The defensive secretions of some chrysomelid beetles belonging to the genera Chrysolina, Chrysochloa, and Dlochrysa contain complex mixtures of cardenolides. The spectral data for some of these compounds suggest that they are monohydroxylated digitoxigenin derivatives linked to a pentose (such as xylose or arabinose). Evidence indicates that the beetles do not sequester these steroid glycosides from their host plants.

• Pasteels JM, Daloze D. Cardiac glycosides in the defensive secretion of chrysomelid beetles: evidence for their production by the insects. Science. 1977 Jul 1;197(4298):70-2. doi: 10.1126/science.867051. PMID: 867051.

The book Biosynthesis in Insects has a figure with the caption: Cardiac glycosides containing xylose made by the beetle Chrysolina coerulans by cholesterol.

• Morgan, E. David (2004). “§ 7.3.1 Sterols in Insects”. Biosynthesis in Insects. Royal Society of Chemistry. p. 112. ISBN 9780854046911.

Ecdysteroids and receptors

Ecdysteroids are arthropod steroid hormones that are mainly responsible for molting, development and, to a lesser extent, reproduction; examples of ecdysteroids include ecdysone, ecdysterone, turkesterone and 2-deoxyecdysone. These compounds are synthesized in arthropods from dietary cholesterol upon metabolism by the Halloween family of cytochrome P450s. Phytoecdysteroids also appear in many plants mostly as a protection agents (toxins or antifeedants) against herbivore insects.

• de Loof A (2006). “Ecdysteroids: the overlooked sex steroids of insects? Males: the black box”. Insect Science. 13 (5): 325–338. doi:10.1111/j.1744-7917.2006.00101.x. S2CID 221810929. 
• Krishnakumaran A, Schneiderman HA (December 1970). “Control of molting in mandibulate and chelicerate arthropods by ecdysones”. The Biological Bulletin. 139 (3): 520–538. doi:10.2307/1540371. JSTOR 1540371. PMID 5494238.
• Margam VM, Gelman DB, Palli SR (June 2006). “Ecdysteroid titers and developmental expression of ecdysteroid-regulated genes during metamorphosis of the yellow fever mosquito, Aedes aegypti (Diptera: Culicidae)”. Journal of Insect Physiology. 52 (6): 558–568. doi:10.1016/j.jinsphys.2006.02.003. PMID 16580015.
• “Ecdysteroids Information”. Examine.com. Retrieved 27 May 2015.
• Mykles DL (November 2011). “Ecdysteroid metabolism in crustaceans”. The Journal of Steroid Biochemistry and Molecular Biology. 127 (3–5): 196–203. doi:10.1016/j.jsbmb.2010.09.001. PMID 20837145. S2CID 23942645.
• Dinan L (June 2001). “Phytoecdysteroids: biological aspects”. Phytochemistry. 57 (3): 325–339. doi:10.1016/S0031-9422(01)00078-4. PMID 11393511.
• Dinan L, Savchenko T, Whiting P (July 2001). “On the distribution of phytoecdysteroids in plants”. Cellular and Molecular Life Sciences. 58 (8): 1121–1132. doi:10.1007/PL00000926. PMID 11529504. S2CID 8496934.

Ecdysterone has been tested on mammals due to the interest in its potential hypertrophic effect. It has been found to increase hypertrophy in rats at a similar level to some anabolic androgenic steroids and SARM S 1. This is proposed to be through increase of Calcium leading to activation of Akt and protein synthesis in skeletal muscles.

• Parr MK, Botrè F, Naß A, Hengevoss J, Diel P, Wolber G (June 2015). “Ecdysteroids: A novel class of anabolic agents?”. Biology of Sport. 32 (2): 169–173. doi:10.5604/20831862.1144420. PMC 4447764. PMID 26060342.
• Gorelick-Feldman J, Cohick W, Raskin I (October 2010). “Ecdysteroids elicit a rapid Ca2+ flux leading to Akt activation and increased protein synthesis in skeletal muscle cells”. Steroids. 75 (10): 632–637. doi:10.1016/j.steroids.2010.03.008. PMC 3815456. PMID 20363237.

The ecdysone receptor is a nuclear receptor found in arthropods, where it controls development and contributes to other processes such as reproduction. The receptor is a non-covalent heterodimer of two proteins, the EcR protein and ultraspiracle protein (USP). It binds to and is activated by ecdysteroids. Insect ecdysone receptors are currently better characterized than those from other arthropods, and mimics of ecdysteroids are used commercially as caterpillar-selective insecticides.

The receptor is a non-covalent heterodimer of two proteins, the EcR protein and ultraspiracle protein (USP). These nuclear hormone receptor proteins are the insect orthologs of the mammalian farnesoid X receptor (FXR) and retinoid X receptor (RXR) proteins, respectively.

The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a nuclear receptor that is encoded by the NR1H4 gene in humans.

• “Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4”.
• Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C (Jun 1995). “Identification of a nuclear receptor that is activated by farnesol metabolites”. Cell. 81 (5): 687–93. doi:10.1016/0092-8674(95)90530-8. PMID 7774010.

The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which is likely to be the major endogenous mammalian RXR-selective agonist.

1. Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006). “International Union of Pharmacology. LXIII. Retinoid X receptors”. Pharmacol Rev. 58 (4): 760–72. doi:10.1124/pr.58.4.7. PMID 17132853. S2CID 1476000.
2. de Lera AR, Krezel W, Rühl R (2016). “An Endogenous Mammalian Retinoid X Receptor Ligand, At Last!”. ChemMedChem. 11 (10): 1–12. doi:10.1002/cmdc.201600105. PMID 27151148. S2CID 269196.
3. Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P, Levin AA (1993). “Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids”. Proc Natl Acad Sci USA. 90 (1): 30–4. Bibcode:1993PNAS…90…30A. doi:10.1073/pnas.90.1.30. PMC 45593. PMID 8380496.
4. Rühl R, Krzyżosiak A, Niewiadomska-Cimicka A, Rochel N, Szeles L, Vaz B, Wietrzych-Schindler M, Álvarez S, Szklenar M, Nagy L, de Lera AR, Krężel W (2015). “9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice”. PLOS Genetics. 11 (6): e1005213. doi:10.1371/journal.pgen.1005213. PMC 4451509. PMID 26030625.

Based on sequence homology considerations, some researchers reserve the term USP for the EcR partner from lepidopteran and dipteran insects, and use RXR in all other instances.

• Hayward DC, Bastiani MJ, Trueman JW, Truman JW, Riddiford LM, Ball EE (September 1999). “The sequence of Locusta RXR, homologous to Drosophila Ultraspiracle, and its evolutionary implications”. Dev. Genes Evol. 209 (9): 564–71. doi:10.1007/s004270050290. PMID 10502114. S2CID 8703952.

Toxicity of cardiac glycosides

From ancient times, humans have used cardiac-glycoside-containing plants and their crude extracts as arrow coatings, homicidal or suicidal aids, rat poisons, heart tonics, diuretics and emetics, primarily due to the toxic nature of these compounds.

• “Cardiac Glycoside Plant Poisoning: Practice Essentials, Pathophysiology, Etiology”. 2017-05-05.

Thus, though cardiac glycosides have been used for their medicinal function, their toxicity must also be recognized. For example, in 2008 US poison centers reported 2,632 cases of digoxin toxicity, and 17 cases of digoxin-related deaths.

• Bronstein AC, Spyker DA, Cantilena LR, Green JL, Rumack BH, Giffin SL (December 2009). “2008 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 26th Annual Report”. Clinical Toxicology. 47 (10): 911–1084. doi:10.3109/15563650903438566. PMID 20028214.

Because cardiac glycosides affect the cardiovascular, neurologic, and gastrointestinal systems, these three systems can be used to determine the effects of toxicity. The effect of these compounds on the cardiovascular system presents a reason for concern, as they can directly affect the function of the heart through their inotropic and chronotropic effects. In terms of inotropic activity, excessive cardiac glycoside dosage results in cardiac contractions with greater force, as further calcium is released from the SR of cardiac muscle cells.

Toxicity also results in changes to heart chronotropic activity, resulting in multiple kinds of dysrhythmia and potentially fatal ventricular tachycardia. These dysrhythmias are an effect of an influx of sodium and decrease of resting membrane potential threshold in cardiac muscle cells.

When taken beyond a narrow dosage range specific to each particular cardiac glycoside, these compounds can rapidly become dangerous. In sum, they interfere with fundamental processes that regulate membrane potential.

They are toxic to the heart, the brain, and the gut at doses that are not difficult to reach.

In the heart, the most common negative effect is premature ventricular contraction.

• “Cardiac Glycoside Plant Poisoning: Practice Essentials, Pathophysiology, Etiology”. 2017-05-05.
• Kanji S, MacLean RD (October 2012). “Cardiac glycoside toxicity: more than 200 years and counting”. Critical Care Clinics. 28 (4): 527–535. doi:10.1016/j.ccc.2012.07.005. PMID 22998989.