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Purpose The objective was to investigate the metabolic fate of phytosteryl/-stanyl fatty acid and ferulic acid esters upon consumption by healthy humans. Methods A capillary gas chromatographic methodology was employed to follow a randomized, single-blind three group crossover clinical trial and to quantify simultaneously individual intact esters, liberated phytosterols/-stanols and their metabolites in feces. Skimmed milk drinking yogurts enriched with complex mixtures of phytosteryl/-stanyl fatty acid esters and ferulates, respectively, were employed as food carriers. Results On average, 73 % of total plant stanyl fatty acid esters and 80 % of total plant steryl fatty acid esters were hydrolyzed. Among the individuals, the hydrolysis rates ranged from 40 to 96 %. In addition, there were subject-dependent discrepancies between the amounts of phytosterols/-stanols actually determined in the feces and the calculated hydrolysis rates. On average, 69 % of the amounts of sterols/stanols expected from the amounts of remaining intact esters were found. Conclusions The study revealed large interindividual variability regarding the recoveries of dietary phytosteryl/-stanyl esters upon gastrointestinal passage in healthy humans. Nevertheless, there was a significant impact of the acid moiety (oleate = linoleate = linolenate > eicosanoate > palmitate > ferulate) on the hydrolysis rates; the influence of the phytosterol/-stanol moiety was less pronounced.

Sterols play important structural and regulatory roles in numerous intracellular processes. Unlike animals, plants contain a distinctive and diverse variety of sterols. Recently, information has emerged showing that stigmasterol is a “stress sterol”. Stigmasterol is synthesized via the mevalonate biosynthesis pathway and has structural similarity to β-sitosterol but differs in the presence of a trans-oriented double bond in the side chain. In plants, the accumulation of stigmasterol has been observed in response to various stresses. However, the precise ways that stigmasterol is involved in the stress responses of plants remain unclear. This comprehensive review provides an update on the biology of stigmasterol, particularly the physicochemical properties of this ethylsterol, its biosynthesis, and its occurrence in higher plants and extremophilic organisms, e.g., mosses and lichens. Special emphasis is given to the evolutionary aspects of stigmasterol biosynthesis, particularly the variations in the gene structure of C22-sterol desaturase, which catalyzes the formation of stigmasterol from β-sitosterol, in a diversity of evolutionarily distant organisms. The roles of stigmasterol in the tolerance of plants to hostile environments and the prospects for its biomedical applications are also discussed. Taken together, the available data suggest that stigmasterol plays important roles in plant metabolism, although in some aspects, it remains an enigmatic compound.

Through bioassay-guided fractionation, the EtOAc extract of a culture broth of the endophytic fungus Phoma species ZJWCF006 in Arisaema erubescens afforded a new α-tetralone derivative, (3S)-3,6,7-trihydroxy-α-tetralone (1), together with cercosporamide (2), β-sitosterol (3), and trichodermin (4). The structures of compounds were established on the basis of spectroscopic analyses. Compounds 1, 2, and 3 were obtained from Phoma species for the first time. Additionally, the compounds were subjected to bioactivity assays, including antimicrobial activity, against four plant pathogenic fungi (Fusarium oxysporium, Rhizoctonia solani, Colletotrichum gloeosporioides, and Magnaporthe oryzae) and two plant pathogenic bacteria (Xanthomonas campestris and Xanthomonas oryzae), as well as in vitro antitumor activities against HT-29, SMMC-772, MCF-7, HL-60, MGC80-3, and P388 cell lines. Compound 1 showed growth inhibition against F. oxysporium and R. solani with EC^sub 50^ values of 413.22 and 48.5 μg/mL, respectively. Additionally, compound 1 showed no cytotoxicity, whereas compound 2 exhibited cytotoxic activity against the six tumor cell lines tested, with IC^sub 50^ values of 9.3±2.8, 27.87±1.78, 48.79±2.56, 37.57±1.65, 27.83±0.48, and 30.37±0.28 μM, respectively. We conclude that endophytic Phoma are promising sources of natural bioactive and novel metabolites. [PUBLICATION ABSTRACT]

Tomato (Solanum lycopersicum) produces a wide range of volatile chemicals during fruit ripening, generating a distinct aroma and contributing to the overall flavor. Among these volatiles are several aromatic and aliphatic nitrogen-containing compounds for which the biosynthetic pathways are not known. While nitrogenous volatiles are abundant in tomato fruit, their content in fruits of the closely related species of the tomato clade is highly variable. For example, the green-fruited species Solanum pennellii are nearly devoid, while the red-fruited species S. lycopersicum and Solanum pimpinellifolium accumulate high amounts. Using an introgression population derived from S. pennellii, we identified a locus essential for the production of all the detectable nitrogenous volatiles in tomato fruit. Silencing of the underlying gene (SlTNH1;Solyc12g013690) in transgenic plants abolished production of aliphatic and aromatic nitrogenous volatiles in ripe fruit, and metabolomic analysis of these fruit revealed the accumulation of 2-isobutyl-tetrahydrothiazolidine-4-carboxylic acid, a known conjugate of cysteine and 3-methylbutanal. Biosynthetic incorporation of stable isotope-labeled precursors into 2-isobutylthiazole and 2-phenylacetonitrile confirmed that cysteine provides the nitrogen atom for all nitrogenous volatiles in tomato fruit. Nicotiana benthamiana plants expressing SlTNH1 readily transformed synthetic 2-substituted tetrahydrothiazolidine-4-carboxylic acid substrates into a mixture of the corresponding 2-substituted oxime, nitro, and nitrile volatiles. Distinct from other known flavin-dependent monooxygenase enzymes in plants, this tetrahydrothiazolidine- 4-carboxylic acid N-hydroxylase catalyzes sequential hydroxylations. Elucidation of this pathway is a major step forward in understanding and ultimately improving tomato flavor quality.

β-sitosterol (BS) could act as an important plant growth regulator when plants are subjected to harsh environmental conditions. Objective of this study was to examine effects of BS on growth and water stress tolerance in white clover based on physiological responses and metabolomics. White clover was pretreated with or without BS and then subjected to water stress for 7 days in controlled growth chambers. Physiological analysis demonstrated that exogenous application of BS (120 µM) could significantly improve stress tolerance associated with better growth performance and photosynthesis, higher leaf relative water content, and less oxidative damage in white clover in response to water stress. Metabolic profiling identified 78 core metabolites involved in amino acids, organic acids, sugars, sugar alcohols, and other metabolites in leaves of white clover. For sugars and sugar alcohol metabolism, the BS treatment enhanced the accumulation of fructose, glucose, maltose, and myo-inositol contributing to better antioxidant capacity, growth maintenance, and osmotic adjustment in white clover under water stress. The application of BS was inclined to convert glutamic acid into proline, 5-oxoproline, and chlorophyll instead of going to pyruvate and alanine; the BS treatment did not significantly affect intermediates of tricarboxylic acid cycle (citrate, aconitate, and malate), but promoted the accumulation of other organic acids including lactic acid, glycolic acid, glyceric acid, shikimic acid, galacturonic acid, and quinic acid in white clover subjected to water stress. In addition, cysteine, an important antioxidant metabolite, was also significantly improved by BS in white clover under water stress. These altered amino acids and organic acids metabolism could play important roles in growth maintenance and modulation of osmotic and redox balance against water stress in white clover. Current findings provide a new insight into BS-induced metabolic homeostasis related to growth and water stress tolerance in plants.

Epithelial Ovarian Cancer (EOC) presents a global health concern, necessitating the development of innovative therapeutic strategies to combat its impact. This study was employed to investigate the unexplored therapeutic efficacy of Cynodon dactylon phytochemicals against EOC using a multifaceted computational approach. A total of 19 out of 89 rigorously curated phytochemicals were assessed as potential drug targets via ADMET profiling, while protein-protein interaction analysis scrutinized the top 20 hub genes among 264 disease targets, revealing their involvement in cancer-related pathways and underscoring their significance in EOC pathogenesis. In molecular docking, Stigmasterol acetate showed the highest binding affinity (−10.9 kcal/mol) with Poly [ADP-ribose] polymerase-1 (PDB: 1UK1), while Arundoin and Beta-Sitosterol exhibited strong affinities (−10.4 kcal/mol and −10.1 kcal/mol, respectively); additionally, Beta-Sitosterol interacting with Mitogen-activated protein kinase 3 (PDB: 4QTB) showed a binding affinity of −10.1 kcal/mol, forming 2 hydrogen bonds and a total of 10 bonds with 10 residues. Molecular dynamics simulations exhibited the significant structural stability of the Beta-Sitosterol-4QTB complex with superior binding free energy (−36.61 kcal/mol) among the three complexes. This study identified C. dactylon phytosterols, particularly Beta-Sitosterol, as effective in targeting MAPK3 and PARP1 to combat EOC, laying the groundwork for further experimental validation and drug development efforts.

Pneumolysin is one of the major virulence factors elaborated by Streptococcus pneumoniae ; this toxin is a member of the cholesterol-dependent cytolysins. Engagement of cholesterol induces the formation of a multi-subunit complex by pneumolysin that lyses host cells by forming pores on the membrane. Because pneumolysin released by bacteria which have been killed by conventional antibiotics is still active, agents capable of directly attacking the toxin are considered advantageous against antimicrobials in the treatment of S. pneumoniae infections. Here we found that the phytosterol, β-sitosterol, effectively protects against cell lysis caused by pneumolysin. This compound interacts with the toxin at Thr459 and Leu460, two sites important for being recognized by its natural ligand, cholesterol. Similar to cholesterol, β-sitosterol induces pneumolysin oligomerization. This compound also protects cells from damage by other cholesterol-dependent toxins. Finally, this compound protects mice against S. pneumoniae infection. Thus, β-sitosterol is a candidate for the development of anti-virulence agents against pathogens that rely on cholesterol-dependent toxins for successful infections.

Hydrolysis of phytosterol ester (PSTE) and phytostanol ester (PSTA) during fat digestion is not well characterised under controlled dietary conditions. The main aims of this study were therefore to quantify the PSTE and PSTA hydrolysis after gut passage and to assess whether or not PSTE and PSTA induce fat malabsorption by measuring the fatty acid excretion following PSTE/PSTA consumption. Ileostomy subjects (n = 7) were investigated in a randomised crossover study with one control and two intervention periods, when either 2.5 g of PSTE or PSTA corresponding to 1.5 g free sterol or stanol equivalents were added to a controlled diet. Ileostomy bags were collected and immediately frozen for analysis of nutrients, fatty acids and sterols. The study showed that 88.4 +/- 5.9% PSTE and 85.7 +/- 6.5% PSTA were hydrolysed following small bowel passage in the ileostomy subjects. The total excretion of fatty acids was similar in all three periods. A majority of the 2.5 g PSTE and PSTA was hydrolysed during small bowel passage,which did not affect fat absorption as indicated by similar excretions of fatty acids in all periods. Consumption of increasing amounts of esterified phytosterols and phytostanols from enriched food formats should thereby have no adverse effects in this regard.

Ebola virus disease (EVD) is an acute life-threatening disease caused by highly pathogenic Ebolavirus (EBOV), with reported case fatality rates reaching 90%. There have been numerous EBOV outbreaks and epidemics since the first outbreak was reported in Africa in 1976. Despite the approval of three vaccines and two monoclonal antibody therapies by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of EVD the urgent need for alternative therapeutic strategies persists. In the present study, we screened a library of 235 phytocompounds derived from Azadirachta indica against the key EBOV viral protein 24 (VP24), VP30, VP35 and VP40 through a random forest-based machine learning model with an accuracy of 84.5%. Initially, 48 compounds were identified as active, and subsequent toxicity assessment refined the selection to a promising candidate, daucosterol. Molecular docking studies indicated that daucosterol exhibited significant binding affinity to all four viral proteins. Subsequent validation through molecular dynamics simulations confirmed the stability of daucosterol protein complexes. These results imply that daucosterol acts as a potential multitarget inhibitor against EBOV proteins and could serve as a promising lead compound for future therapeutic development against EVD.

Plant-parasitic nematodes ingest and convert host phytosterols via dealkylation to cholesterol for both structural and hormonal requirements. The insect 24-dehydrocholesterol reductase (DHCR24) was shown in vitro as a committed enzyme in the dealkylation via chemical blocking. However, an increased brood size and ovulation rate, instead compromised development, were observed in the engineered nematode Caenorhabditis elegans where the DHCR24 gene was knocked down, indicating the relationship between DHCR24 and dealkylation and their function in nematodes remains illusive. In this study, a defect in C. elegans DHCR24 causes impaired growth of the nematode with sitosterol (a major component of phytosterols) as a sole sterol source. Plant sterols with rationally designed structure (null substrates for dealkylation) can’t be converted to cholesterol in wild-type worms, and their development was completely halted. This study underpins the essential function of DHCR24 in nematodes and would be beneficial for the development of novel nematocidal strategies.