Active Compounds with Medicinal Potential Found in Maxillariinae Benth. (Orchidaceae Juss.) Representatives—A Review

Orchids are widely used in traditional medicine for the treatment of a whole range of different health conditions, and representatives of the Neotropical subtribe Maxillariinae are not an exception. They are utilized, for instance, for their spasmolytic and anti-inflammatory activities. In this work, we analyze the literature concerning the chemical composition of the plant extracts and secretions of this subtribe’s representatives published between 1991 and 2022. Maxillariinae is one of the biggest taxa within the orchid family; however, to date, only 19 species have been investigated in this regard and, as we report, they produce 62 semiochemicals of medical potential. The presented review is the first summary of biologically active compounds found in Maxillariinae.


Introduction
Subtribe Maxillariinae Benth. counting ca. 420 [1] to 750 taxa [2] is one of the richest species groups within the orchid family. It is also one of the most controversial since its taxonomy has been under ongoing discussion for the past 200 years. According to different authors, it has been divided into practically a single genus [3], through 17 [4,5] to 36 genera [6], with the genus Maxillaria Ruiz & Pav. always being the core of the subtribe. Its distribution range is exclusively Neotropical as it covers both Central and South America (with the Caribbean). A large number of taxa and a wide distribution range make Maxillariinae an important Neotropical flora compound and an excellent candidate for further phytochemical studies with potential commercial outcomes.
Studies conducted since the middle of the 20th century revealed a great diversity of labellar epidermis in many groups of orchids. The first attempts to investigate the micromorphological features in Maxillaria sensu lato were conducted in 1998 [7], and, since then, several dozen papers have been published (e.g., [8][9][10][11][12][13]). Glabrous labella are not common in Maxillaria and tend to occur mainly in species assigned to the M. cucullata alliance [14]. The labellar papillae and trichomes of Maxillaria show great diversity as they may be conical, obpyriform, villiform, fusiform, or clavate. Labellar papillae may contain protein, lipids, and starch. Many papillae contain pigment or act as osmophores, which may play a role in attracting insects. Some of them may have a protective role in preventing desiccation [14]. Papillae are largely responsible for the production of labellar secretions that may have different chemical compositions. These secretions may contain active compounds of potential medical importance.
While preparing the presented review we analyzed the literature published between 1991 and 2022 that concerned the chemical composition of extracts and labellar secretions produced by the Maxillariinae subtribe members. To date, only several species have been investigated in this regard: Brasiliorchis gracilis (G. Lodd.) R.B. Singer, S. Koehler & Carnevali [15] (Figure 1a), B. marginata (Lindl.) R.B. Singer, S. Koehler & Carnevali [15] ( Figure 1b,c), B. picta (Hook.) R.B. Singer S. Koehler & Carnevali [15][16][17][18] (Figure 1d) [27] (Figure 2f), Trigonidium obtusum Lindl. [15], Trigonidium cf. turbinatum Rchb. f. [15], and Xanthoxerampellia rufescens (Lindl.) Szlach. & Sitko [15,Lipińska & Haliński,unpbl. data] (Figure 3f) (classification sensu Szlachetko [6]).     Orchids are widely used in traditional medicine for the treatment of a whole range of different health conditions: skin issues, infectious diseases, digestive problems, respiratory issues, reproduction malfunctions, circulation and heart problems, tumors, pain, and fever. Indeed, throughout the ages, orchid extracts were attributed to some activities such as diuretic, anti-inflammatory, or antimicrobial. For example, Ecuadorian healers (los curanderos) use stem and flower extracts of Epidendrum secundum Jacq. to heal Orchids are widely used in traditional medicine for the treatment of a whole range of different health conditions: skin issues, infectious diseases, digestive problems, respiratory issues, reproduction malfunctions, circulation and heart problems, tumors, pain, and fever. Indeed, throughout the ages, orchid extracts were attributed to some activities such as diuretic, anti-inflammatory, or antimicrobial. For example, Ecuadorian healers (los curanderos) use stem and flower extracts of Epidendrum secundum Jacq. to heal nervous disorders and liver diseases [28]. Stanhopea anfracta Rolfe is utilized in treating cough and lung diseases thanks to the presence of eucalyptol in its flowers [28]. Some species are used as emetics, aphrodisiacs, vermifuges, bronchodilators, and sex stimulators or to treat scorpion stings and snake bites [29]. Representatives of Maxillaria sensu lato are not an exception and are also widely used in traditional medicine for instance for their antispasmodic and anti-inflammatory activities [30].
Within the compounds detected with the use of gas chromatography/mass spectrometry (GC-MS) and liquid chromatography/tandem mass spectrometry (LC-MS/MS) in the tissues of different Maxillariinae representatives (mainly lip secretions), several of them have already been investigated for their medicinal uses (see Table 1). The presented work aimed to summarize published data on semiochemicals that have therapeutic potential and that could be sourced from representatives of Maxillariinae. Additionally, we add information on examples of other sources of these substances (see Appendix A). We hope that this review will lead specialists in the field to design further studies to better understand and exploit orchids, especially Maxillariinae, as sources of biologically active compounds. Activity: antidiarrheal activity [31]; antimicrobial activity against Gram-positive and Gram-negative bacteria; antifungal activity [32].
Activity: antioxidative and antimicrobial activity [35,36]; beneficial effect on DSSinduced ulcerative colitis, usefulness in the regulation of chronic intestinal inflammation and effectiveness in the management of immune or inflammatory responses [37]; immunomodulating activities and suppressing effect on hepatic fibrosis in chronic liver injury [38]; neuroprotective agent in the treatment of vascular dementia and cerebrovascular insufficiency states, inflammation, and neurological diseases (e.g., Alzheimer's disease and Parkinson's Disease) [39]; significant α-glucosidase-inhibitory activity [26].
Activity: bacteriostatic and bactericidal properties against a variety of aerobic and anaerobic microorganisms; effective in the treatment of comedonal acne and inflammatory (papulopustular, nodular, and nodulocystic) acne, as well as various cutaneous hyperpigmentary disorders characterized by hyperactive/abnormal melanocyte function, including melasma and, possibly, lentigo maligna; antiproliferative and cytotoxic effect on the human malignant melanocyte; preliminary findings indicate that it may arrest the progression of cutaneous malignant melanoma [56].

4.
Tetradecanoic acid (Myristic acid; n-tetradecanoic acid; n-tetradecan-1-oic acid)  [25]. Activity: antibacterial activity against Staphylococcus aureus; wound closure; collagen deposition; fibroblast proliferation effects; potency to be used as an active ingredient in the formulation of a diabetic wound-healing cream [75]; positive effect on the skin wound healing process; inhibition of ethanol-induced mucosal ulceration based on antioxidant activity; diminishing inflammation; upregulation of Hsp70 and downregulation of Bax protein in skin and stomach tissue; support collagen synthesis in skin tissue and mucus production in the stomach [76].
Activity: potential as an antifungal agent against a wide spectrum of fungal species frequently implicated in human mycoses, particularly candidiasis, cryptococcosis, and dermatophytosis [86].
Activity: dehumidification, insecticide, and analgesia activity [95]; attenuation of ceruleininduced acute pancreatitis via an anti-inflammatory mechanism and by combating oxidative stress [96]; anti-inflammatory and antioxidant activity mainly via the regulation of NF-κB and Nrf2, an important role in the treatment of cardiovascular illness, cancers, digestive disorders, Alzheimer's disease (AD); respiratory ailments such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD); bacilli ( [97] and references therein).
Activity: inhibition of tumor cell growth [121]; anti-inflammatory properties; potential in the treatment of asthma and related inflammatory and allergic diseases ([122] and references therein); inhibition of the growth of Bacteroides fragilis cells and biofilms [123]; antitumor and cytotoxic activity against cancer cells; effective against a wide range of microorganisms, in addition to acting as anti-inflammatories by activating or inactivating several factors involved in the inflammatory process; gastroprotective, cicatrizing, analgesic, and antioxidant potentials [124].
Activity: steroidal anti-mineralocorticoid activity and anti-androgen, weak progesterone properties, with some indirect estrogen and glucocorticoid effects [155]; used primarily as a diuretic and antihypertensive, to treat heart failure and ascites in patients with liver disease, lowering hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn's syndrome (primary hyperaldosteronism); frequently used to treat a variety of skin conditions including hirsutism, androgenic alopecia, acne, and seborrhea in females and male pattern baldness [156]; antioxidant activity; acetylcholinesterase inhibitory potential [157].

Conclusions
In the presented paper, on the basis of a literature review, we reported the presence of 62 biologically active compounds produced by Maxillariinae representatives. We divided them into 12 categories: aldehydes (one), aromatics (eight), carboxylic acids (four), fatty acids and their esters (five), hydrocarbons (two), ketones (two), monoterpenes (10), sesquiterpenes (15), phenanthrene derivatives (six), phenol derivatives (three), sterols (two), and others (four). Even though the number of species examined to date is extremely scarce (19 species investigated of ca. 600 belonging to the subtribe), it can already be noted that Maxillariinae representatives are a promising source of biologically active compounds with medical potential, and further investigations are urgently needed.