah . The mycelia was extracted with ethyl acetate and was evaluated for radical scavenging activity using DPPH. The extract showed an IC50 value of 10.3 μg/mL compared to 9.8 μg/mL in case of ascorbic acid. The extract was isolated and identified as a sesquiterpene 3,5-dihydroxy-2,5-dimethyltrideca-2,9,11-triene-4,8-dione with antioxidant activity [53] (Fig. 1).
Fig. 1

Isolate with antioxidant activity from Kandis gajah

3.1.12 Passiflora incarnata L.

Three endophytes fungi are isolated from methanolic extract of Passiflora incarnata L. and identified as A. alternata (KT380662), C. capsici (KT373967), and C. taiwanense (PI-3 KX580307). A. alternata (KT380662) produce a high level of 5,7-dihydroxy-flavone (chrysin). The antioxidant activity was evaluated by the method of DPPH scavenging activity at different concentrations ranging from 20 to 100 μg/mL. Chrysin showed inhibition in the range of 9–27% compared to the standard BHT at 42–83% [54] (Fig. 2).
Fig. 2

Isolate with antioxidant activity from A. alternata

3.1.13 Polygonum cuspidatum

The roots of Polygonum cuspidatum have been used for centuries for medicinal purposes. Endophytic actinomycete fungi Streptomyces sp. A0916 was isolated from Polygonum cuspidatum. The antioxidant activities were significantly inhibited by both extracts when subjected to DPPH radical assay. The results were not significantly different among both extracts, P. cuspidatum (92.7% inhibition) and Streptomyces sp. A0916 (93.2% inhibition), whereas ascorbic acid used as positive control showed an inhibition of 93.8%. It was inferred that both P. cuspidatum and Streptomyces sp. A0916 extracts showed strong antioxidant activities [55]. The chemical composition of Streptomyces sp. A0916 extract was 3-methyl-1-butanol, 4-methyl-1-pentanol, 1-nonanal, 6-methyl-2-oxiranyl-hept-5-en-2-ol, 2,6,11,15-tetramethylhexadecane, 2,6-dimethylocta-2, 7-dien-6-ol, 2,4-di-tert-butylphenol, glacial acetic acid, linoleic acid, 4-methylvaleric acid, 4-hexenoic acid, dehydroacetic acid, heptanedioic acid, 2-methyl butyric acid, and 1-p-menthen-8-ol identified by GC/MS.

3.1.14 Rhodiola Plants

Three hundred forty-seven endophytic fungi were isolated from rhizomes of three Rhodiola plants classified into 180 representative morphotypes (71, 57, and 52 isolates from Rc, Ra, and Rs, respectively) based on the characteristics of their cultures. In addition, these were also identified based on their related taxa or rRNA-ITS sequences. Isolated Rac88 from host Rawas is affiliated to phylum Glomeromycota and is placed in the genus Entrophospora. However, Rct60 was closely associated to Mucor hiemalis (99%), and Rac18 was assigned to Umbelopsis sp. (78%) of order Mucorales in Zygomycota. Isolates Rac69, Rac81, and Rac85 within Basidiomycota were closely matched to the sequences of Ceratobasidium sp. Rsc51 and Rsc45 were associated to Rhizoctonia solani (100%) and Coprinellus xanthothrix (99%), respectively. Other endophytic fungi belonging to classes Leotiomycetes, Dothideomycetes, and Sordariomycetes and phylum Ascomycota were also isolated [56].

Endophytic fungi in the rhizomes of Rhodiola spp. are diverse and abundant with 180 representative isolates distributed in 57 genera belonging to 4 fungal phyla. Isolates such as Rsc57, Rct45, Rac76, Rct64, and Rct63 exhibit strong antioxidant activity. Numerous investigations indicate that flavonoid and phenolic compounds could be considered as the main antioxidants in plants [57]. Rhodiola spices contain rosavins, p-tyrosol, and salidrosides [58]. Nevertheless, no comparative study has been carried out on their endophytes. The fermentation broth of Rac12 was seen to produce salidroside and p-tyrosol when subjected to HPLC. Data indicate that endophytes may produce the same bioactive chemicals as those of their hosts (Fig. 3).
Fig. 3

Isolates with antioxidant effect from rhizomes of Rhodiola spp.

3.1.15 Salvia miltiorrhiza Bge.f. alba

Endophytic fungi from Salvia miltiorrhiza Bge.f. alba have been considered a promising source of antioxidants. Fourteen fungal endophytes were identified by molecular and morphological methods as Fusarium and Alternaría species. However, six fungi were identified using internal transcribed spacer (ITS) rRNA gene sequence analysis as non-sporulating fungi. The results of phytochemical analysis carried out using ethanolic extracts of endophytic fungi from S. miltiorrhiza showed the presence of alkaloids, phenols, saponins, tannins, terpenoids, flavonoids, and steroids like those in the extracts of the roots of host plants [59]. The antioxidant activities of the extracts of endophytic fungi F. proliferatum SaR-2 and A. alternata SaF-2 and plant root were measured based on their ability to scavenge the DPPH free radicals compared to the standards, BHT and ascorbic acid. Findings indicated that both endophytic fungi at a concentration of 0.1 mg/mL showed higher radical scavenging activities than that of the plant root projecting 90.14%, 83.25%, and 80.23% values, respectively. Data showed that F. proliferatum SaR-2 could be a promising source of antioxidant compounds [60].

3.1.16 Scapania verrucosa

Forty-nine endophytic fungi were isolated from ethyl acetate extract of Scapania verrucosa . Based on their molecular and morphological characteristics, the isolated endophytic fungi were found to belong to the family Xylariaceae and seven genera Creosphaeria, Nemania, Xylaria, Tolypocladium, Chaetomium, Penicillium, and Hypocrea. However, the majority of these isolated endophytic fungi belonged to Xylaria, Creosphaeria, and Chaetomium. Forty-nine strains were evaluated for their in vitro antioxidant activities by different methods such as DPPH radical scavenging, hydroxyl radical scavenging, and reducing power and ferrous ion chelating assays. Of the isolated endophytic fungi strains, T24 (Chaetomium globosum) and T38 (Creosphaeria sp.) exhibited the highest antioxidant capacity [61].

3.1.17 Sudanese Medicinal Plants

Twenty-one endophytic fungi were isolated from Sudanese medicinal plants Trigonella foenum-graecum , Vernonia amygdalina, Euphorbia prostrata, Catharanthus roseus, and Calotropis procera. The isolated endophyte strains were assigned to 12 different taxa. Of them, ten strains were identified to belong to Ascomycetes, seven strains were found to be fungal, and four strains of Deuteromycetes belong to Mycelia sterilia [62]. Chaetomium and Mycelia sterilia were the most important fungal taxa isolated. The Aspergillus sp. endophyte isolated from T. foenum-graecum and Curvularia sp. from V. amygdalina exerted significant antioxidant activities in DPPH radical scavenging assay [63].

3.1.18 Terminalia morobensis

Pestalotiopsis microspora was isolated as an endophyte from Terminalia morobensis which grows in Papua New Guinea. P. microspora was of interest because of its antioxidant properties, and it produced two isobenzofuranones which have been isolated previously with substitutions at positions 5 and 7 with –OCH3, –CH3, or –OH functional groups. Isopestacin, having the basic structural features of an isobenzofuranone, possesses a 3-benzo substituent. Both pestacin and isopestacin showed similarities to flavonoids suggesting that it might possess antioxidant activity [64]. This was confirmed with their ability of scavenging the hydroxyl free radical (OH.) (Fig. 4).
Fig. 4

Pestacin and isopestacin with antioxidant effect isolated from Pestalotiopsis microspora

3.1.19 Trachelospermum jasminoides

A total of 1626 endophytic strains were isolated from Trachelospermum jasminoides LINDL. Among them, endophytic fungus Cephalosporium sp. IFB-E001 which inhabits in the roots of T. jasminoides was extracted with CHCl3:MeOH (1:1) containing graphislactone A as the most bioactive secondary metabolite with high antioxidant and free radical scavenging activities greater than those of ascorbic acid and butylated hydroxytoluene (BHT) used as standards [65] (Fig. 5).
Fig. 5

Compound with antioxidant effect from Cephalosporium sp.

3.1.20 Taxus sumatrana

Taxus sumatrana (Miq.) de Laub, found in Indonesia, is a plant known for its medicinal properties. Fourteen endophytic fungi were isolated from the plant, and their methanolic and ethyl acetate extracts were prepared [66]. The extracts were evaluated in vitro for their antidiabetic and antioxidative effects using α-glucosidase, DPPH free radical scavenging activity, and β-carotene bleaching assays [67]. Isolated endophytic fungi Colletotrichum sp. (TSC13) showed higher α-glucosidase inhibitor activity suggesting a promising antidiabetic activity, whereas TSC 24 showed higher antioxidant activity [68].

3.1.21 Tinospora cordifolia

Tinospora cordifolia , an Indian plant known as amrita (guduchi) in Sanskrit belonging to the family Menispermaceae, is used as a traditional medicinal plant. An endophytic fungus Cladosporium velox TN-9S was isolated from T. cordifolia and extracted using ethyl acetate, and total phenolic content was evaluated by Folin-Ciocalteu assay, and the antioxidant activity was measured by DPPH and FRAP methods. High phenolic content was recorded from the fungal extract which was found equivalent to 730 μg/mL of gallic acid. Significantly reduced radical scavenging activity was observed in DPPH assay with an IC50 value of 22.5 μg/mL [69].

3.2 Endophytes from Marine Plants with Antioxidant Activity

3.2.1 Mangroves

The endophytic fungi isolates from the leaves of mangroves Rhizophora stylosa and R. mucronata collected from the South China Sea were identified using a combination of phylogenetic analysis and morphology study of the internal transcribed spacer (ITS) sequences. Among them, 17 genera belonging to 8 taxonomic orders of Ascomycota were identified of which orders Xylariales (35.49%) and Diaporthales (27.61%) were the most common. Orders like Pleosporales, Hypocreales, Glomerellales, Eurotiales, Capnodiales, and Botryosphaeriales were also characterized. The radical scavenging ability was evaluated using DPPH and ABTS assays. Of the 46 mangrove isolates, fungal endophytes HHL38 and HHL55 showed the most potent antioxidant effect. Of the isolates, HQD-6 showed significant levels of flufuran in ABTS and DPPH radical scavenging assays [70].

In other studies, a marine-derived endophytic fungi Phomopsis sp. A123 was isolated from the leaves of mangrove Kandelia candel (L) which contains a novel depsidone and phomopsidone A together with excelsione and four known isobenzofuranones, 7-methoxy-6-methyl-3-oxo-1,3-dihydroisobenzofuran-4-carboxylic acid, diaporthelactone, 7-hydroxy-4,6-dimethyl-3H-isobenzofuran-1-one, and 7-methoxy-4,6-dimethyl-3H-isobenzofuran-1-one [71]. These compounds showed weak antioxidant effect against DPPH radicals (Fig. 6).
Fig. 6

Structure of antioxidants from Phomopsis sp. A123

3.2.2 Resveratrol Derivatives Isolated from the Endophytic Fungus Alternaria from Mangrove

Three new stilbene derivatives, resveratrodehydes A, B, and C, were isolated from the mangrove endophytic fungus Alternaria which showed lower radical scavenging activity in DPPH assay with IC50 values of 447.62–572.68 μM compared to resveratrol (IC50 value of 70.22 ± 0.35 μM) [72]. However, resveratrodehyde B showed only few activities. Findings indicated that electron-withdrawing substituents such as COOH and COOR in ortho- or para-positions stabilize the phenol form of antioxidants and destabilize the phenoxy radical form to increase the O–H bond strength and decrease the antioxidant effect [73, 74, 75] (Fig. 7).
Fig. 7

Resveratrol derivatives with antioxidant activities

3.2.3 Anthraquinone Derivatives from Endophytic Fungus Eurotium rubrum Associated with Mangrove Hibiscus tiliaceus

Seven compounds were isolated and identified from Eurotium rubrum , an endophytic fungus associated with mangrove Hibiscus tiliaceus . One new bisdihydroanthracenone derivative eurorubrin (1), 2-O-methyl-9-dehydroxyeurotinone (2), 4,2-Omethyl-4-O-(α-D-ribofuranosyl)-9-dehydroxyeurotinone (3), one new anthraquinone glycoside [6,3-O-(α-d-ribofuranosyl]questin] (4), and three known compounds, asperflavin (5), 2-O-methyleurotinone (6), and questin (7) were isolated. All of these compounds were evaluated using DPPH radical scavenging assay. Results suggested that compounds 1 and 6 showed strong activities which were stronger than that of the antioxidant butylated hydroxytoluene. Nevertheless, the other compounds showed moderate or weak activities [76] (Fig. 8).
Fig. 8

Anthraquinone derivatives with antioxidant activities

4 Endophytes with Antidiabetic Activity

4.1 Endophytes from Medicinal Plants with Antidiabetic Activity

4.1.1 Acacia nilotica

Thirty-six endophytic fungi were isolated and identified from methanolic extract of Acacia nilotica . An endophyte Aspergillus awamori produces the peptide lectin (N-acetylgalactosamine, 64 kDa) containing amino acids valine, tyrosine, threonine, and serine. The peptide showed inhibitory alpha-glucosidase activity (80%) and alpha-amylase activity (81%) with IC50 values of 5.625 and 3.75 μl/mL, respectively. The peptide is highly stable at optimum pH and temperature [77].

4.1.2 Adhatoda beddomei

An endophyte Syncephalastrum sp. was isolated from the plant Adhatoda beddomei . The mycelial endophyte was extracted with ethyl acetate, and the crude extract demonstrated an inhibitory activity of 75.2% on α-amylase with IC50 value 0.25 μg/mL compared to the IC50 value 0.75 μg/mL in case of acarbose. α-Amylase inhibitor blocks digestion and absorption of carbohydrate [78].

4.1.3 Ficus religiosa

The leaves of Ficus religiosa carry the endophytic fungus Dendryphion nanum . From the EtOAc extract of Dendryphion nanum naphthoquinones, herbarin and herbaridine were obtained. Herbarin induced glucose uptake in rat skeletal muscles in the presence of insulin when rosiglitazone, a known glucose uptake activator, was used as standard in the assay. However, herbaridine did not show any such activity [79] (Fig. 9).
Fig. 9

Isolates with antidiabetic activity from Dendryphion nanum

4.1.4 Paeonia delavayi

A chemical study conducted on fermentation product of Phomopsis sp. YE3250 derived from Paeonia delavayi led to isolation of seven new polyoxygenated cyclohexenoids named as phomopoxides A−G. All compounds showed significant α-glycosidase inhibition using acarbose as a positive control. In relation to the structural activity, the compounds D–G forming an epoxy moiety produce a weak α-glycosidase inhibition than those of A−C, indicating that tetrahydroxyl substitution in cyclohexene ring is crucial for α-glycosidase inhibition [80] (Fig. 10).
Fig. 10

Chemical structures of compounds phomopoxides A–G

4.1.5 Piper auritum

Pseudomonas protegens strain 8-1 was isolated from the leaves of Piper auritum . The ethyl acetate extract from the culture showed glycation inhibitory activity in vitro, and the isolated active compound was identified as the polyketide metabolite 2,4-diacetylphloroglucinol (DAPG). This compound inhibited protein glycation much more than aminoguanidine used as standard in BSA-glucose model. DAPG also inhibited AGE formation as assessed by the three other assay models, BSA-MGO, fructosamine, and benzoate hydroxylation [81] (Fig. 11).
Fig. 11

2,4-Diacetylphloroglucinol inhibited protein glycation

4.1.6 Salvadora oleoides Decne.

Seventeen endophytic fungi were isolated from Salvadora oleoides Decne (Salvadoraceae) which were classified as Aspergillus sp. and Phoma sp. The fungi mycelium were extracted with methanol (Aspergillus sp. JPY2 and Aspergillus sp. JPY1) and acetone (Phoma sp.). The antidiabetic activity of the extracts were evaluated using the model alloxan-induced diabetic rat. The extracts significantly reduced blood glucose levels in a range of 11.3%–28.04%, whereas the tolbutamide used as the standard drug reduced the blood glucose level up to 40%. The methanolic extract of Aspergillus sp . JPY1 produces 2,6-di-tert-butyl-p-cresol and phenol, 2,6-bis[1,1-dimethylethyl]-4-methyl as the main constituents [82] (Fig. 12).
Fig. 12

Isolate with antidiabetic activity from Aspergillus sp. JPY1

4.1.7 Tabebuia argentea

Ten endophytes fungi were obtained from the Tabebuia argentea and identified as A. niger, A. flavus, Penicillium sp., Rhizopus sp., Fusarium sp., Alternaria sp., and Trichoderma sp. which were used to obtain the methanolic extract and analyze phytochemical constituents by gas chromatography mass spectrometry (GC-MS). The methanolic extract was evaluated for its in vitro effect on α-glucosidase and α-amylase activity. Eighteen secondary metabolites were obtained by GC-MS, and their antidiabetic activities were evaluated against 21 different diabetic proteins/enzymes by in silico assay. Data indicated that octadecanoic acid methyl ester and 3 phthalates interacted more with all the 21 diabetic proteins/enzymes tested [83]. In addition, antioxidant activity was evaluated by various methods involving scavenging of free radical DPPH, FRAP, and TBA and superoxide radical FTC and iron. Results indicated that the methanolic extracts of Aspergillus niger, Penicillium sp., and Trichoderma sp. were found to be the most effective in showing in vitro antioxidant activity [84].

4.1.8 Viola odorata

Twenty-seven endophytes were isolated from Viola odorata Linn and were classified on the basis of microscopic and morphocultural characteristics. Anti-obesity potential of endophytic fungi associated with Viola odorata was evaluated using porcine pancreatic lipase (type II) employing 4-nitrophenyl butyrate as substrate. Aspergillus sp. (VOLF4) showed the most potent PL inhibitory effect followed by Peniophora sp. (VOLF5) and Fusarium nematophilum (VOR5). Previous data indicated that Aspergillus spp., Penicillium, and Colletotrichum showed good pancreatic lipase inhibitory activity [85].

4.1.9 Viscum album

A strain of the endophytic fungi Alternaria was isolated from Viscum album . The soluble proteins in crude extract were fractionated with ammonium sulfate to produce the peptide N-acetylgalactosamine, a 64 kDa protein lectin. The antidiabetic activity of peptide was evaluated in vitro by α-glucosidase, α-amylase, and sucrase assays and in vivo in alloxan-induced diabetes in rats. The N-acetylgalactosamine inhibited the enzymes α-amylase (85.26 ± 1.25), α-glucosidase (93.41 ± 1.27), and sucrase (81.61 ± 1.05). Also, diabetic rats showed significantly increased body weight (8.50%) compared to the standard drug (9.01%) after 14 days of treatment with the N-acetylgalactosamine. In addition, regeneration of pancreatic tissues and reducing the levels of urea (43.7 ± 5.8), creatinine (0.32 ± 0.01), serum cholesterol (103.54 ± 2.13), and triglycerides (124.68 ± 2.49) [86] were observed in the study.

4.2 Endophytes from Marine Plants with Antidiabetic Activity

4.2.1 Mangrove Endophytic Fungus Xylaria sp.

Endophytic fungus Xylaria sp. BL321 was isolated from the mangrove from which the four eremophilane sesquiterpenes were derived (1–4) and were then evaluated for their inhibitory effects on α-glucosidase employing an enzyme-based bioassay. Compound 4 showed the most potent α-glucosidase inhibitory effect. However Compound 1 had a minimum effect on α-glucosidase [87] (Fig. 13).
Fig. 13

Compounds with α-glucosidase inhibitory effect

4.2.2 Endophyte Trichoderma sp. 307 from Mangrove

A study of the simultaneous cultivation of aquatic pathogenic bacterium, Acinetobacter johnsonii B2 and endophyte Trichoderma sp. 307, from mangrove leads to the isolation of 2 new sesquiterpenes, microsphaeropsisin B (1), microsphaeropsisin C (2), 2 new de-O-methyllasiodiplodins, microsphaeropsisin (3), (3R, 7R)-7-hydroxy-de-O-methyllasiodiplodin (4), (3R)-5-oxo-de-O-methyllasiodiplodin (5), and 12 known compounds (3R)-7-oxo-de-O-methyllasiodiplodin (6), microsphaeropsisin (3), (3R)-5-oxolasiodiplodin (7), (3S)-6-oxo-de-O-methyllasiodiplodin (8), (3R)-de-O-methyllasiodiplodin (9), (3R,4R)-4-hydroxy-de-O-methyllasiodiplodin (10), (3R,5R)-5-hydroxy-de-O-methyllasiodiplodin (11), (3R,6R)-6-hydroxy-de-O-methyllasiodiplodin (12), (3R)-lasiodiplodin (13), (3S)-ozoroalide (14), (3S,5R)-5-hydroxylasiodiplodin (15), (E)-9-etheno-lasiodiplodin (16), and (3R)-nordinone (17).

The α-glucosidase inhibitory activities of all compounds isolated were evaluated. Findings indicated that compounds 4, 5, 8, 9, 10, 16, and 17 showed potent α-glucosidase inhibitory effect which was higher than that produced by the acarbose used as a positive control, whereas compounds 2, 6, 7, and 14 showed moderate inhibitory activity. The other compounds 1, 3, 11, 12, 13, and 15 were inactive. In relation to the structure activity, it was observed that the methoxy group at C-15 in the lasiodiplodin derivatives decreased the activity and the position of the hydroxyl and carbonyl groups also significantly altered the effect. However, the presence of C-9 to C-10 double bond was essential for the α-glucosidase inhibitory activity [88] (Fig. 14).
Fig. 14

Compounds with α-glucosidase inhibitory activities

4.2.3 Endophytic Fungus Nectria sp. HN001 from Mangrove Plant Sonneratia ovata

Four new polyketides nectriacids A–C (1–3) and 12-epicitreoisocoumarinol (4) and three known compounds, citreoisocoumarinol (5), citreoisocoumarin (6), and macrocarpon C (7), were isolated from the endophytic fungus Nectria sp. HN001 associated with the mangrove Sonneratia ovata collected from the South China Sea. Compounds 2 and 3 exhibited stronger in vitro α-glucosidase inhibitory activity than acarbose used as positive control. Nevertheless, compounds 4, 5, and 6 showed moderate activity, while compound 7 showed no inhibitory activity compared to acarbose [89] (Fig. 15).
Fig. 15

Chemical constituents of Nectria sp. HN001

5 Conclusions

An extensive literature review revealed that very limited reports have focused on isolation of endophytes or extraction of their bioactives. Only few of the isolated compounds have been investigated so far. There is a need in the future to carry out research on endophytes through bioassay-guided isolation, chemical characterization, structure-activity relationship study, and mechanisms of action. Currently, all the studies found on antioxidant and antidiabetic activities from endophytes have been carried out in vitro, but using animal models for investigating their biological effects has not yet been carried out. This chapter might help the pharmacologists and chemists to investigate the pharmacological and phytochemical properties of endophytes.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Rosa Martha Perez Gutierrez
    • 1
    Email author
  • Adriana Neira González
    • 2
  1. 1.Laboratorio de Investigación de Productos Naturales, Escuela Superior de Ingenieria Quimica e Industrias ExtractivasInstituto Politecnico Nacional (IPN) Unidad Profesional Adolfo Lopez Mateos S/N Av, Instituto Politécnico Nacional Ciudad de MexicoMexico CityMexico
  2. 2.Laboratorio de Productos NaturalesInstituto de Química, Universidad Nacional Autónoma de México, Ciudad UniversitariaMexico CityMexico

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