Pharmacological Maneuver of Mangrove Endophytic Fungi in the South China Sea – A review

ABSTRACT Conventional products have a role in addressing the thriving universal demands for biologically active substances. Since the South China Sea is a prodigious province of geostrategic and mercantile importance, it meets the basic needs of people who dwell there. The South China Sea is dominant in mangrove biodiversity which, represents 11.4% of the world’s 15.5 million hectares of mangrove forest. Mangroves are harbored by multifaceted fungal communities that represent the second colossal ecological breed of marine fungi. The symbiotic association between the plants and fungi stimulates the bioactive components such as alkaloid, depsipeptides, cyclic peptides, quinone, terpenes, lactones, terpenoid, flavonoid, phenolic acid, steroids. These components have multifaceted pharmacological activities likely, anti-inflammatory, antidiabetic, anticancer, antioxidant, and antimicrobial. This review article attempts to present a piece of insightful information currently being explored on the biologically active components generated by mangrove endophytic fungi of the South China Sea.


INTRODUCTION
People experience multifaceted maladies that devastate their health. Several synthetic and natural therapy are available to curb and treat these diseases. Utmost people globally entrusted natural medicine than synthetic due to its minimal side effects and cost-effectiveness. Hitherto, plants and microbes are appraised to be a root source of natural medicine. Ethnopharmacological proficiency provides the unrivaled groundwork for the future endeavor of medicinal expedients in traditionally used plants. With the aid of advanced technologies, researchers can identify, isolate and extract an enormous number of new components from natural resources. From 1981 to date, merely 50% of anti-microbial drugs are in the practice of the pharmacy market. Roughly 75% of it is from natural or derivates of natural products (Salini 2015). However, increased demand for commercially successful natural products causes an overwhelm of plant material to produce an adequate quantity of drugs, which has engendered threat concerns like species extinction, biodiversity loss, and environmental depletion. These jeopardized situations kindle the researcher to scrutinize and isolate Taxol (cancer drug) producing endo-

MANGROVE ENDOPHYTIC FUNGI
The microscopic community of microorganism is hidden and reside within the plant known as endophytes. Endophytes (actinomycetes, bacteria, fungi) spend their life cycle entirely or partially in the tissues of the plants that cause no menace to the plant. Plants harbor a varied cluster of endophytes ubiquitously distributed in roughly 300,000 plant species (Sridhar 2019). The endophyte symbiotically associated with the plants are knowns as symbionts. Moreover, the endophytic colonies are beneficial to our surroundings. For instance, endophytes aid the plants to flourish by generating growth hormones, nutrient cycling, biodegrading. It also takes part in phytoremediation that reduces detritus load in our landscape (Das et al. 2018).
Mangroves are harbored by versatile fungal communities, which account for the second colossal ecological breed of marine fungi. Mangrove endophytic fungi are robustly resistant to oceanic environments, temperature for example, Alternaria, Aspergillus, Cladosporium, Clolletotrichum, Fusarium, Paecilamyces, Penicillium, Pestalotiopsis, Phomopsis, Phyllosticta, and Trichoderma (Bibi et al. 2020). Repeated flooding and drastic climatic fluctuation make the mangrove plant resilient both physiologically and morphologically. This acclimatization engenders the plant to generate a broad spectrum of biologically active secondary metabolites. Endophytes were grown in such an ecosystem with a unique nature that produces remarkable secondary metabolites such as flavonoids, quinones, alkaloids, terpenoids, tetralones, benzopyranones, xanthones among others. The plant-endophyte association generates bioactive components with promising pharmacological effects such as antioxidant, anticancer, and antimicrobial properties (Das et al. 2018).

BIOACTIVE METABOLITES OF MANGROVE ENDOPHYTES
Unrivaled research of plants and microbes generates a trove of novel natural products that act as happening and growing demand to curb diverse aliments. Multifarious biologically active metabolites have been extracted and identified from fungi habitats around countries bordering the South China Sea. Thatoi et al. (2020) stated that enzymes extracted from the mangrove endophytes have an ecological role in the decomposition and a bioactive role towards the medical environment. Secondary metabolites obtained from these endophytes have an efficient role in mitigating various ailments which have bioactive potential in both the medical and pharmaceutical fields. Camptothecin, Irinotecan, Podophyllotoxin, Taxol, Vinblastine, Vincristine are the commercially available metabolites among them (Bibi et al. 2020).
With the evolution of the latest modern technologies, such as chromatographic and spectroscopic techniques, CD spectra analysis, in-vitro bioassay methods, and nuclear magnetic resonance (NMR), researchers can skillfully perform mangrove fungal isolation, cultivation, and extraction of captivating beneficial bioactive metabolites (Perera et al. 2019). Endophytes produce versatile secondary metabolites such as isocoumarins, xanthones, lactones, and ergosterl with antimicrobial properties that preclude the plants from pathogens (Sridhar 2019). Several comprehensive types of research have been carried out in the last decades, related to the characterization and isolation of metabolites from the mangrove endophytic fungi.  recognized polyketides from Penicillium sp. ZJ-SY2 endophytic fungus of mangrove which shows an immunosuppressive activity. Li et al. (2019) extracted polyketide alkaloid derivatives namely phomopsols A and B from the Phomopsis sp. xy21 endophytic fungus of mangrove.  obtained polyketide (1) from the endophyte Ascomycota sp. SK2YWS-L conducts an anti-inflammatory activity. One new natural amide alkaloid and two new benzophenones are identified by Zheng et al. (2019) from Penicillium citrinum mangrove fungus that has an antibacterial property against Staphylococcus aureus and shows strong cytotoxic action against A549 human cell lines.  obtained ascomylactams A-C metabolites from the endophyte Didymella sp. CYSK-4 of mangrove that performs average cytotoxicity towards HCT116, MDA-MB-435, PC-3, NCI-H460, MDA-MB-231, and SNB19. From these discussions, we can drive that those endophytic fungi extracted from the mangrove species are the prime origin of bioactive metabolites and requires further studies for other feasibilities.

BIOLOGICAL ACTIVITIES OF MANGROVE ENDOPHYTES
An endophytes-plants symbiotic relationship activates the inheriting properties of the bioactive compounds of the host. They are the warehouse of novel bioactive secondary metabolites that possess various biological applications in the pharmaceutical field, likely anticancer, anti-inflammatory antidiabetic, and antioxidant. Table 1 represent the metabolites generated from the mangrove endophytic fungi of the SCS and their bioactive significance. Figure 1 depict the pharmacological benefits of secondary metabolites of mangrove endophytes.

Rhizosphere of Kandelia candel and Excoecaria agallocha
Non-ribosomal peptide synthetase, type-I polyketide synthase, and type-II polyketide synthase are the enzymes that show cytotoxic activities against CNE-2 and Hela.

Antimicrobial
Pathogenic microbes such as fungi, bacteria, and viruses can cause contiguous diseases that disseminate through different modes of transmission. It can be cured either by the administration of synthetic or herbal antimicrobial drugs. Synthetic drugs are well known for curing several communicable ailments but have high side effects on human health. Chronic uses of antibiotic drugs cause the influence of new multi-drug resistant microbes ongoing threats to the world. This threat urges an investigation of alternative sources of naturally available antimicrobial drugs. The discoveries of drugs from diverse natural sources (plants, animals, and non-pathogenic microbes) may have fewer side effects and more effective antimicrobial properties. Based on the proof of scientific research, mangrove endophytes render potential and notable robust sources of antimicrobial activities. Phytochemical compounds of mangrove endophytes can act as antimicrobial agents to cure communicable diseases (Kuzhalvaymani et al. 2020). Penicillium citrinum HL-5126 spotted from Bruguiera sexangula var. rhynchopetala produce benzopyran derivative compound (6) (MIC = 6.94 μg/mL) exhibit the most efficient inhibition of Micrococcus tetragenus, Bacillus subtilis, and Bacillus cereus (Zheng et al. 2016), Penicillium sp. GD6 spotted from Bruguiera gymnorrhiza has the metabolites 2deoxy-sohirnone C (1) with MIC = 80 μg/ml that has an average resistance of Methicillin-resistant Staphylococcus aureus (MRSA) (Jiang et al. 2018). Penicillium aculeatum (No. 9EB) endophytes present in Kandelia candel has chromone metabolites derivative such as bacillisporin A (2) (MIC = 0.13 ± 0.02 μM), bacillisporin B (3) (MIC = 0.13 ± 0.02 μM) with significant antibacterial inhibition of Bacillus subtilis, whereas metabolite (1) known as (2ʹS*)-2-(2ʹhydroxypropyl)-5-methyl-7, 8-dihydroxy-chromone, exhibit antibacterial activity oppose to Salmonella with a MIC = 2.00 ± 0.02 μM .

Antidiabetic
Diabetes is a chronic hyperglycemia disease that results from a disorder in insulin action and insulin secretion. It has common symptoms such as increased thirst, increased urinary discharge, ketonemia, and ketonuria. Diabetes is one of the globally occurring diseases, predicted to affect approximately a 693 million adults by 2045. Microvascular and macrovascular are the complications are provoked by diabetes. It causes several defects in the kidneys, nerves, eye, and cardiovascular, which elevates the mortality rate and ruin the quality of life of diabetic patients. Alpha-glucosidase inhibitors treat type2 diabetic patients. The inhibitors slow down carbohydrates' absorption in the small intestine and mitigate the postprandial level of insulin and blood glucose (Van De Laar et al. 2005

Antioxidant
Any disproportion between the production of reactive oxygen species (ROS) and antioxidants induces oxidative stress, which damages the tissue. Free radicals are highly reactive and unstable molecules generated in the body either by the normal metabolic process of cells as a by-product of oxidation or by exposure to carcinogens in our environment (smoke, air pollution, some viruses, chemical exposure, ultraviolet radiation, and medical radiation). Cells get damaged by antioxidant deficiency that engenders more accumulation of free radicals, leading to various kinds of ailments such as cancer, asthma, diabetes, atherosclerosis, and many others. An antioxidant is a compound available in diverse forms (natural or artificial) that inhibits or delays the accumulation of free radicals (Pizzino et al. 2017). Phenolic compounds present in the endophytes were the primary sponsor of the antioxidant properties. Cladosporium sp. OUCMDZ-302 endophytes are spotted from Excoecaria agallocha has an antioxidant activity of secondary metabolite polyketide compounds (4) (IC 50 = 2.65 μM), (8) (IC 50 = 0.24 μM), (9) (IC 50 = 5.66 μM) and (10) (IC 50 = 6.67 μM) showed promising DPPH antioxidant scavenging . Ascomycota sp. SK2YWS-L obtained from Kandelia candel produces an antioxidant metabolite ascomindones A (1) (IC 50 = 18.1 μM) possesses efficient scavenging activities that inhibit DPPH (Tan et al. 2016).

Anti-Acetylcholinesterase
Acetylcholinesterase (AChE) is the prime enzyme of the cholinergic nervous system. Predominant in the neuromuscular junctions and cholinergic synapses. AChE ceases neurotransmission at cholinergic synapses by rapid hydrolysis of acetylcholine to choline and acetate this enzyme activity is inhibited by Acetylcholinesterase inhibitors (AChEIs), which in turn augment the accumulation of acetylcholine in neuromuscular junctions, central nervous system, and autonomic ganglia, where acetylcholine receptors are surplus (Cheung et al. 2012). Hence, AChEIs treat dementia with Lewy body, Parkinson's, and Alzheimer's diseases. Plants are considered a most efficient and enormous source for AChEIs enzyme but, microbes' production of these enzymes indicates an eco-friendly, cost-effective, efficient, and alternative approach easily manipulated (Zhang et al. 2019). Kandelia candel is a mangrove plant that stores a plethora of endophytes one of them is Penicillium sp. SK5GW1L which has α-pyrone meroterpenoids compounds (3) (IC 50 = 3.03 μM), (4) (IC 50 = 0.23 μM) and (5) (IC 50 = 0.028 μM) shows sturdy inhibition of acetylcholinesterase (AchE) (Ding et al. 2016). , reported that compounds 1,2-dehydro-terredehydroaustin (1) (IC 50 = 42.3 ± 0.20 nM) resist the AChE enzyme produced by Aspergillus terreus H010 endophytes of Kandelia obovata mangrove plants.

CONCLUSION
This review accentuates that mangrove endophytic fungi of SCS has more capacity to generate an impressive range of metabolites. The plant-endophyte symbiotic concomitant activates the production of bioactive components likely alkaloid, depsipeptides, terpenes, lactones, allenolic, cyclic peptides, quinone, chinone or terpenoid, flavonoid, phenolic acid, steroid, with propitious biopharmaceutical potential including anticancer, antimicrobial, antioxidant, anti-inflammatory and antidiabetic. Out of 84 mangrove species recorded currently, only 27 of them have been pharmacologically corroborated in terms of endophytic fungi. Still, there is a meager of knowledge that insists more investigation is needed to explore the relationship and mechanism of