Keywords

1 Introduction

Inflammation is a complex biological reaction by which the human body responds to tissue damage and to various harmful stimuli, including toxic compounds, damaged cells, and infectious agents and pathogens. In addition, inflammation plays a vital role in tissue repair and regeneration toward homeostasis (Tsoupras et al. 2018). Generally, acute and controlled inflammation is beneficial, while unresolved and chronic inflammatory response can occur due to the continuous and unresolved presence of the triggering agent(s) and risk factors, and due to a subsequent inappropriate immune response, that usually results in further tissue injury, destruction, and several other harmful inflammatory manifestations (Tsoupras et al. 2018).

Thus, it has now been well established that unresolved and chronic inflammation and its thrombo-inflammatory manifestations are major causes of several chronic disorders (Tsoupras et al. 2018; Furman et al. 2019), such as atherosclerosis and cardiovascular diseases (CVD) (Tsoupras et al. 2018, 2019; Furman et al. 2019), renal (Tsoupras et al. 2007, 2018), and neurodegenerative disorders (Tsoupras et al. 2018), tumor and metastatic procedures (Tsoupras et al. 2018; Tsoupras et al. 2009; Lordan et al. 2019), asthma, allergy and several autoimmune diseases (Tsoupras et al. 2018), and persistent infections, including HIV infection (Tsoupras et al. 2012a), SARS-COV-19 infection (Tsoupras et al. 2020a; Zabetakis et al. 2020), periodontitis (Tsoupras et al. 2006; Antonopoulou et al. 2003), sepsis (Tsoupras et al. 2011a), and their associated inflammatory conditions and comorbidities (Tsoupras et al. 2018). Interestingly, the presence of one or more of such pathological conditions further triggers and propagates the co-development of other ones through further inflammatory activation and a subsequent vicious cycle of inflammatory, thrombotic, and oxidative manifestations (Fig. 14.1) (Tsoupras et al. 2018, 2019, 2007, 2009, 2012a, 2020a, 2006, 2011a; Furman et al. 2019; Lordan et al. 2019; Zabetakis et al. 2020; Antonopoulou et al. 2003).

Fig. 14.1
A schematic explains how inflammation can lead to a variety of health problems, including anxiety, asthma, and autoimmune disorders. It exhibits a cycle of inflammation, starting with its induction and reduction of anti-inflammatory processes, leading to unbalanced and thrombotic inflammatory responses.

Unbalanced inflammatory and thrombotic responses due to the presence/co-presence of several risk factors can lead to continuous and unresolved inflammation with subsequent thrombo-inflammatory manifestations that are implicated in the initiation, propagation, and development of several inflammation-related chronic disorders. Such thrombo-inflammatory processes are also implicated in the induction of a chronic disorder(s) due to the unresolved presence of another one of these disorders. Natural bioactives, and especially those from microorganisms of biotechnological and agro-food-medical interest, including fungi bioactives with anti-inflammatory and antithrombotic properties are potential candidates for drug development against inflammation, thrombosis, and the prevention of inflammation-related chronic disorders

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Several compounds of natural and/or synthetic origin with anti-inflammatory actions have been extensively studied for potential benefits and amelioration of the inflammatory burden in these disorders, with natural bioactives being on the hotspot lately, especially for the food/feed supplements and drug industries (Tsoupras et al. 2018, 2007, 2009, 2020a, b, 2022a, b, c, 2011b; Lordan et al. 2019; Zabetakis et al. 2020, 2022; Conde et al. 2021; Glenn-Davi et al. 2022; Verouti et al. 2013; Karantonis et al. 2022). Natural products have been relevant sources for drug discovery and the development of medicines since ancient times. Several such bioactive compounds of natural origin have been found in plants, animals, or marine organisms, and microorganisms of different environments (aquatic, terrestrial, or air), with emphasis being given to natural bioactives derived from sustainable sources on a circular economy approach.

Among these natural sources, the cultivation of microorganisms as sustainable sources for isolating their bioactive metabolites has gained ground in the drug and supplements industries. Attention has been given to microorganisms with low toxicity and well-established tolerance in human nutrition and other non-toxic applications, not only well-established ones used in fermentation processes, including yeasts for the production of fermented foods (Moran et al. 2021; Fragopoulou et al. 2004) and bacteria for bioethanol production (Tsoupras et al. 2012b), but also microorganisms used in other fields, such as fungi of bio-agro/food technological applications like those used as natural entomopathogenic agents for organic cultures (Tsoupras et al. 2022b).

Fungi are a group of heterotrophic and essentially aerobic, with limited anaerobic capabilities, and eukaryotic microorganisms (McGinnis and Tyring 1996). Fungi can occur as yeasts, molds, or as a combination of both forms. Yeasts are microscopic fungi consisting of solitary cells that reproduce by budding. Molds, in contrast, occur in long filaments known as hyphae, which grow by apical extension. Hyphae can be sparsely septate to regularly septate and possess a variable number of nuclei. Regardless of their shape or size, fungi are all heterotrophic and digest their food externally by releasing hydrolytic enzymes into their immediate surroundings (absorptive nutrition). Other characteristics of fungi are the ability to synthesize lysine by the L-α-adipic acid biosynthetic pathway and possession of a chitinous cell wall, plasma membranes containing the sterol ergosterol, 80S rRNA, and microtubules composed of tubulin.

Apart from these general properties of fungi, lately they have been proposed as a promising sustainable source of an enormous number of natural bioactives, which have made significant contribution to almost each sphere of human, plant, and veterinary life. Natural compounds obtained from fungi have proved their value in nutrition, agriculture, and healthcare. Primary metabolites, such as amino acids, enzymes, vitamins, organic acids, and alcohol, are used as nutritional supplements and in the production of industrial commodities through biotransformation (Singh et al. 2017). In addition, highly bioactive fungi compounds have also been found to be some secondary metabolites (SMs) of fungi, meaning organic biomolecules with a low molecular weight that form at the end or near the stationary phase of growth, and are not directly associated with growth, development, and reproduction of fungi. SMs are not only essential for the growth and development of their microbial producer, but they can also increase the tolerance of microorganisms to different types of environmental stresses and hostile conditions and, consequently, their survival rate. On this accord, and since the unanticipated discovery of antibiotic penicillin by Fleming in 1929, this has drawn the interest of scientists to investigate the therapeutic role of microbial products not only for combating life-threatening infections as antimicrobial and antiparasitic agents, but also for several other healthcare applications, such as their use as antitumor, anti-inflammatory, anticoagulant and antithrombotic agents, enzyme inhibitors, anabolics, hemolytics, hypocholesterolemics and vasodilators, anesthetics, anthelmintics, and immunosuppressants (Singh et al. 2017).

Bioactive SMs are produced mainly by fungi of soil microbiota, marine environments, or extreme environments, but also of underexplored niches, including plant-associated fungi called endophytes, which live in symbiotic relationships with host plants (Conrado et al. 2022). They usually are obtained by extraction and other separation procedures, and they are primarily used in the biopharmaceutical industry and as ingredients in functional foods due to their capability to reduce inflammatory and infectious diseases in human beings and animals and thus increase life expectancy (Singh et al. 2017; Conrado et al. 2022).

Health care is the largest end-user market for microbes like fungi and such beneficial microbial products, which reflects the importance of microbe-based biopharmaceutical industry (Singh et al. 2017). To date, among the approved SMs by the US Food and Drug Administration (FDA) for drug discovery, ~ 15% belongs to microbial origin. In microbial groups of fungi and their products, for example, enzymes, fermented foods, animal feed, antibiotics, pharmacy products, and pigments have contributed significantly to humans and many biotechnological industries, as well as for several other applications such as the use of SMs from a basidiomycetous fungus, for example, Ganoderma lucidum and Trametes versicolor, as flavoring compounds, in flavored coffee, and in cosmeceutical products (Shankar and Sharma 2022). In addition, recent research has demonstrated that among fungi species, the endophytes are a great source of bioactive SMs. These microorganisms have functional diversity and, in association with plants, can produce a plethora of SMs (Conrado et al. 2022).

Fungi-derived nutrients and bioactive compounds have great potential as ingredients of functional foods, supplements, and drugs, since they can exhibit various beneficial effects along with medicinal properties and additional health benefits, including anti-inflammatory effects. From the several applications of fungi metabolites within this chapter, the current status of the anti-inflammatory and antithrombotic benefits of several fungi bioactives will be extensively reviewed, with emphasis on compounds with potential use in the development of supplements and drugs for the prevention and treatment of a range of inflammatory disorders and associated chronic diseases.

2 Fungi as Sustainable Sources for Bioactive Compounds of Natural Origin

Fungi are a miscellaneous group of organisms comprising several beneficial and damaging biological activities, which have a major impact on flora and fauna of the biome. For example, fungi are known to produce some potent antibiotics such as penicillin and cephalosporin. On the other hand, some fungal species are able to synthesize and excrete extremely toxic metabolites, such as aflatoxins, curvularin, and helminthosporin. These filamentous fungi show huge diversity in their metabolites including lipids, polyketides, alkaloids, quinones, and carotenoids. The metabolic diversity of fungal genera is extraordinary, making it possible for them to produce metabolites with various biological activities such as antioxidant, anticancer, antiviral, antimicrobial, and anti-inflammatory (Mehta et al. 2022).

The optimum extraction of such natural bioactives from fungi can be performed by controlling and optimizing their growth conditions and using low-cost and fast approaches, thus representing an economically valid and biosustainable alternative production of natural bioactives for the development of supplements and drugs. Usually, the isolation of a fungi strain for the development of a pharmaceutical product begins with the isolation of the fungus strain from diverse environmental sources (e.g., water, plants, and soil) and the culture of the microorganisms. The product of the culture is processed for extraction and purification of fungi metabolites. Subsequently, biological assays and clinical trials are performed to define the possibility of future pharmaceutical applications of the SM (Fig. 14.2).

Fig. 14.2
An illustration exhibits a flow from the environment to the pharmaceutical product through isolation and identification, culture, extraction, purification, natural product, biological assay, and clinical trials.

Representation of fungal strain isolation and development of medicines containing natural products as the bioactive component. Penicillin is being used just as an example. Reproduced from Conrado et al. (2022)

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However, there are several limitations and drawbacks in this field, such as the handling and isolation of new strains. There are several well-described isolation processes of fungi, including that for endophytes; however, there is some challenge in isolating new fungi species, mainly due to the current techniques applied for the cultivation and strain purification that usually have remained the same in the last years. For obtaining new species, it is mandatory to design new approaches that are able to simulate the condition of the natural habitat from which the microorganisms were isolated. In this aspect, it is essential to overcome challenges related to growing conditions such as pH, temperature, nutrients, and preservation in the laboratory. Fungal culture for obtaining its bioactive metabolites can be performed in either solid-state fermentation (SSF) or submerged fermentation (SmF). The first one, on a solid substrate, can produce a high concentration of metabolites. The SmF occurs in aqueous liquid nutrient media, and it is the most widely used due to the ease of control of fermentation parameters such as pH, temperature, dissolved oxygen, and types of culture media (Conrado et al. 2022).

Also, there is an ongoing search for highly productive fungi for desired compounds followed by their strain improvement through epigenetic modulations, mutations, and genetic engineering to make them suitable for industrial applications. Furthermore, the elucidation of their complete biosynthesis route is more than needed, including all the enzymes and related genes involved through “omics”—genomics, transcriptomics, proteomics, and metabolomics—to regulate and manipulate the biosynthesis process for improved productivity (Fig. 14.3). Alternatively, the identified biosynthetic pathway of the bioactive compounds can be assembled and mimicked in convenient systems, offering an approach to produce target compounds with ease (Shankar and Sharma 2022; Singh et al. 2021).

Fig. 14.3
An illustration in part A explains the process of multi-omic analysis for the identification of B C G genes. An illustration of strategies for production of metabolite divided into heterogenous expression, co-cultivation of microbes, site directed mutagenesis, and system biology approach.

(a) Flow chart depicts multi-omic tool with data integration and artificial intelligence modeling used for fungal metabolite studies. (b) The use of multi-omics for screening and isolating novel fungal secondary metabolites. Reproduced from Shankar and Sharma (2022)

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Once the limitations for microorganism isolation, culture, genetic manipulation, and characterization through omics of the biosynthetic route have been overcome, the next step is to proceed with extraction, purification, physicochemical characterization of the SMs, structural elucidation, and metabolomics with multi-omics, along with bioassay techniques for evaluating their bioactivities and structure–activity relationships. In addition, new and advanced omic approaches are needed to screen newer fungi, increase the pool of novel metabolites with their molecular interaction, and exploit the fungal cultures with their metabolic capacity (Fig. 14.3) (Shankar and Sharma 2022). All these processes are very well-described and widely applied in natural product research and have enabled the rapid characterization of valuable novel fungi-derived natural products, which along with cytotoxicity tests and targeted clinical trials have allowed the appropriate design, development, and release in the market of drugs and supplements containing fungi metabolites (Figs. 14.2 and 14.3).

3 Fungi Bioactive Metabolites with Anti-Inflammatory and Antithrombotic Properties as Candidates for the Development of Supplements and Drugs

Within this section, the most important and promising fungi metabolites with anti-inflammatory and antithrombotic potential that are/can be used for the development of supplements and drugs against inflammation-related disorders are presented. These are fungi-derived vitamins, carotenoid-colored metabolites, phenolic compounds/pigments, lipid bioactives, alkaloids, terpenes, polyketides, and several other bioactive fungi metabolites, which possess various biological activities including anticancer, anti-inflammatory, antithrombotic, antimicrobial, and antioxidant potential against chronic disorders.

3.1 Fungi-Derived Vitamins and Bioactive Carotenoid-Based Colored Pigments

Micronutrients known as vitamins are crucial for sustaining the body’s normal physiological functions and are required in small quantities. As mammals are unable to produce these essential nutrients, it is imperative to obtain them through dietary supplementation from external sources to ensure balanced metabolism in all living organisms (Shimizu 2001; Gupta and Gupta 2015). Certain vitamins act as coenzymes that assist in the biochemical reactions catalyzed by enzymes. For example, vitamin K is essential for normal blood clotting and plays a vital role in activating receptors that facilitate transcription mechanisms in bone tissues, making it a valuable treatment option for osteoporosis (Berg et al. 2002; Bolander 1997). The presence of vitamin A is necessary as a precursor to rhodopsin and other visual pigments, and it also plays a role in activating specific gene transcription processes that aid in growth and development (Berg et al. 2002). Microorganisms, such as fungi, naturally produce vitamins during regular metabolism, which are commonly used as food additives, health supplements, and therapeutic agents (Singh et al. 2017). To commercially produce fungi-derived vitamins, suitable fungi can be utilized in direct fermentation or through a combination of chemical and microbiological processes (Shimizu 2001; Bhalla et al. 2007). Characteristic examples of industrial production of vitamins from several fungi species are riboflavin (1) and β-carotene (2) (Fig. 14.4) (Bhalla et al. 2007; Demain 1999; Survase et al. 2006; FAO/WHO. 2001; Wang et al. 2012a; Mata-Gómez et al. 2014).

Fig. 14.4
Chemical structures of Riboflavin, beta carotene, astxanthine, and lutein exhibit a chain structure.

Chemical structures of natural fungi vitamins and bioactive carotenoid pigments with anti-inflammatory potential. Structures were obtained from https://molview.org/ (accessed on April 2, 2023)

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Vitamin B2, also known as riboflavin, is a water-soluble vitamin that is necessary for growth and reproduction. A lack of this essential vitamin can lead to cheilosis and dermatitis in humans. Eremothecium ashbyii and Ashbya gossypii, which are closely related ascomycetes, are commonly utilized microorganisms for the fermentative production of riboflavin (Demain 1999; Survase et al. 2006). Of the two, A. gossypii is the preferred choice due to its remarkable efficiency in producing riboflavin. It can generate up to 40,000 times the amount of vitamin necessary for its own growth (Survase et al. 2006).

Provitamin A, called β-carotene, is necessary for healthy growth, reproduction, and vision. Night blindness, changes in the skin, and mucosal membranes are all brought on by a vitamin A deficiency or malabsorption (FAO/WHO. 2001). The formation of β-carotene involves the fungi Blakeslea trispora, Phycomyces blakesleeanus, Mucor circinelloides, Rhodotorula spp., and Choanephora cucurbitarum. Due to their high yield of β-carotene, Blakeslea trispora and Phycomyces blakesleeanus are chosen and employed for submerged fermentation in industrial production (Wang et al. 2012a; Mata-Gómez et al. 2014).

Carotenoid-based bioactive pigments have been found in a variety of fungi, primarily those found in marine habitats, while engineered fungi such as yeasts can also be used for their production in industrial scale (Elbandy 2022; Galasso et al. 2017; Elbandy et al. 2009; Takahashi et al. 2020). Even though microalgae are the primary source of carotenoids used in industry, however, alternative organisms like fungi may be of use in other fields such as the cosmetics or pharmaceutical industries (Ambati et al. 2014; Maoka 2011; Corinaldesi et al. 2017). Thus, while the focus of carotenoid production has been on algal sources, marine fungi and pigmented yeasts can also be used for de novo synthesis of such biomolecules (Corinaldesi et al. 2017).

More specifically, several carotenoids are synthesized by various yeast species that have been isolated from the marine environment. Notably, the genera Xanthophyllomyces, Rhodotorula, and Phaffia have been utilized to produce one of the most bioactive carotenoids used in supplements, astaxanthin (3) (Fig. 14.4) (Ambati et al. 2014). Despite yeasts and bacteria yielding smaller quantities of astaxanthin compared to algae, they have the advantage of quicker rates of growth and more straightforward cultivation techniques (Mata-Gómez et al. 2014; Bumbak et al. 2011). Marine organisms, notably fungi and prokaryotes, exhibit tremendous potential for the creation and commercialization of novel antioxidant compounds and carotenoids, which can be used in a variety of industries (Corinaldesi et al. 2017). Marine carotenoids offer numerous advantages due to their potent antioxidant, repairing, antiproliferative, and anti-inflammatory properties. They can be employed to provide skin photoprotection against the detrimental impact of solar UV radiation or as nutraceutical/cosmeceutical components to safeguard against oxidative stress-induced diseases (Nichols and Katiyar 2010; Berthon et al. 2017; Gonzalez et al. 2011).

Fungi-derived α- and β-carotene (2), lutein (4), and astaxanthin (3) are examples of exogenous antioxidants that are crucial in preventing oxidative damage caused by free radicals via their scavenging activity (Birben et al. 2012; D’Orazio et al. 2012). These compounds have lipophilic properties, which allow them to act as a natural defense for both marine and earth-bound plants by crossing the cellular membrane. Their ability to cross the blood–brain barrier allows them to be biologically active in organs such as the brain (Elbandy 2022).

Di Tomo et al. (2012) found that the addition of carotene and lycopene was able to reduce TNF-α induced inflammatory response in human umbilical vein endothelial cells (HUVECs). These antioxidant molecules inhibited monocyte (U937)–endothelial adhesion while also limiting gene expression of the vascular adhesion proteins, VCAM-1, ICAM-1, and E-selectin. Lycopene and β-carotene helped sustain nitric oxide (NO) bioavailability resulting in control of the cellular redox environment (Di Pietro et al. 2016; Bian et al. 2023).

Lutein (4) is another carotenoid with strong antioxidant capacity and an important component of macular pigment in the retina, and thus, it possesses wide applications in pharmaceutical, food, feed, and cosmetics industries. Besides extraction from plant and algae, microbial fermentation using engineered cell factories of fungi (mostly engineered yeasts, such as Saccharomyces cerevisiae) to produce lutein has emerged as a promising route (Bian et al. 2023). Dwyer et al. (2001) research, comprising in vitro, in vivo, and epidemiological studies, demonstrates lutein’s potential as a protective agent against the early stages of atherosclerosis (Dwyer et al. 2001). Their co-culture model of lipoprotein oxidation with the artery wall revealed a significant dose-dependent reduction in the chemotactic signal for monocytes in the presence of lutein (0.1, 1, 10, and 100 nM), resulting in the inhibition of monocyte inflammation associated with LDL in the artery wall. This effect was observed in both apoE-null and LDL receptor-null mice, wherein an enriched lutein diet led to a significant reduction in atherosclerotic lesion size in the aortic arch. Furthermore, high plasma lutein levels were correlated with the progression of intima-media thickness (Dwyer et al. 2001).

The red pigment astaxanthin (3) can inhibit peroxidation by the protection of lipid bilayers from free radicals. The scavenging properties of this marine fungi carotenoid are associated with the molecular structure (Fig. 14.6), which is thought to be responsible for its 10 times higher antioxidant activity compared to previously mentioned carotenoids like β-carotene and lutein (Galasso et al. 2017; Gammone et al. 2015).

Astaxanthin was also found to reduce COX-2 expression-related neuroinflammation (Si and Zhu 2022). Endothelial function was improved in resistance arteries with astaxanthin enriched diet in hypertensive rats (Monroy-Ruiz et al. 2011). In addition to this effect, a decrease in oxidative stress was also observed and an improvement in NO bioavailability. 10 μM of astaxanthin was able to reduce pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, previously induced by the treatment with 100 μM of H2O2 (Galasso et al. 2017; Si and Zhu 2022).

It has also been proposed that astaxanthin’s anti-inflammatory and anti-apoptotic effects in the neural system are also related to elevated myelin basic protein (MBP) expression and decreased levels of caspase-3, iNOS, granulocyte colony-stimulating factor, and growth-related oncogene (Elbandy 2022; Aslankoc et al. 2022). Furthermore, astaxanthin decreased microglial activation and the expression of various pro-inflammatory cytokines, which further resulted in the suppression of neuroinflammation. The anti-inflammatory activity of astaxanthin was demonstrated by the nuclear translocation of NFκB p65, as well as by the suppression of p38 and Erk1/2 phosphorylation (Elbandy 2022; Pietrasik et al. 2022; Zhao et al. 2021).

3.2 Fungi-Derived Classic and Complex Bioactive Phenolic Compounds/Pigments with Anti-Inflammatory and Antithrombotic Properties

Several fungi produce a plethora of phenolic compounds, phenylpropanoids and aromatic amino acids. Such secondary metabolites consist of phenolic compounds and are secreted from the fungal metabolic pathways and/or the plant metabolic pathway (of plants that symbiote with endophyte fungi), which is called the shikimate pathway. Metabolites of this group include compounds like folic acid and salicylic acid, which help in reducing inflammation and pain, while they also produce the antioxidant drug resveratrol (5) (Fig. 14.5) (Singh et al. 2017, 2021). Phenolic compounds have many functions, while due to the high antioxidant effect and free radical scavenging property, phenylpropanoid compounds have major attention in the area of human health, and nowadays, their functions are updated by the use of multi-omic tools (Singh et al. 2017, 2021; Shankar and Sharma 2022).

Fig. 14.5
Chemical structures of resveratro, xanthone, azaphylone monapurpureusone, monapurpureusin, and mycophenolic acid.

Chemical structures of fungi bioactive phenolic compounds/pigments with anti-inflammatory potential. Most of the structures were obtained from https://molview.org/ (accessed on April 2, 2023), while (7) and (8) were reproduced from Takahashi et al. (2020)

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Resveratrol (trans-3,5,4′-trihydroxystilbene) is the most well-established polyphenol used as drug and is found mostly in grapes, berries, and fermented alcoholic beverages like wine, where S. cerevisiae is used as the main yeast for the fermentation, but can also be made by some fungi. It is a phytoalexin, i.e., a low molecular weight secondary metabolite. Alternaria sp. 61, isolated from Merlot cobs, can also produce resveratrol, as well as recombinant S. cerevisiae upon feeding of coumaric acid or L-tyrosine (Sanchez and Demain 2017; Shi et al. 2012; Shin et al. 2012). Resveratrol has exhibited potent antioxidant and anti-inflammatory activities, as well as anti-platelet aggregation and anti-atherogenic properties, and thus, it possesses beneficial effects against inflammation, carcinogenesis, oxidation, aging, diabetes, and renal and neurodegenerative disease (Tsoupras et al. 2007, 2009; Fragopoulou et al. 2004; Sanchez and Demain 2017; Sánchez-Fidalgo et al. 2010). Moreover, resveratrol was also found to reduce the levels of the potent inflammatory mediator and platelet-activating factor (PAF) by inhibiting its synthesis and thus reducing the inflammatory status (Tsoupras et al. 2007, 2009). Such bioactive phenolic compounds from fungi like resveratrol, which can reduce the levels and/or inhibit the activities of thrombo-inflammatory mediators like PAF and thrombin, may potentially reduce the risk of developing chronic disorders (Tsoupras et al. 2018, 2009, 2022a).

Moreover, a phenolic fraction derived from the HPLC separation of a bioactive extract from B. bassiana exhibited potent anti-inflammatory and antithrombotic activities against PAF in rabbit platelets (Tsoupras et al. 2022b). However, more studies are needed in order to elucidate the bioactive phenolic molecules that can be derived from such entomopathogenic fungus.

A mushroom species with high functional and nutraceutical potential of high market value is Agaricus subrufescens (synonymy Agaricus blazei and Agaricus brasiliensis). It is commercialized in several countries such as Brazil (brand name “Sun mushroom”), China (Ji Song Rong), and Japan (Himematsutake). Sun mushroom contains polyphenols and polysaccharides and is known to decrease oxidative stress and prevent non-transmitted chronic disorders (NTCD); it is indicated to have antioxidant, antitumor, anti-inflammatory, and immunomodulatory properties (Shankar and Sharma 2022; Takahashi et al. 2020; Navegantes-Lima et al. 2020).

For example, Agaricus brasiliensis extract rich in polyphenols showed anti-inflammatory, immunomodulatory, and antioxidant effects in the cecal ligation and puncture (CLP) sepsis model (Navegantes-Lima et al. 2020). More specifically, the aqueous extract of A. brasiliensis reduced systemic inflammatory response and improved bacteria clearance and mice survival. In addition, A. brasiliensis decreased the oxidative stress markers in serum, peritoneal cavity, heart, and liver of septic animals, as well as ROS production (in vitro and in vivo) and tert-butyl hydroperoxide-induced DNA damage in peripheral blood mononuclear cells from healthy donors in vitro. In conclusion, the aqueous extract of A. brasiliensis was able to increase the survival of septic animals by a mechanism involving anti-inflammatory, immunomodulatory, and antioxidant protective effects (Navegantes-Lima et al. 2020).

Xanthone (6) (Fig. 14.5) is the basis of several xanthones, including fungi-derived xanthones, which are another class of bioactive phenolic compounds showing antioxidant and anti-inflammatory properties and potential medicinal benefits (Feng et al. 2020). For example, the anti-neuroinflammatory assay of Hypoxylon xanthone A from soil fungus Hypoxylon sp., as manifested by the inhibitory effect on LPS-induced NO production in BV-2 microglial cells, indicated almost the same inhibitory effect as the antibiotic minocycline in a dose-dependent manner within the concentration of 1–50 μM, suggesting that hypoxylon xanthone A could be a new potential neuroinflammation inhibitor (Takahashi et al. 2020; Xiao et al. 2020).

Another example to enhance the quantity of easily available phenolic pigments from fungi is engineered Monascus species by subjecting them to mutations. One of these mutant strains of M. purpureus was grown in fermented rice extract, leading to the production of two new compounds—the azaphylone monapurpureusone (7) and the brownish natural product monapurpureusin (8) (Fig. 14.5). These compounds and their derivatives produced by reactions with other biomolecules (i.e., the water-soluble red pigments monascorubramine and rubropunctatin) have exhibited remarkable superoxide radical scavenging activity, either comparable to or surpassing the control gallic acid, and superior anti-inflammatory activity in comparison with the control quercetin (Wu et al. 2019). In general, Monascus pigments come in 54 different varieties. They have a remarkable range of functions, including antibacterial, anticancer, antimutagenesis, antidiabetes, anti-obesity, anti-inflammatory, cholesterol-lowering, immunosuppressive, and hypotensive (Sanchez and Demain 2017; Feng et al. 2012; Lee and Pan 2012).

Some classic and/or more complex fungi phenolic molecules can reduce the inflammatory response indirectly as immunosuppressants. For example, mycophenolic acid (9) is a mesoterpenoid with a phenolic functional group, synthesized by the fungi Penicillium brevicompactum, Penicillium stoloniferum, and P. echinulatum, with a primary use as an immunosuppressive drug and especially to prevent organ transplant rejection. It reversibly inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes, which concludes to immunosuppressant and reduced inflammatory response (Patel et al. 2017; Anderson et al. 1988; Bills and Gloer 2016).

3.3 Fungi Lipid Bioactives with Anti-Inflammatory and Antithrombotic Properties

3.3.1 Fungi-Derived Anti-Inflammatory and Antithrombotic Fatty Acids

Fungi produce several unsaturated fatty acids, in a combination that usually has anti-inflammatory potential (Fig. 14.6). For example, almost all fungi contain the monounsaturated fatty acid (MUFA) oleic acid (OA; 18:1 omega 9) (10), which has shown strong anti-inflammatory and antithrombotic properties against several inflammatory mediators, including PAF (Nunez et al. 1990). In addition, various fungi produce also several of the long-chain polyunsaturated fatty acids (PUFA), such as gamma linoleic acid (GLA; 18:3 omega-6) and alpha-linolenic acid (ALA; 18:3 omega-3) (11) and (12) (i.e., from Mucor circinelloides), arachidonic acid (ARA; 20:4 omega-6) (13) (i.e., from Mortierella alpine), docosahexaenoic acid (DHA; 22:6 omega-3) (14) (i.e., from Crypthecodinium cohnii spp.), and eicosapentaenoic acid (EPA; 20:5 omega-3) (15) (i.e., from genetically modified Y. lipolytica. The oil produced from fungi has much higher levels of EPA than natural oils. EPA is important for the anti-inflammatory activity of fish oils, thus contributing to cardiovascular and joint health (Tsoupras et al. 2022a; Sanchez and Demain 2017). Consumption of such PUFA-containing oily products with a low ratio of omega-6/omega-3 PUFA promotes an anti-inflammatory potential since diets and foods containing such a ratio have been found to possess strong anti-inflammatory health benefits against several inflammation-related disorders (Simopoulos 2008). PUFAS are the principal component of cell membrane phospholipids and thus are used heavily in the infant formula industries (especially ARA and DHA). EPA and DHA can be utilized to avoid heart issues. They control cell fluidity, the attachment of certain enzymes to cell membranes, and the transmission of signals and other metabolic activities. They are involved in the manufacture of eicosanoids, leukotrienes, prostaglandins, and resolvins, which have anti-inflammatory, anti-arrhythmic, and anti-aggregatory properties. Several of them promote cardiovascular health, and others increase visual function and cognition in newborns and adults (Sanchez and Demain 2017).

Fig. 14.6
6 chemical structures for Oleic acid, gamma linoleic acid, alpha linolneic acid, arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid.

Chemical structures of fungi bioactive unsaturated fatty acids with anti-inflammatory potential. Structures were obtained from https://molview.org/ (accessed on April 2, 2023)

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3.3.2 Polar Lipids

Polar lipids are important biomolecules and structural elements for all cells in nature, with a plethora of diverse bioactivities. Polar lipids are amphiphilic molecules that generally have two fatty acids esterified to a glycerol- or a sphingosine-based backbone and a phosphorus functional group for phospholipids or a sugar for glycolipids that is linked to a head group (Fig. 14.7a). Lately, it has been found that bioactive polar lipids with unsaturated fatty acids in their structures (usually at the sn2 position), such as polar lipids with EPA (16), polar lipids with DHA (17), polar lipids with ALA (18), and polar lipids with OA (19) (Fig. 14.7a), possess higher bioavailability of their unsaturated fatty acids throughout the body, due to their amphiphilic properties, while most importantly they possess strong anti-inflammatory and antithrombotic properties against several mediators and inflammatory pathways, by a variety of mechanisms of actions (Fig. 14.7b), with promising health benefits against atherosclerosis and CVD, cancer and metastatic procedures, renal and neurodegenerative disorders, persistent infections and associated inflammatory manifestations, allergy and asthma, sepsis, etc. (Tsoupras et al. 2018, 2022a).

Fig. 14.7
Illustration A exhibits special fats like E P A and D H A. Illustration B explains how these fats work against inflammation and blood clotting.

Structures (a) and mechanisms of action (b) of classic bioactive polar lipids with anti-inflammatory and antithrombotic properties; (a) bioactive polar lipids with unsaturated fatty acids at their sn2 position of their glycerol backbone. EPA eicosapentaenoic acid (C20:5 omega-3), DHA docosahexaenoic acid (C22:6 omega-3), ALA alpha-linolenic acid (C18:3 omega-3), OA oleic acid (C18:1 omega-9). (b) Modes of beneficial actions of bioactive polar lipids (in blue color) against the thrombo-inflammatory related pathways and cell responses (red color). PL polar lipids, PAF platelet-activating factor, ADP adenosine 5′ diphosphate, GPCMR G-protein-coupled membrane receptors, cPLA2 cytoplasmic phospholipase A2, LPCAT and PAF-CPT basic regulatory biosynthetic enzymes of PAF, ARA arachidonic acid, COX cyclooxygenase. Reproduced with modifications from Tsoupras et al. (2022a)

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For example, such bioactive polar lipids have modulated or even reduced the formation of arteriosclerotic plaques, by reducing the levels of the inflammatory and thrombotic mediator, PAF, and its atherogenic effects. Apart from modulating PAF metabolism toward reduced PAF levels, such fungi-derived bioactive polar lipids have also inhibited the inflammatory and thrombotic pathways of both PAF and thrombin, while they have reduced the platelet activation and aggregation induced by well-established platelet agonists, collagen, and ADP (Moran et al. 2021; Fragopoulou et al. 2004; Tsoupras et al. 2022b). More specifically, it has recently been found that several yeasts used for the production of fermented foods and beverages (Moran et al. 2021; Fragopoulou et al. 2004) and fungi of bio-agro/food technological applications like those used as natural entomopathogenic agents for organic cultures, such as Beauveria bassiana (Tsoupras et al. 2022b), contain such bioactive polar lipids with strong anti-inflammatory and antithrombotic properties against the thrombo-inflammatory mediators, PAF and thrombin, and against the well-established platelet agonists, collagen, and ADP (Moran et al. 2021; Fragopoulou et al. 2004; Tsoupras et al. 2022b).

It seems that the anti-inflammatory and antithrombotic anti-PAF properties of these fungi-derived polar lipid bioactives occur either through affecting beneficially PAF metabolism toward reduction in its levels of homeostatic ones and/or through inhibiting the binding of PAF on its receptor and thus inhibiting PAF-related inflammatory and thrombotic pathways and activities (Fig. 14.7b) and subsequently reducing the risk for PAF-associated inflammatory chronic disorders such as atherosclerosis, CVD, and cancer (Tsoupras et al. 2018, 2009, 2022a). Moreover, apart from the strong anti-inflammatory and antithrombotic properties of the whole structures of such bioactive polar lipids, it has also been proposed that once the rich in unsaturated polar lipids have surpassed the intestine barrier and are bound to and transferred from plasma lipoproteins to the cell membranes of all tissues, there a cytoplasmic phospholipase A2 (PLA2) releases their unsaturated fatty acids from their structure of these membrane-bound polar lipids, while the released unsaturated fatty acids interacts with the eicosanoids pathways (COX-enzymes) for reducing and resolving inflammation and the inflammatory cell-response (Fig. 14.7b).

3.3.3 Other Fungi-Derived Lipid Bioactives with Anti-Inflammatory and Antithrombotic Properties

Several other fungi-derived lipid bioactives have also been found to possess anti-inflammatory and antithrombotic potential. For example, ergosterol (20) (Fig. 14.8), the main sterol present in various fungal membrane cells, has a range of activities including cell cycle control, regulation, and permeability, as well as several health-promoting effects such as, anti-inflammatory, antioxidant, anticancer, and anti-hypercholesteremic (Rousta et al. 2023). Ergosterol is also implicated in the synthesis of vitamin D2 (ergocalciferol) by conversion of ergosterol by UV radiation. This form of vitamin D2 is converted to calcitriol, the biologically active form of vitamin D by the body. Vitamin D is an important vitamin for the prevention of various metabolic diseases like hypertension, diabetes, and cancer (Feng et al. 2020). Deficiency of vitamin D has been associated with COVID-19 mortality (Tsoupras et al. 2020a, b; Zabetakis et al. 2020).

Fig. 14.8
4 chemical structures for ergosterol, anticin, chlamydosterol A, and myriocin.

Chemical structures of other fungi lipid bioactives with anti-inflammatory potential. Structures of (20), (21), and (23) molecules were obtained from https://molview.org/ (accessed on April 2, 2023), while (22) was reproduced from Al-Rabia et al. (2021)

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Vitamin D and its analogs like paricalcitol have also exhibited strong anti-inflammatory and antithrombotic properties by inhibiting the inflammatory actions of PAF in vitro in platelets, they reduced PAF synthesis in vitro in cell cultures of mesangial cells, while in an in vivo trial daily administration of paricalcitol in hemodialysis patients for a month resulted also in modulation of PAF metabolism toward reduced PAF synthesis and increased PAF catabolism and thus toward reduced PAF levels in their blood, which subsequently resulted in reduced levels of other inflammatory cytokines and a beneficial decrease in the inflammatory status in the blood of these patients versus control subjects (Verouti et al. 2013). Since the rich diet source of vitamin D is animal products, the fungi as the only vegetarian source of vitamin D are highly considered.

Another class of fungi-derived bioactive lipid compounds of increasing prominence found in edible mushrooms includes antcins (21) (Fig. 14.8) and steroids that contain an ergostane-type skeleton and are produced by Antrodia species such as Antrodia cinnamomea and Antrodia salmonea (Takahashi et al. 2020). Studies suggest that these compounds are promising agents in the treatment of cancer, inflammation, diabetes, and diseases resulting from oxidative stress (Takahashi et al. 2020). A study tracking 36,499 middle-aged and elderly Japanese men over an average of 13.2 years found a positive relationship between regular mushroom consumption and decreased incidence of prostate cancer (Zhang et al. 2020).

Two other ergosterol derivatives namely chlamydosterols A (22) (Fig. 14.8) [(22E,24R)-ergosta-7,22-diene-3β,5α,6β-triol 6-decanoate] and ergosta-5,7,22-triene-3β-ol, from the EtOAc extract of the endophytic fungus Fusarium chlamydosporum isolated from Anvillea garcinia (Asteraceae) leaves growing in Saudi Arabia, showed a 5-lipoxygenase (5-LOX) inhibitory potential compared to a classic 5-LOX inhibitor, indomethacin (Al-Rabia et al. 2021).

Some classic and/or more complex fungi lipid molecules can reduce the inflammatory response indirectly as immunosuppressants. For example, myriocin (ISP-I) (23) (Fig. 14.8) is an amino acid lipid produced by the fungus Isaria sinclairii, whose structural model is used as a template for the synthesis of fingolimod, commercially available as Gilenya. Used in the treatment of multiple sclerosis through the activation of its structure, this drug connects with extracellular G protein-coupled receptors, preventing the release of lymphocytes that enter the central nervous system and thus indirectly prevent the neuroinflammatory response of sclerosis (Fujita et al. 2000).

3.4 Alkaloids

Alkaloids are an important group of nitrogen-containing secondary metabolites, such as caffeine, cocaine, nicotine, morphine, and strychnine, which consist of one or more nitrogen atoms within their heterocyclic ring. Alkaloids have several biological activities including anti-inflammatory properties (Mehta et al. 2022; Debnath et al. 2018). For example, the addition of pyrrole alkaloid into the cell of fungus Curvularia sp. IFB-Z10, associated with white croaker, induces the generation of an anti-inflammatory metabolite named curindolizine (24) (Fig. 14.9) (Mehta et al. 2022; Han et al. 2016). In general, several species of Curvularia are known to synthesize various bioactive alkaloid compounds including curvulamine, curindolizine, and curvupallides, which show antimicrobial and anti-inflammatory activities (Mehta et al. 2022). Moreover, marine fungi-derived indole alkaloids are also very promising and an active group of molecules. They possess various biological activities like antiparasitic, cytotoxic, serotonin and antagonistic realms, anti-inflammatory, and antiviral (Shankar and Sharma 2022; Gul and Hamann 2005).

Fig. 14.9
3 chemical structures for curindolizine, triterpenoid, and cucurbitacins.

Chemical structures of characteristic fungi-derived alkaloids and terpenoids with anti-inflammatory potential. Structures were obtained from https://molview.org/ (accessed on April 2, 2023)

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3.5 Terpenoids

Terpenes are a major class of bioactive metabolites that are produced from a higher class of Polyporales group of basidiomycetes. These compounds are structural constituents of another group of metabolites that are formed through the linkage of isoprene units. Different NMR and other omic tools confirm the member of the terpenoid class of compounds such as steroids, menthol, and taxol, which have key components for anticancer drugs and β-carotene properties. These bioactive compounds possess anti-inflammatory properties and anti-infection, anticancer, antiproliferative, and antiangiogenic medicinal benefits (Shankar and Sharma 2022). Mushroom secondary metabolites triterpenes (25) (Fig. 14.9), abundant in reishi mushroom (Ganoderma lucidum), inhibit various pro-inflammatory mediators, such as TNF-α, interleukin-6, nitrogen monoxide free radical, prostaglandin E, nuclear factor-kappa B (NF-κB), and cyclooxygenase-2 (COX-2), while Poria cocos mushroom incorporates lanostane triterpenoids (25) (Fig. 14.9) that improve inflammation and treat tumors (Bell et al. 2022). Cucurbitacins (26) (Fig. 14.9) belong to cucurbitane-type tetracyclic triterpenoid saponins that are abundant in several natural sources, while they are also present in some fungi. Several studies have shown that cucurbitacins have significant biological activities, such as anti-inflammatory, antioxidant, antimalarial, antimicrobial, hepatoprotective, and antitumor potential (Varela et al. 2022).

3.6 Other Fungi Metabolites with Well-Established Pharmaceutical Health Benefits That Also Exhibit Anti-Inflammatory Effects

A plethora of well-established pharmaceutical compounds have been derived from several fungi species. These compounds have been used against specific pathological conditions with high specificity and pharmacological actions. Nevertheless, there are a lot of studies lately indicating the potential pleiotropic effects of several of these drugs. Thus, apart from their classic pharmaceutical actions, the newly observed pleiotropic effects and multifunctional applications of these compounds, and especially their potential anti-inflammatory and antithrombotic properties, may provide additional perspectives for the appropriate choice of a drug/drug combination against a specific inflammation-related condition where anti-inflammatory actions will provide further health benefits by reducing the inflammatory burden. Characteristic examples of such fungi-derived metabolites and their derivatives that are used as several drugs and also possess pleiotropic effects, including anti-inflammatory potency, are further analyzed below.

3.6.1 Drugs Containing Fungal Polyketides and Their Derivatives with Anti-Inflammatory Potential

Fungal polyketides are common metabolites present in large groups of ascomycete and basidiomycete fungi. All groups of microbial polyketides are synthesized by multi-domain polyketide synthases (PKSs), which are structurally diverse. These secondary metabolites contain also a fatty group and are formed through the acetate pathway within the cell by coupling of acetate groups. In the fatty acid group, crude fat is considered under all categories of lipid compounds, including fatty acids, monoglycerides, diglycerides, triglycerides, sterols, and phospholipids. These groups of metabolites include antibiotics, statins (lowers cholesterol levels), and antidepressant drugs. Characteristic pharmaceutically modified polyketides that are used as drugs are the cholesterol-lowering statin, lovastatin (27) (Fig. 14.10), and the anti-mycotic drug griseofulvin (28) (Shankar and Sharma (2022).

Fig. 14.10
5 chemical structures for lovastatin, griseofulvin, simvastatin, piperacillin, and tazobactam.

Chemical structures of characteristic fungi-derived drugs that also possess anti-inflammatory properties. Structures were obtained from https://molview.org/ (accessed on April 2, 2023)

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Statins are one of the most well-established cholesterol-lowering drugs used for the prevention and treatment of cardiovascular disorders. In 1976, Akira Endo at the Sankyo Company, Tokyo, identified the first inhibitor of the HMG-CoA reductase, which drives down the levels of intracellular cholesterol, thereby embarking on the long journey of evolution of statin drugs (Sultan et al. 2019). Several statins are fungi metabolites, such as lovastatin, a bioactive polyketide commercially sold as mevacor, and its semisynthetic product, simvastatin (29) (Fig. 14.10), which is on the market as zocor and simvador. Lovastatin biosynthesis has been reported in several fungal species, including Aspergillus terreus, Monascus purpureus, Penicillium citrinum, Paecilomyces viridis, Penicillium purpurogenum, Pleurotus sp., and Trichoderma viride, with the latent being the species used for industrial production.

These statins block 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and prevent the conversion of mevalonate into cholesterol, being the most frequently used drugs in the treatment of hypercholesterolemia to reduce the risk of cardiovascular diseases and to manage abnormal lipid levels by inhibiting the endogenous production of cholesterol in the liver. Another fungi-derived statin is compactin, which is produced by the fungi P. citrinum and Penicillium solitum and is commercially available as pravachol, selektine, or lipostat, while it also reduces the risk of cardiovascular diseases through the same pathway and is also used as a substrate for the biotransformation or partial chemical synthesis of mevastatin.

Additional studies have indicated several important pleiotropic applications of statins, with lovastatin for example to be used as an antimicrobial and agent for treatments of cancers and bone diseases (Conrado et al. 2022). Nevertheless, apart from their proposed beneficial cardioprotective properties through lowering cholesterol levels, recent studies have also demonstrated several side effects of statin use, such as diabetes mellitus, cancer, early premature cataracts, hearing loss, suicidal ideation, peripheral neuropathy, depression, benign intention tremors and Parkinson’s disease, pulmonary interstitial pneumonitis and dysfunctional breathing, interstitial cystitis and bladder wall instability, herpes zoster, impotency, and cognitive impairments, while several researchers have also suggested that statin treatment ultimately offer little protection against cardiovascular risk by their effects on cholesterol levels (Sultan et al. 2019).

Interestingly, some but not all statins, including simvastatin with an intact lactone ring, have also exhibited in vitro a strong anti-inflammatory inhibitory effect against the pro-inflammatory and thrombotic mediator, platelet-activating factor (PAF), and its inflammatory signaling in platelets. Moreover, incubation of human mesangial cells in the form of simvastatin with an intact lactone ring resulted in decreased PAF biosynthesis toward reduced PAF levels. Furthermore, in six simvastatin-treated volunteers a reduction in PAF biosynthesis was observed in their leukocytes explaining the lower levels of PAF in the blood of these subjects, while total cholesterol and low-density lipoprotein cholesterol were also significantly decreased. Within the same period of this administration, high-density lipoprotein cholesterol, triacylglycerol, the effective concentration (EC50) for inducing 50% of PAF-induced plasma-rich platelet aggregation, and lag time of plasma oxidation were unaffected in these participants. Since PAF is implicated in several inflammation-related chronic disorders, the observed anti-inflammatory and cardioprotective anti-PAF effects of statins should be further evaluated as part of their pleiotropic activities, which can provide novel perspectives on the use of statins against chronic disorders (Tsantila et al. 2011).

Griseofulvin is a natural product that was first discovered and isolated from Penicillium griseofulvum. In addition to Penicillium, griseofulvin may be isolated from other genera of ascomycetes. Griseofulvin has a wide range of applications, from agriculture to medicine. In medicine, griseofulvin has been widely used as an antifungal drug and in treating ringworm and dermatophyte infections in humans and animals due to its low toxicity. This fungistatic has gained increasing interest for multifunctional applications in the last decades due to its anticancer and antiviral potential (Aris et al. 2022). Moreover, it has recently been found that griseofulvin has exhibited indirect anti-inflammatory protection against the inflammatory burden of SARS-CoV-2 infection, through its vasodilation and increased capillary blood flow effects, by beneficially affecting the ACE2 signaling of the renin–angiotensin–aldosterone system (RAAS) toward reduction in inflammation. It seems that griseofulvin binds to ACE2 and competes against SARS-CoV-2 binding to the extracellular domain of ACE2, therefore improving ACE2 vasodilation and tissue protection anti-inflammatory functions. These findings suggest that griseofulvin and its derivatives might be considered when developing future SARS-CoV-2 treatment options (Aris et al. 2022).

Further studies reported the effectiveness of griseofulvin in the treatment of non-fungal skin inflammation diseases, suggesting that it may also have anti-inflammatory and immunomodulatory potential. This is while, earlier studies have shown that griseofulvin is effective in treating shoulder-hand syndrome and a few other inflammatory, rheumatic conditions, such as posttraumatic reflex dystrophies and scapulohumeral periarthritis. Additionally, griseofulvin has been shown effective for inflammatory skin diseases through inducing inhibitory effects on vascular cell adhesion molecule 1 (VCAM-1) in both TNF-alpha and IL-1 stimulated human dermal microvascular endothelial cells (HDMEC) (Aris et al. 2022).

3.6.2 Fungi-Derived Antibiotics with Anti-Inflammatory Properties

Apart from their general and well-established antimicrobial actions, several antibiotics have also exhibited specific anti-inflammatory and antithrombotic potency. For example, the semisynthetic derivatives of penicillins, the firstly reported fungi-derived β-lactam antibiotics originally obtained from Penicillium molds, principally P. chrysogenum and P. rubens, namely the β-lactam antibiotic piperacillin (30) and the beta-lactamase antibiotic tazobactam (31) (Fig. 14.10), which are widely used in combination for the management and treatment of serious, hospital-acquired infections, including sepsis, were also found to possess strong anti-inflammatory and antithrombotic properties against the activities and the synthesis of the inflammatory and thrombotic mediator, PAF, and in lesser potency against thrombin (Tsoupras et al. 2011a).

More specifically, the combination of piperacillin–tazobactam inhibited strongly PAF-induced aggregation of both washed rabbit platelets and rabbit plasma-rich platelets in a concentration-dependent manner, while when combined with other antibiotics such as netilmycin and amikacin, they synergistically inhibited more potently PAF actions in these cells. Higher concentrations of these antibiotics were needed in order to inhibit platelet aggregation induced by the classic thrombotic mediator, thrombin, suggesting that they have higher specificity against the PAF-related signaling pathway of inflammation and thrombosis. In addition, these antibiotics were also able to inhibit PAF synthesis of rabbit leukocytes, suggesting that they can also reduce PAF levels during inflammatory activation of leukocytes and platelets. These newly found properties of fungi-derived antibiotics used in sepsis suggest that apart from their general actions, these drugs may present additional beneficial anti-inflammatory and antithrombotic effects against the onset and establishment of sepsis and of other microbial-induced inflammatory manifestations and associated disorders, by inhibiting the PAF/PAF receptor inflammatory and thrombotic signaling and/or the thrombin/protease-activated receptor-1 thrombotic signaling, as well as by reducing PAF levels through both PAF biosynthesis inhibition and PAF catabolism induction (Tsoupras et al. 2011a). These promising in vitro results need to be further studied and confirmed by in vivo tests, in order to optimize the efficacy of antibiotic treatment in sepsis and other microbial-induced inflammatory conditions.

3.7 Other Fungi Metabolites with Anti-Inflammatory Properties and Health Benefits

Apart from all these bioactive metabolites, a variety of several other molecules of different structures and activities have also been found in fungi, with a direct or indirect anti-inflammatory and antithrombotic potential (Fig. 14.11). Classic example of such molecules is cinnabarinic acid (32). Pycnoporus, a white-rot basidiomycete mushroom, secretes enzymes and pigments that break down cellulose, hemicelluloses, and lignin. Specifically, the species P. sanguineus produces cinnabarinic acid, which is highly effective at inhibiting the growth of bacteria and common foodborne pathogens. Cinnabarinic acid has been proposed as a potential therapeutic agent in the treatment of neuroinflammatory diseases. Given these powerful properties, Pycnoporus should be further studied for applications in food and medicine (Shankar and Sharma 2022; Fazio et al. 2017).

Fig. 14.11
9 chemical structures for Cinnabarinic acid, chitosan, beta glucan, sorbicillin, macrocyclic lactone, 1,2-cyclobutanedicarbonitrile, benzeneethanamine, terrain, and cordycepin.

Chemical structures of other fungi metabolites with anti-inflammatory properties. Structures were obtained from https://molview.org/ (accessed on April 2, 2023)

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Fungi are classified based on the presence of the essential long-chain polymer, chitin, and its derivative chitosan (33). Like other fungal-derived compounds, they possess antimicrobial effects and research has suggested they could be used for the production of new therapeutics with antitumor, anti-inflammatory, and anti-hypertensive activities (Rousta et al. 2023).

Another structural component of many microbial organisms like fungi, yeasts, and mushrooms is β-glucan (34). This glucose polymer is a common ingredient in skin care products due to its positive effects on wound healing, skin moisture, and oxidative stress. Additionally, β-glucan has been proposed as a treatment for several health conditions including, cancer, inflammatory bowel disease, and arthritis (Rousta et al. 2023).

Hexaketide metabolites known as sorbicillinoids were initially discovered in 1948 as a penicillin contaminant. It is composed of the base sorbicillin (35) structure with cyclization at the carboxylate terminus. Great advances have been made in the structural elucidation of sorbicillinoids derived from fungi with 62 additional structures discovered between 2016 and 2021. These compounds have many bioactivities, including anti-inflammatory, antiviral, cytotoxic, and antibacterial characteristics. Fungi from the Pezizomycotina subphylum of the Ascomycota phylum, including species like Aspergillus sp., Penicillium notatum, and Trichoderma sp., generate sorbicillinoids. From maritime habitats, certain sorbicillinoid-producing fungus have been isolated. Due to their health-promoting properties, fungal sorbicillinoids have shown great potential in the pharmaceutical industry (Conrado et al. 2022).

Both macrocyclic lactone and macrocyclic ketone (36) were recently isolated from filamentous fungi from various species of Curvularia. They have been posed as potential bioactive compounds for application in agricultural and pharmaceutical industries. They seem to possess radical scavenging properties contributing to antioxidant effects. Additionally, they have been found to possess anti-inflammatory and anticancer activities (Mehta et al. 2022).

A. alternata has been found to produce bioactive endophytes, which have potential to inhibit the HIV and reduce the viral load. Specifically, 1,2-cyclobutanedicarbonitrile (37) and benzeneethanamine (38) have been found to possess anti-inflammatory, antimicrobial, and antioxidant properties. Thus, these bioactive compounds have potential to serve as treatments for HIV infection (Nzimande et al. 2022).

In vitro studies have demonstrated the anti-inflammatory and antioxidant properties of terrain (39), a secondary metabolite produced by A. terreus. These significant medicinal properties, combined with the high initial yield of this metabolite, facilitate large-scale production and technological advancements in the crude extract of A. terreus for the prevention of certain non-transmissible chronic disorders (NTCDs) associated with aging (Takahashi et al. 2020; Asfour et al. 2019; Lee et al. 2015).

Cordyceps militaris is a well-known mushroom that possesses beneficial nutraceutical properties and produces several metabolites. The global market offers numerous nutraceuticals containing cordyceps that support the immune system, vascular system, cognition, anticancer and antioxidant activities, and mental health. The primary metabolite produced by C. militaris, cordycepin (40), is effective in reducing hyperlipidemia and the accumulation of LDL, total cholesterol, triglycerides, and other lipids caused by high-fat diets. Cordycepin has various pharmacological properties, including anti-inflammatory, immunomodulatory, antioxidant, anti-aging, anticancer, antiviral, cardio, and hepatoprotective effects. Cordyceps sinensis, which contains cordycepin, stimulates the production of interleukin-10, an anti-inflammatory cytokine. Cordycepin products, which contain adenosine receptor agonists, are being studied as potential treatments for COVID-19 pneumonia and brain protection (Takahashi et al. 2020; Ashraf et al. 2020).

4 Plant-Derived Compounds from Fungal Endophytes with Potential Anti-Inflammatory and Antithrombotic Benefits

Many plant-derived compounds are actually synthesized by symbiotic/parasitic fungi living inside plants, called endophytes, rather than by the plants themselves. In recent years, increasing researchers have demonstrated the ability of endophytic fungi derived from important medicinal plants to produce the same bioactive metabolites as their host plants. It is now established that endophytes can produce, induce, and modify a variety of plant-derived metabolites inside and outside of host plants, which opens up new possibilities for producing medicinal compounds from endophytes, since only a small fraction of plant species have been studied for their endophytes and their produced bioactives. Thus, as the demand for natural products increases endophytes are becoming more attractive targets for isolating typical host-derived compounds. Given that medicinal plants are a rich source of therapeutic compounds, exploring their endophytes is crucial for identifying and isolating such compounds (Singh et al. 2021; White 2018; Xingyuan et al. 2022). Characteristic examples are nonribosomal peptides, polyketides, terpenes, alkaloids, coumarins, flavonoids, lignans, saponins, quinones, xanthones, and miscellaneous compounds, for which their health benefits and mode(s) of action have been extensively presented elsewhere by Singh et al. (2021), Toghueo (2019), and Nicoletti and Fiorentino (2015). Moreover, many anti-inflammatory compounds currently isolated from medicinal plants have been identified in the metabolome of endophytic fungi. We are presenting in this section a few numbers of well-established and promising bioactive metabolites with anti-inflammatory and antithrombotic potential, which are produced by the interaction(s) of endophytes with their host plants, as summarized in Table 14.1, along with subsequent associated health benefits and/or putative side effects.

Table 14.1 Bioactive metabolites derived from the interaction(s) between plants and fungal endophytes, with anti-inflammatory and antithrombotic potential and several other health benefits
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5 Conclusions

Within this chapter, it was presented that bioactive fungi metabolites, such as phenolics, bioactive polar lipids, alkaloids, terpenoids, and other miscellaneous compounds, are a new type of promising products for drug and supplements’ development with multi-purpose and multi-target aspects, as these active substances do not regulate the inflammatory response through a single reaction path, rather than through their pleiotropic protective effects against several thrombo-inflammatory signaling pathways. The research on the action mechanism of modern pharmacological research shows that bioactive secondary metabolites produced from natural fungi or by engineered species can effectively interact with relevant immune cells, inflammatory factors, and intestinal flora, play an anti-inflammatory role, possess antithrombotic benefits and repair the inflammatory reaction disorder of the body. Advances have been made in the understanding of the mechanism of action of various fungi metabolites, but many questions remain unanswered. For the past few years, there has been an exponential growth in the field of fungi-derived medicine and these drugs are gaining popularity both in developing and developed countries because of their natural origin and less side effects.

At present, most of the studies are based on in vitro research and/or animal models, while the anti-inflammatory and antithrombotic mechanism of these fungi-derived metabolites in human body by targeted trials has not yet been fully described for all fungi compounds, as well as for combinations of fungi metabolites. Therefore, the action mechanism of fungi-derived bioactives in the process of anti-inflammatory response needs to be further studied. The research on the separation process and the study of structure–activity relationship of monomer components of fungi-derived products should be built upon, as well as the putative synergistic effects of multi-targeting anti-inflammatory fungi metabolites. In the future, active components in fungi and mixtures of fungi compounds with synergistic effects can be analyzed with the help of modern research means, such as network pharmacology, modern multi-omics and metabolomics, artificial intelligence-based docking modeling molecular biology, genetics, and epigenetics, to determine the relevant anti-inflammatory response mechanism and provide a basis for the clinical application of fungi-derived metabolites.

Moreover, the library of fungi-derived anti-inflammatory and antithrombotic bioactives has dramatically been increased by the inclusion of specific plant-derived medicinal compounds efficiently biosynthesized by hundreds of endophytic fungi. Nonetheless, the exciting progress that has been made in the field of functional genomics, genome mining and genome scanning, fermentation technology, green combinatorial chemistry, and systems biology might remove the roadblocks in the way of commercial success of this innovative approach. The design of endophyte-dependent enhanced in vivo and in vitro production of plant-derived valuable metabolites is of prime importance for the pharmaceutical industries and provides a plethora of valuable compounds with future perspectives for the healthcare systems and for a “green drug revolution.”