Biologically-Guided Isolation of Natural Lead Antithyroid Drug from Medicago sativa L. Sprouts and Its Toxic Profile in Comparison with Propylthiouracil

Abstract

Hyperthyroidism is a common endocrine disorder associated with increased risk of cardiovascular complications and mortality. Although antithyroid drugs (ATDs) are approved as first line option for many hyperthyroidism cases, including pregnancy and childhood, they exert significant toxic profile. Medicago sativa L. (alfalfa) also called "The father of all food" was among the diet consumed by mares that gave birth to foals with congenital hypothyroidism. Since, greenfeed was accused for the development of such condition, alfalfa may possess constituents with promising antithyroid potential that could be a valuable substitute for the conventional ATDs. The current work was designed to identify the most biologically active antithyroid phytoconstituent separated from alfalfa sprouts and comparing its antithyroid mechanism, efficacy and toxic profile to the standard ATD; propylthiouracil (PTU). The most biologically active solvent fractions from alfalfa sprouts extract were identified by in vitro screening for anti-thyroid peroxidase (TPO) activity, from which different phytoconstituents were separated and identified by interpretation of spectroscopic data. These compounds were then in vitro screened for anti-TPO and virtually screened via GLIDE XP docking into the crystal structures of the enzymes; bovine lactoperoxidase, as an alternative to TPO, and mammalian selenocysteinedependent iodothyronine deiodinase (IDI), that are both uniquely dually prohibited by PTU. The compound that showed the least TPO IC 50 and highest combined docking XP score was elected for comparing its antithyroid mechanism, efficacy, tendency to reverse hyperthyroidism-triggered complications and toxicity to PTU using L-thyroxineinduced hyperthyroidism model in rats. Seven compounds (1e7) were isolated from the most biologically active fraction, whilst, compounds (4e7) were reported for the first time from alfalfa sprouts. Compound 5 (apigenin) showed the least TPO IC 50 and highest in-silico combined score, thus, apigenin was selected for further in-vivo investigations. Apigenin was found to more effectively interfere with type 1-IDI than with TPO in vivo. Apigenin therapy resulted in nearly euthyroid state, without incidence of hypothyroidism, thyroid hypertrophy, hepatotoxity or WBCs count reduction. In addition, apigenin, but not PTU, corrected hyperthyroidism-induced left ventricular hypertyrophy. Therefore, apigenin is a natural lead antithyroid drug that represents a possible safer alternative to conventional ATDs.

In Vitro and In Silico Anti-Picornavirus Triterpene Alkanoic Acid Ester from Saudi Collection of Rhazya stricta Decne

“…The empirical scoring function of the Glide-Dock program was used to create modeling scores. The 2D and 3D ligand-target protein interactions as ion pairs, hydrogen bonds, and hydrophobic interactions have been demonstrated in the Maestro interface to investigate their most preferred binding modes [ 21 , 22 ].…”

“…The empirical scoring function of the Glide-Dock program was used to create modeling scores. The 2D and 3D ligand-target protein interactions as ion pairs, hydrogen bonds, and hydrophobic interactions have been demonstrated in the Maestro interface to investigate their most preferred binding modes [21,22]. A) (1): White powder; IR (KBr) ν max/cm −1 1729 (C0), 3489 (OH); 1 H and 13 C NMR see Tables 1 and 2; HRESIMS [M+Na] + m/z: 703.6001 (calcd for C 46 H 80 O 3 +Na, 703.6005).…”

Comprehensive transcriptomic and metabolomic profiling reveals the differences between alfalfa sprouts germinated with or without light exposure

“…Alfalfa has been named "the father of all food" and "the queen of forages" since ancient times for its nutrient-dense contents and beneficial health effects (Ibrahim et al, 2020). For instance, apigenin, a substance extracted from alfalfa sprouts, can revert thyroid function in hyperthyroid rats back to normal (Ibrahim et al, 2020).…”

“…Alfalfa has been named "the father of all food" and "the queen of forages" since ancient times for its nutrient-dense contents and beneficial health effects (Ibrahim et al, 2020). For instance, apigenin, a substance extracted from alfalfa sprouts, can revert thyroid function in hyperthyroid rats back to normal (Ibrahim et al, 2020). Adding alfalfa sprouts to diets improved the fat and fatty acid contents, and phytochemical characteristics in rabbit meat (Dal Bosco et al, 2015), reducing the plasma cholesterol content in hen eggs (Mattioli et al, 2016).…”