CYNOMORIUM PLANTS: BIOACTIVE COMPOUNDS AND PHARMACOLOGIC ACTIONS

Cynomorium coccineum and Cynomorium songaricum are unusual parasitic plants in the family Cynomoriaceae characterized by their unusual appearance and way of life. Due to their special habit and extremely rare occurrence, in the past, various magical properties have been attributed to these plants. The plant Cynomorium coccineum, which is found in the Mediterranean, has been used in Europe since the Middle Ages in folk medicine under the name fungus maletensis (maltese fungus). It was used for the same purpose in Arabic cultures under the name tarthuth. The Asian species (Cynomorium songaricum), sometimes considered a subspecies of C. coccineum, is still used in traditional Chinese medicine under the name Suo Yang. Recent studies show that the plant has a number of beneficial effects on the body and there is a real possibility that the substances present in Suo Yang or substances derived therefrom will be used in the future for therapeutic purposes. Of particular interest are their effects on sexual function. Preclinical experiments in male rats showed an increase in fertility after administration of Cynomorium extract. In these tests, an increase in the weight of the testes and an increase in the number of spermatozoa and their viability were observed. Cynomorium plants offer a new approach to the treatment of human infertility, which is currently a major problem.


Introduction
The use of medicinal plants has accompanied mankind throughout its history. Fragments of some medicinal plants (Ephedra, Althaea, Achillea) were found even in the 60,000-year-old settlements of Neanderthals. Cannabis has been used in China 8,000 years ago and in Mesopotamia, poppy has been used at least 4,500 years ago. The Egyptian Ebers Papyrus, which dates back to 1,550 BC, lists a number of medicinal plants that were used at that time (Tyler, 2000;Samuelsson and Bohlin, 2010). Also nowadays, substances from plants and substances derived from them are of a great importance as medicines for many diseases. Some natural substances may be used directly, others serve as precursors for the production of other semi-synthetic bioactive substances. Also interesting is the possibility of using the known chemical structure of a natural substance as an inspiration in the development of new

Ethnobotany
Cynomorium plants have long been used for medicinal purposes. In Europe they were used in the Middle Ages under the name fungus maletensis (Maltese mushroom) according to a well-known site on a rocky cliff near the Maltese island of Gozo (Gebla tal-General, General's Rock, now Fungus Rock). The reef is poorly accessible, about 60 m high and 180 m long (Lebling, 2003) (Fig. 2). The rarity and mystical nature of the plant has led people to attribute special power to it. Based on the signature theory, the plant was attributed to a phallic shape to help treat sexual problems. This property, together with its extraordinary rarity, made it highly valued (Attenborough, 1995). Knights of St. John of Jerusalem, they knew the plant already from Jerusalem. When they were forced to leave Jerusalem in the 16 th century, they resorted to Malta and found Cynomorium on Fungus Rock. He was then closely guarded by soldiers and the thieves awaited severe punishment (sent to galleys and death). In 1651, the Dwejra Tower was built to protect the reef with its growing Cynomorium. Knights Hospitaller used dried inflorescences to stop bleeding, prevent infections and to regenerate after combat (Leonti et al., 2020). The plant was also used to treat stomach problems, dysenteria, diarrhoea, hemorrhoids and as an aphrodisiac. Dried inflorescences were sent as a valuable gift to European kings, queens and nobility (Attenborough, 1995;Lebling, 2003;Patocka et al., 2010). Carl von Linné (1755) also mentions the plant. The plant also played a very important role in Arab countries, where it was used under the name tarthuth, for example, to treat high pressure, vomiting, colic, stomach ulcers, irregular menstruation, impotence, infertility and venereal diseases. In addition, Cynomorium has been used for food, as a spice and as a fabric coloring agent (Lebling, 2003;Nickrent et al., 2005; Heide-Jørgensen, 2008). C. songaricum had an important position in traditional Chinese medicine. Under the name Suo Yang, it has been used as a tonic and for the treatment of kidney diseases, digestion and impotence (Lebling, 2003;Nickrent et al., 2005;Wu et al., 2007). For medical reasons the interest in recent years seems to have increased again, and measures must be taken to protect it (Heide-Jørgensen, 2008). The pharmacologically most important can be considered.

Saccharides, Polysaccharides and other Sugar Derivatives
Glucose (Tao et al., 1999), sucrose  Extract of fresh C. coccineum plant has a hypotensive effect, the active ingredient has not been identified (Ikram et al., 1978). Orally administered Cynomorium songaricum extract to ovariectomized rats had a learning and memory enhancing effect in the Morris water maze assay and its effect was probably exerted by p-CREB / BDNF mediated ERK / p38MAPK regulative (Tian et al., 2019). In vitro, Cynomorium songaricum extracts protect human neuroblastoma cells from β-amyloid and superoxide anion induced injury . They also prevent damage to nerve and muscle cells during hypoxia, increase superoxide dismutase activity and reduce malonylaldehyde and lactic acid content in nervous cells. They also affect the protein content of muscle cells (Luo et al., 2007). The extract also improves the learning process and memory (Zhao et al., 2002). In perimenopausal rats, Cynomorium flavonoids attenuate depressive symptoms (Miao at al., 2017). C. songaricum ingredients enhance humoral and nonspecific immunity in mice after cyclophosphamide immunusuppression (Zhang et al., 2008). Very interesting are the effects on the genital system. Cynomorium songaricum extract enhances spermatogenesis and expression of GDNF (a factor secreted by Sertoli cells that induces proliferation of undifferentiated spermatogonia). In an experiment in rats, an increase in sperm count and testicular weight was observed when administering the extract (Yang et al. A randomized, double-blind, placebo-controlled crossover study of Cappra® for the treatment of mild or mild to moderate erectile dysfunction in Thai male was provided. Cappra® is a herbal medicine which consists of 13 Chinese herbs including Cynomorium songaricum. The efficacy was assessed by the International Index of Erectile Function (IIEF) questionnaire and adverse events. There was an improvement of IIEF score for all domains in Cappra® group compared with placebo group. The mean change of IIEF score from baseline for erectile function domain of Cappra® was significantly higher than placebo (4.87 vs. 3.44, p = 0.032) (Punyawudho et al., 2012).
A major problem for many developed countries is the steady decline in birth rates, which is due to a number of factors. An important cause is the rise of male infertility, the main cause of which is the inability to produce enough healthy sperm (Krausz, 2011). Cynomorium resp. the ingredients of this plant, with their positive effect on spermatogenesis, present a challenge for contemporary medicine, which is not yet very successful in the treatment of male infertility.

Toxicity
Acute toxicity, genetic toxicity and the 90-day repeated oral toxicity of C. songaricum (Suo Yang) have been studied in mice . The acute toxicity test revealed no unusual behavior or increased animal mortality. It has been found that the maximum tolerable dose of this herbal preparation is greater than 15 g/kg. No toxicity effects were observed in three genotoxicity studies. For genotoxicity testing, a bacterial reverse mutation assay, a mouse micronucleus bone marrow assay and a chromosomal spermatocyte aberration assay were used. No increased micronucleus frequencies or structural abnormalities of spermatocyte chromosomes were found in in vivo assays. In a 90-day subchronic oral toxicity study in Wistar rats, no haematological changes were observed, nor were any significant toxicological manifestations in the clinical investigation. The NOAEL was 2.83 g/kg of body weight and LOAEL was 5.66 g/kg of body weight (Fu et al., 2019). All of these results suggest that Suo Yang at a given dose is a safe herbal remedy.

Perspectives and Conclusions
Scientific research into new safe and effective drugs has recently rediscovered natural substances as a huge reservoir of innovative therapeutic agents for human health. Relatively recently, several research groups have begun to seek confirmation of the effect of some traditional treatments with natural substances and to study their previously unknown biological activities (Zucca et al., 2019). Recent animal studies show that the substances of C. coccineum and C. songaricum have a number of interesting effects on the body. Numerous studies have confirmed the empirical knowledge gained over thousands of years of use of these plants. Further research is therefore perspective and their use in the future can be expected. Abroad, dietary supplements containing plant extracts for the treatment of sexual dysfunctions are on the market. It is not clear how many active substances these preparations contain (if any). Experiments Griffin et al. (2017) provided initial evidence for the direct production of high-quality Cynomorium nanoparticles with preserved biological activity. This may be more convenient and much cheaper for the preparation of medicaments than the time-consuming extraction, separation and isolation of individual biologically active compounds. What is certain, however, is the need to develop cultivation techniques for the cultivation of these plants. The cultivation of parasitic plants is problematic, but their excessive collection in the wild threatens to eventually kill of them (Nickrent et al., 2005). Once an extinct species is lost forever (evolution does not repeat), it is important to preserve not only these species for the future.

Funding
This work was supported from Institutional support for a long-term conceptual project of the University Hospital Hradec Králové, Czech Republic. The authors thank Mgr. Michal Duchacek and Mgr. Elena Rimekova for unique photos.