Codiaeum variegatum (L.) Rumph. ex A. Juss. (Euphorbiaceae): An overview of its botanical diversity, traditional uses, phytochemistry, pharmacological effects and perspectives towards developing its plant-based products.

ETHNOPHARMACOLOGICAL RELEVANCE: Codiaeum variegatum also called miracle shrub, is a plant species constituted of more than 300 cultivars which are mostly used as indoor plants for decoration. However, some of these varieties are used by indigenous populations for the treatment of diarrhoea, stomach ache, external wounds, intestinal worms and ulcers. AIM OF THE STUDY: This study describes an overview of the botanical diversity, medicinal uses, phytochemical composition of C. variegatum. Then it critically discusses its pharmacological activities versus toxic potential and new perspectives are suggested for the development of its plant-based products. MATERIALS AND METHODS: A bibliographic assessment of publications on C. variegatum indexed in Google Scholar, PubMed, Science Direct, Scopus, Springer Link, and Web of Science online databases was conducted from 1970 to 2020, and 89 relevant articles related to the botanical diversity (17), traditional uses (22), phytochemical analysis (11), pharmacological activity (31) and toxicity profile (18) of C. variegatum were selected for this review. RESULTS: Most commonly, it was found that aqueous leaf extracts or decoctions of C. variegatum are used in traditional medicine to treat amoebic dysentery and stomach ache while a bath with root decoction or sap is applied in small quantities on skin related infections. A total of 14 identified and 24 non-identified varieties of C. variegatum were reported for pharmacological activity, and prominent research topics include the anti-amoebic, antimicrobial, antiviral and cytotoxic activities. Alkaloids (3), terpenoids (5) and phenolics (15) were the major compounds identified, and a new antiviral cyanoglucoside was isolated from the sap of C. variegatum. Toxic substances (5-deoxyingenol and phorbol esters) were found in some varieties used as ornamental plants, but the Mollucanum variety used in traditional medicine was found to be safe. CONCLUSION: The present review revealed that the native variety of C. variegatum (cv. Mollucanum) can be used to treat amoebic dysentery. Alkaloids, terpenoids and phenolic compounds have been characterized in this plant species while other classes of phytochemicals are not yet investigated. The development of new cultivars recommends an in-depth toxicological study before any use. No clinical trial has been reported to date, and further studies are needed to evaluate other claimed medicinal uses. Due to its efficacy and safety, the Mollucanum variety is most likely suitable for the development of a medicine against amoebiasis, which will surely lay the foundation for clinical studies.

Precursor-Directed Biosynthesis and Fluorescence Labeling of Clickable Microcystins.

Microcystins, cyclic nonribosomal heptapeptides, are the most well-known cyanobacterial toxins. They are exceptionally well studied, but open questions remain concerning their physiological role for the producing microorganism or their suitability as lead compounds for anticancer drug development. One means to study specialized metabolites in more detail is the introduction of functional groups that make a compound amenable for bioorthogonal, so-called click reactions. Although it was reported that microcystins cannot be derivatized by precursor-directed biosynthesis, we successfully used this approach to prepare clickable microcystins. Supplementing different azide- or terminal alkyne containing amino acid analogues into the cultivation medium of microcystin-producing cyanobacteria strains, we found that these strains differ strongly in their substrate acceptance. Exploiting this flexibility, we generated more than 40 different clickable microcystins. We conjugated one of these derivatives with a fluorogenic dye and showed that neither incorporation of the unnatural amino acid analogue nor attachment of the fluorescent label significantly affects the cytotoxicity against cell lines expressing the human organic anion transporting polypeptides 1B1 or 1B3. Using time-lapse microscopy, we observed that the fluorescent microcystin is rapidly taken up into eukaryotic cells expressing these transporters.

Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2.

In this study, the influence of halide ions on [7.7]paracyclophane biosynthesis in the cyanobacterium Nostoc sp. CAVN2 was investigated. In contrast to KI and KF, supplementation of the culture medium with KCl or KBr resulted not only in an increase of growth but also in an up-regulation of carbamidocyclophane production. LC-MS analysis indicated the presence of chlorinated, brominated, but also non-halogenated derivatives. In addition to 22 known cylindrocyclophanes and carbamidocyclophanes, 27 putative congeners have been detected. Nine compounds, carbamidocyclophanes M-U, were isolated, and their structural elucidation by 1D and 2D NMR experiments in combination with HRMS and ECD analysis revealed that they are brominated analogues of chlorinated carbamidocyclophanes. Quantification of the carbamidocyclophanes showed that chloride is the preferably utilized halide, but incorporation is reduced in the presence of bromide. Evaluation of the antibacterial activity of 30 [7.7]paracyclophanes and related derivatives against selected pathogenic Gram-positive and Gram-negative bacteria exhibited remarkable effects especially against methicillin- and vancomycin-resistant staphylococci and Mycobacterium tuberculosis. For deeper insights into the mechanisms of biosynthesis, the carbamidocyclophane biosynthetic gene cluster in Nostoc sp. CAVN2 was studied. The gene putatively coding for the carbamoyltransferase has been identified. Based on bioinformatic analyses, a possible biosynthetic assembly is discussed.

The pharmacological potential of mushrooms.

This review describes pharmacologically active compounds from mushrooms. Compounds and complex substances with antimicrobial, antiviral, antitumor, antiallergic, immunomodulating, anti-inflammatory, antiatherogenic, hypoglycemic, hepatoprotective and central activities are covered, focusing on the review of recent literature. The production of mushrooms or mushroom compounds is discussed briefly.