research on plant sterol

The role of sterols in plant response to abiotic stress

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• Published: 10 July 2020
• Volume 19 , pages 1525–1538, ( 2020 )

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• Agata Rogowska   ORCID: orcid.org/0000-0002-7177-827X 1 &
• Anna Szakiel   ORCID: orcid.org/0000-0001-6963-0666 1  

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Sterols are integral components of the membrane lipid bilayer and they are involved in many processes occurring in plants, ranging from regulation of growth and development to stress resistance. Maintenance of membrane homeostasis represents one of the principal functions of sterols in plant cells. Plant cell membranes are important sites of perception of environmental abiotic factors, therefore, it can be surmised that sterols may play an important role in the plant stress response. The aim of this review was to discuss the most representative trends in recent studies regarding the role of sterols in plant defense reactions to environmental factors, such as UV radiation, cold and drought stress. Some correlations were observed between changes in the sterol profile, referring to the ratios of individual compounds (including 24-methyl/ethyl sterols and sitosterol/stigmasterol) as well as the relative proportions of conjugated sterols (ASGs, SGs and SEs) and the nature of the stress response. Diversity of sterols and their conjugated forms may allow sessile plants to adapt to environmental stress conditions.

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Introduction

Sterols are natural organic compounds belonging to the isoprenoid class which have diverse and essential functions in all eukaryotes. Together with glycerolipids and sphingolipids, sterols are structural components of cell membranes and contribute to maintaining their permeability and fluidity (Hartmann 1998 ; Clouse 2002 ). Sterols regulate acyl chain ordering, thereby sustaining and reinforcing the domain structure of cell membranes (Schaller 2004 ; Dufourc 2008 ). Some sterols also play a role in controlling the metabolic processes associated with membranes by forming special structures with sphingolipids, referred to as microdomains (also known as nanodomains or lipid rafts). Microdomains have been shown to increase the stability and activity of embedded protein complexes, and they are believed to play an important role in processes such as channel regulation, protein trafficking, signal transduction and plant-pathogen interactions (Dufourc 2008 ; Tapken and Murphy 2015 ). Thus, in addition to their membrane architectural function, sterols also affect the activity of integral membrane proteins, including enzymes, ion channels, receptors and components of signal transduction pathways such as ATPases (Clouse 2002 ; Schaller 2004 ). Metabolic and regulatory functions of sterols involve plant growth and development, cellular proliferation and differentiation. Sterols are the biosynthetic precursors of steroid hormones in various organisms, including brassinosteroids in higher plants. Due to their crucial role as components of cell membranes and their additional functions relating to fundamental metabolic and developmental processes, these compounds are classified as “primary” (or general) metabolites in plants. They have also been identified as important precursors of specialized metabolites, such as steroidal sapogenins, steroidal glycoalkaloids or cardenolides (Hartmann 1998 ; Moreau et al. 2002 ).

Considering all the manners in which sterols contribute to the maintenance of the homeostasis of cell membranes, it can be expected that sterols play an important role in plant response to stress, particularly abiotic stress factors. Environmental conditions such as UV radiation, low/high temperatures, salinity and drought might cause dramatic alterations in the physical state and chemical composition of plant cells (Hollósy 2002 ; Barrero-Sicilia et al. 2017 ; Kumar et al. 2018 ). Relative proportions of constituent lipid classes determine membrane fluidity and permeability. Alterations in these proportions, as well as changes in the saturation of the fatty acid residues of phospho- and glycolipids, lead to modifications in the physical and chemical properties of the membrane (Valitova et al. 2019 ). Abiotic stress factors significantly influence membrane composition, since membranes act as primary sensors of temperature and maintain selective permeability of the membrane to ions and other molecules (Örvar et al. 2000 ; Valitova et al. 2016 ). It is widely understood that sterols can affect the state of the membrane, not only by changes in their total content, but also by variations in their profile, specifically the composition ratios of compounds such as sitosterol and stigmasterol (Valitova et al. 2019 ; Aboobucker and Suza 2019 ).

Plant response to abiotic stress is complex and multi-leveled, including numerous mechanisms and activating a wide range of signaling pathways. Among various environmental impacts of global climate change, the effects of abiotic stress on plant growth, development and metabolism has attracted increasing attention. The aim of this review was to provide a representative overview of recent studies concerning the role of sterols in plant defense responses to abiotic stress. Numerous previous reports concerned the functions of sterols in the model plant Arabidopsis thaliana (Clouse 2002 ; Schaller 2004 ), which remains the species of choice for many types of molecular and metabolic studies (Darnet and Schaller 2019 ), however, an increasing number of studies have focused on economically important crops, such as barley ( Hordeum vulgare ) grapevine ( Vitis vinifera) , oat ( Avena sativa ), potato ( Solanum tuberosum ), rice ( Oryza sativa ), rye ( Secale cereale ), tomato ( Lycopersicon esculentum ) and wheat ( Triticum aestivum ). Moreover, some abiotic stress factors, particularly those which are reproducible under experimental conditions such as UV-irradiation, have been evaluated for their ability to increase the content of sterols or their specialized derivatives, steroidal saponins, in various medicinal plants and some algae.

Biosynthesis of sterols

Plant, fungal and animal cells differ in their content and diversity of sterols, a difference which originates during post-squalene sterol biosynthesis, primarily at the cyclization step of 2,3-oxidosqualene leading to lanosterol in fungi and mammals or cycloartenol in some protists and plants (Benveniste 2004 ; Darnet and Schaller 2019 ). Fungal and mammalian cells each contain one major sterol, namely ergosterol and cholesterol, respectively, whereas plants synthesize a complex mixture of sterols, with sitosterol, stigmasterol and campesterol being some of the most abundant compounds (Fig.  1 ). However, significant levels of cholesterol can also be found in some plants, such as in representatives of the Solanaceae family. It is uncertain why plants require a mixture of sterols rather than one unique compound as found in other organisms (Hartmann 1998 ). Nevertheless, it is possible that the fluctuations in the sterol composition, such as changes in the ratio of campesterol to sitosterol or of sitosterol to stigmasterol, may be essential for certain processes relating to plant growth and development, as well as processes involved in stress compensation (Schaeffer et al. 2001 ; Aboobucker and Suza 2019 ). Therefore, the diversity of sterols may be related to the broad spectrum of their vital functions in plants (Valitova et al. 2016 ).

Structures of the most common plant sterols, sitosterol, stigmasterol and campesterol (from left to right)

In addition to structural diversity of their carbon skeleton, sterols occur in plants in many forms, including steryl esters (SE), steryl glycosides (SG) and acyl steryl glycosides (ASG). The relative content and profile of conjugated sterols may vary among species and can change under different environmental conditions (Ferrer et al. 2017 ).

The sterol biosynthetic pathway in plants is a complex and multi-stage process, beginning with the initial step of acetate conversion to squalene, the common precursor of all sterols and triterpenoids, via the mevalonic acid pathway (MVA). This is followed by cyclization of the oxidized linear precursor (2,3-oxidosqualene) into cycloartenol and further transformations of this into various end products. Major enzymes involved in post-oxidosqualene cyclization of phytosterols are C24-sterol methyltransferases and C22-sterol desaturase (CYP710A). The side chain of phytosterols usually feature additional methyl or ethyl group at position C24. Two distinct isoforms of SMT enzymes (SMT1 and SMT2), localized in the endoplasmic reticulum, are involved in C24 primary and secondary methylation. SMT2 activity determines the ratio of 24-methyl- and 24-ethylsterols, which is crucial during plant ontogenesis and response to stress factors (Valitova et al. 2016 ). Secondary methylation is the final step in sterol biosynthesis and results in the formation of 24-ethylsterols like sitosterol and stigmasterol. Conversion of sitosterol into stigmasterol is catalyzed by C22-sterol desaturase by introduction of a double bond at C22 (Raksha et al. 2016 ; Valitova et al. 2016 ).

Thus, the biosynthetic pathway of sterols in plants passes through many branching points and can be regulated at various levels. Several of the final steps of this pathway, starting from squalene, might be crucial for plant response to stress factors. First, the cyclization of 2,3-oxidosqualene represents a very important branch point between sterols and triterpenoids, i.e. between general and specialized metabolism (Moses et al. 2013 ). Secondly, there are two branches from cycloartenol leading either to cholesterol or to other precursors of plant sterols (Aboobucker and Suza 2019 ). Downstream in the phytosterols pathway, the branch point at 24-methylenelophenol and 24-ethylidenelophenol directs metabolic flux either to campesterol and, subsequently, brassinosteroids, or to the 24-ethyl sterols, sitosterol and stigmasterol. This branch point contributes to establishment of the campesterol to sitosterol ratio (Schaller 2004 ). The intracellular balance of 24-methyl- and 24-ethylsterols, in addition to the ratio between sitosterol and stigmasterol, are of great physiological importance for plant growth and development, as well as for the stress response (Valitova et al. 2016 ). Lastly, free sterols can be converted into various sterol conjugates, influencing the liquid-ordered phase formation in membranes and modulating plant response to environmental stimuli (Grosjean et al. 2015 ).

Sterol forms occurring in plants

As previously mentioned, sterols can be found in plants in free as well as conjugated forms (Fig.  2 ). In all conjugated forms, the C3 position hydroxyl group plays a major role in distinguishing between sterol compounds: in SEs it is esterified with fatty acid, whereas in SGs it is linked with sugar through a β-glycosidic bond. ASGs are SG derivatives with fatty acids which are esterified to the C6 hydroxyl group of the sugar moiety (Ferrer et al. 2017 ). Steryl ferulates (SFs), found in numerous cereal grains and other seeds, are types of SEs which are esterified with ferulic acid at the C3 hydroxyl group (Mandak and Nyström 2012 ).

Conjugated forms of sterols occurring in plants. a  Steryl ester (SE), b  steryl glycoside (SG), c  acyl steryl glycoside (ASG). R- side chain

Distribution of conjugated sterols varies among organs and tissues and depends on both the ontogenesic stage of the organ and the influence of stress factors. In plant tissues like the tapetal cells of anthers, pollen grains, seeds and mature leaves, SEs are the most abundant sterol forms (Villette et al. 2015 ). SE accumulation has been observed when plant cell cultures reach stationary phase or during seed maturation (Bouvier-Navé et al. 2010 ). The length of esterified fatty acids may range from C12 to C22, with the most common compounds being palmitic, stearic, oleic, linoleic and linolenic acids (Ferrer et al. 2017 ). SEs can be regarded as a storage pool of sterols in plant cells that ensures an appropriate level of free sterols and is also involved in the recycling of free sterols and fatty acids released from cell membranes in senescing tissues. Enzymes involved in SE biosynthesis are sterol acyltransferases, proteins which catalyze the transfer of fatty acids to the hydroxyl group at position C3 of the sterol core (Lara et al. 2018 ; Bouvier-Navé et al. 2010 ).

Cholesterol, campesterol and sitosterol glucosides are the most abundant glycosylated sterols (SGs and ASGs) occurring in plants. The enzyme involved in SGs synthesis is UDP-glucose sterol glucosyl transferase (SGT), a protein localized in plasma membrane (Schaller 2004 ). Levels of glycosylated sterols differ depending on the tissue and these may change in response to developmental and environmental cues. The predominant sugar found in glycosylated sterols is glucose, but other monosaccharides such as galactose, xylose and mannose have also been reported. SGs may contain up to four sugar residues per molecule. ASGs usually consist of saturated and unsaturated C16 and C18 fatty acids, but unusual fatty acids can also be conjugated. SGs and ASGs are usually a minority in the total sterol fraction obtained from the most plant species. Nevertheless, plants belonging to the genus Solanum are characterized by a high content of glycosylated sterols (Ferrer et al. 2017 ).

Impact of UV radiation on the content of sterols

Solar ultraviolet (UV) light consists of three types of radiation with different ranges in wavelength, namely UV-A (315–400 nm), UV-B (280–315 nm) and UV-C (100–280 nm). UV-C radiation carries more energy per photon in comparison to other types, but it does not reach the Earth’s surface, being absorbed by atmospheric oxygen and ozone. In contrast, the stratospheric ozone layer absorbs only a fraction of UV-B and even less of UV-A radiation. Moreover, due to the anthropogenic production of ozone depleting substances and the progressive reduction of the ozone layer, UV radiation is reaching the Earth’s surface in increasing intensity. Exposure to sunlight is inevitable for photosynthetic organisms like plants, so they are particularly at risk of exposure to enhanced UV irradiation (Hollósy 2002 ; Matus 2016 ).

UV radiation is harmful to most living organisms. In plants, apart from damaging DNA and proteins, it is destructive to membrane lipids and the photosynthetic apparatus, eventually leading to tissue necrosis. Plants respond to this damage through induction of a complex antioxidant defense system involving various enzymes, specialized metabolites and the accumulation of various compounds that absorb excessive UV radiation (Brosché and Strid 2003 ; Lake et al. 2009 ; Zlatev et al. 2012 ; Robson et al. 2015 ; Matus 2016 ). As sterols are an integral part of the cell membrane and maintain their fluidity and permeability, it is possible that these compounds also play a role in repairing the damage caused by UV radiation (Ahmed and Schenk 2017 ).

A high value crop which is potentially exposed to enhanced UV-B radiation is grapevine ( Vitis vinifera ). V. vinifera is one of the most extensively cultivated fruit crops in the world, well-adapted to UV radiation and can, therefore, serve as a suitable model for the study of plant UV stress responses and adaptation (Matus 2016 ). The effect of a “field-simulating” dose of UV-B radiation (4.75 kJ m − 2 per day), administrated at low- and high-fluence rates to grapevine leaf tissues, was investigated (Gil et al. 2012 ). Low intensity UV-B treatment (16 h at 8.25 µW cm − 2 ) resulted in increased levels of sitosterol and stigmasterol, especially in young leaves. The concentration of sitosterol, the most abundant sterol in grapevine, increased 16.4-fold in young leaves and eightfold in mature leaves after low UV-B treatment. After high intensity UV-B radiation (4 h at 33 µW cm − 2 ), the levels of this compound increased much less significantly (4.8-fold in young leaves and 1.8-fold in mature leaves). The concentration of stigmasterol increased 3.2-fold and 2.3-fold (exclusively in young leaves) upon low and high intensity UV-B radiation, respectively. Thus, the biosynthesis and accumulation of sitosterol and stigmasterol was stimulated most potently by low intensity UV-B. In turn, high intensity UV-B induced accumulation of other compounds with antioxidant properties, including mono- and diterpenes, tocopherol and phytol. These results might suggest that low intensity UV-B radiation applied to grapevine leaves induces acclimation responses including synthesis of sterols, compounds related with membrane stability, while higher intensity radiation activates defensive mechanisms counteracting oxidative damage. Low intensity UV-B appears to induce the synthesis of enzymes of the terpene cytosolic mevalonic acid (MVA) pathway leading to increased production of sterols and triterpenoids (such as lupeol, occurring in grapevine leaves) involved in stress adaptation, whereas high intensity UV-B radiation promotes the production of plastidic terpenes via the methylerytritol phosphate (MEP) pathway so as to cope with increased levels of reactive oxygen species (ROS) (Gil et al. 2012 ).

In contrast to what has been observed in grapevine, excessive UV-B radiation did not influence biosynthesis and accumulation of sterols in the leaves of olive ( Olea europaea ). O. europaea is one of the most important crops cultivated in Mediterranean regions, where UV-B radiation level is generally high. The application of low (6.5 kJ m − 2 day − 1 ) and high (12.4 kJ m − 2 day − 1 ) doses of UV-B radiation did not increase the content of sterols (represented by sitosterol) in olive leaves, however, increased accumulation of triterpenoids, ursolic acid and lupeol was observed. The increase in levels of triterpenoids (particularly ursolic acid) as well as long-chain alkanes could indicate that exposure of olive leaves to UV-B radiation may result in strengthening and thickening of cuticle, notably the leaf surface layer of cuticular waxes (Dias et al. 2018 ).

Based on the increased production of sterols and sterol derivatives in response to UV-induced stress, the application of UV irradiation as an elicitor of these metabolites has been explored with the aim of improving the quality of medicinal plants. One such study involved Withania somnifera , an indigenous medicinal plant occurring in northern India, which is used to treat neurological disorders. The medicinal properties of W. somnifera are primarily attributed to alkaloids and withanolides (steroidal lactones). The effects of supplemental UV-B (3.6 kJ m − 2 day − 1 above ambient) radiation on the metabolite profile and free radical scavenging activity observed in W. somnifera leaves and roots were investigated under otherwise normal field conditions. Increased levels of stigmasterol and steroidal lactone withaferin A (183% and 155%, respectively, as compared with the control) were detected in UV-B-treated leaves, while the levels of campesterol, crinosterol and cholesterol significantly decreased to 48%, 44% and 21%, respectively, as compared with the control). Stigmasterol acetate was detected in leaves only after UV-B treatment. In roots, the level of cholesterol decreased to 21% after the exposure of plants to UV-B radiation, whereas two steryl esters, stigmasterol acetate and sitosterol oleate, appeared after treatment. As in the case of grapevine, UV-B irradiation stimulated the synthesis of various compounds with antioxidant properties, such as eugenol, β-carotene, lycopene and tocopherol in W. somnifera leaves. The results obtained in this study suggest profound alterations in sterol composition as a result of redirections in sterol biosynthesis induced by UV-B treatment, as well as a considerable increase in levels of steryl esters (Takshak and Agrawal 2015 ).

Similar studies were performed on another medicinal plant, Achyranthes bidentata native to China. This plant, applied as anti-inflammatory and antibacterial agent, is rich in triterpenoid saponins (glycosides of oleanolic acid) and a steroidal derivative, ecdysterone (Li et al. 2018 ). A. bidentata plants were exposed to UV-B radiation for different durations and doses: 1 h (0.74 kJ m − 2 ), 2 h (1.48 kJ m − 2 ), 3 h (2.21 kJ m − 2 ) and 4 h (2.95 kJ m − 2 ). The content of ecdysterone increased 2.5-fold in leaves and 3.5-fold in roots after 2 h UV-B exposure. In turn, the highest content of oleanolic acid was observed after 3 h of UV-B treatment, with a twofold increase detected in the leaves and 3.2-fold in the roots. It was demonstrated that after UV-B exposure the expression levels of several genes involved in terpene/sterol biosynthesis pathway were upregulated, including squalene synthase ( SS ), squalene epoxidase ( SE ), β-amyrin synthase ( β-AS ) and cycloartenol synthase ( CAS ). Thus, the expression levels of key enzyme genes of both post-squalene parallel branches of biosynthetic pathways leading to sterols and triterpenoids were found to be simultaneously induced (Li et al. 2018 ).

Although potentially more harmful than UV-B, UV-C radiation has also been used as an abiotic elicitor to increase the production of sterols in algae (Ahmed and Schenk 2017 ). In the last few decades, after the discovery that phytosterols can reduce the intestinal absorption of cholesterol and thus help maintain cardiovascular health, these compounds have become valuable to the biotechnological industry especially with regard to production of various food additives. Microalgae present a source of phytosterols because these organisms can easily adapt to varying environmental conditions and are relatively easy to cultivate, even in wastewater, meaning that competition with other food production can be eliminated. The haptophyte microalgae Pavlova lutheri produces relatively high quantities of sterols (up to 5.1% DW). UV-C irradiation applied at 100 mJ cm − 2 doubled the total bioaccumulation of sterols in P. lutheri . Among nineteen sterol compounds identified in P. lutheri , the content of only six compounds (poriferasterol, epicampesterol, methylergostenol, fungisterol, dihydrochondrillasterol and chondrillasterol) increased after elicitation with UV-C irradiation. In unirradiated samples, the levels of fungisterol and chondrillasterol were undetectable, while in irradiated samples the quantities of those compounds increased considerably. These observations may suggest that fungisterol and chondrillasterol are more active in membrane repair processes than other sterols (Ahmed and Schenk 2017 ).

The effects of UV radiation on the synthesis and metabolism of sterols observed in the reviewed plant studies are presented in Table  1 . The most ubiquitous response to stress induced by UV irradiation is the increase in synthesis and accumulation of sterols, often accompanied by alterations in sterol composition and sometimes by increased formation of conjugated steryl forms, particularly esters. The increase in sterol biosynthesis seems to be more pronounced in response to lower doses of UV irradiation, whereas at higher doses the production of various ROS scavengers is a priority. However, this observed pattern cannot be generalized to all species, as some plants, such as the olive tree, exhibit no change in terms of sterol biosynthesis. Thus, in some plants, alternative mechanisms of response to stress induced by UV radiation may be more prevalent, for instance those based on strengthening the protective barriers (such as cuticular waxes) or accumulation of pigments which absorb excessive UV irradiation.

Sterols in cold stress

Cold stress in plants has an immense impact on their phenotype and metabolism. Exposure to low temperature suppress growth and development of the plant, cause alterations in cell membrane composition as well as changes in cell metabolism. Plants have needed to evolve to adapt to cold stress, not least due to the natural occurrence of periodic seasonal changes in temperature. Currently, increases in the frequency, severity and duration of temperature extremes are anticipated to be a frequent feature of the weather. Climate changes have resulted in even greater temperature fluctuations, including frequent periods of cold temperatures (Barrero-Sicilia et al. 2017 ).

The process by which plants adapt to low temperatures is known as cold acclimation. Non-acclimated rye is killed by temperatures as low as − 5 °C, but after an appropriate acclimation period it can survive freezing down to − 30 °C (Thomashow 1999 ). Plant acclimation to cold stress is a complex and systemic process, involving a multi-level regulatory network. Changes in cells are observed on transcriptomic, proteomic and metabolic levels (Barrero-Gil and Salinas 2013 ; Barrero-Sicilia et al. 2017 ; Degenkolbe et al. 2012 ).

Cell membranes are important sites of cold perception and simultaneously they are the most susceptible to cold injury. Therefore, membrane stabilization against freezing damage is crucial in cold acclimation (Thomashow 1999 ). The primary changes in plasma membrane composition are related to the maintenance of metabolite homeostasis and involve mostly proteins and lipids. This mechanism also serves as a “temperature sensor” for the cell (Barrero-Sicilia et al. 2017 ). Fluidity of the membrane is determined by the proportion of unsaturated and saturated fatty acid, as well as other components of the membrane, including sterols. During exposure to low temperatures, the level of unsaturated lipids in cell membranes increases and this is when the transition of the membrane from fluid state to rigid gel form occurs. This process allows the cells to mechanically adapt to freezing (Barrero-Sicilia et al. 2017 ; Chen and Thelen 2013 ).

The ability of plants to respond to cold stress, of great importance to agriculture, has been the subject of numerous studies, and the alterations in sterol content in plants exposed to cold acclimation treatment had been intently observed (Palta et al. 1993 ; Whitaker 1993 ). The effect of cold acclimation on plasma membrane lipids was investigated in two Solanum species, a freezing-tolerant, cold-acclimating wild potato species ( S. commersonii ) and a freezing-sensitive, non-acclimating cultivated species ( S. tuberosum ). Following cold acclimation treatment, several characteristic changes were observed in both species. These included an increase in unsaturated to saturated fatty acid ratio, an enhancement of the content of free sterols, particularly sitosterol, and a slight decrease in cerebrosides. In turn, a decrease in sterol to phospholipid ratio and an increase in ASGs to SGs ratio were detected only in the acclimating species, whereas they were either absent or inverted in the non-acclimating species. It was concluded that there is a correlation between a decrease in sterol to phospholipid ratio and an increase in freezing tolerance following cold acclimation. The results also suggested that a lower sterol-to-phospholipid ratio could be associated with higher membrane fluidity, and that SGs and ASGs could alter lipid bilayer fluidity through less orderly packing in the bilayer as compared with free sterols. Moreover, after acclimation treatment, both species exhibited a reduction in the proportion of cholesterol content in ASG, SG and free sterol fractions, as well as an increase in the proportions of free sitosterol and isofucosterol (Palta et al. 1993 ). In another plant belonging to Solanaceae family, tomato ( Lycopersicon esculentum ), cold-induced changes in sterol profile were observed. L. esculentum mature-green fruit was stored at chilling (2 °C) or non-chilling temperature (15 °C) for either 4 or 12 days. The content of free sterols increased more as a result of storage at 2 °C than at 15 °C in membranes from pericarp tissue, whereas the ratio of stigmasterol to sitosterol increased more at 15 °C than at 2 °C (Whitaker 1993 ).

Compositional changes of plasma membrane and detergent resistant membrane fractions (representing microdomains) in leaves of low-freezing tolerant oat ( Avena sativa ) and highly freezing tolerant rye ( Secale cereale ) during cold acclimation were investigated by Takahashi et al. ( 2016 ). In both species, detergent resistant membrane fractions (microdomains) contained higher proportions of sterols, sphingolipids and saturated phospholipids than were found in the plasma membrane. Three sterol classes, comprising free sterols, ASGs and SGs, were found in plasma membrane and microdomains, however, ASGs were the predominant sterol found in the microdomains of oat, while microdomains of rye contained free sterols as the major fraction. During cold acclimation the compositions of these structures differed between the two species. The total sterol content, as well as the fraction of free sterols, were reduced in plasma membrane and microdomains of A. sativa . In S. cereale , only the level of ASGs were reduced in both plasma membrane and microdomains. Despite the observed differences between these two species, the findings indicate that cold acclimation induces changes in the thermodynamic properties and physiological functions of microdomains. The change in proportions of sterol forms (free sterols, ASGs and SGs) may result in variable membrane behavior under freeze-induced dehydration, and thus ultimately influence plant freezing tolerance. Differences in sterol composition in microdomains may also affect the activity of some microdomain-associated proteins, particularly H + -ATPase, which is up-regulated by cold and may be involved in the regulation of intracellular pH and membrane potential. The results obtained in this study also suggested the importance of glycosylated forms of sterols, such as ASGs, in plant cell defense mechanisms against freeze-induced dehydration (Takahashi et al. 2016 ).

The recent work of Valitova et al. ( 2019 ) investigated the role of sterols in plant acclimation to low positive temperature (+ 4 °C) stress in the roots and leaves of wheat ( Triticum aestivum ) seedlings. The results demonstrated that cold treatment causes marked changes in the ratios between 24-methyl/ethyl sterols, phospholipids and glycoceramides. Short-term (1 h) cold treatment increased the total sterol content in both roots and leaves, however, after 12 h of exposure to cold the total sterol content returned to control levels. The increase in free sterol levels by 13–16% was also reported in other studies on cold acclimation of wheat seedlings during 3 weeks at + 2 °C (Bohn et al. 2007 ). The decline in sterols by 12 h, as was observed in T. aestivum , may be the result of modifications of free sterols, such as acylation and glycosylation, which have been shown to occur during cold acclimation in rye and oat (Takahashi et al. 2016 ). In the roots of cold-treated wheat seedlings, a slight increase in the ratio of 24-methyl/ethyl sterols resulted from an increase in campesterol content. In contrast, in the leaves of cold-treated seedlings, the ratio of 24-methyl/ethyl sterols was reduced due to an increase in the amounts of sitosterol and stigmasterol. Based on these data, the roots of wheat appeared to be more sensitive to cold than the leaves (Valitova et al. 2019 ).

The role of glycosylated forms of sterols in cold stress was confirmed in a study involving Arabidopsis mutants (Mishra et al. 2015 ). As previously mentioned, the proportions of SGs and ASGs are significantly altered during cold stress. That makes sterol glycosyltransferases a promising subject of research concerning the role of sterols in cold acclimation. In plants, sterol glycosyltransferases catalyze the transfer of carbohydrate molecules to sterol core, which results in SGs and ASGs synthesis. The role of TTG15/UGT80B1 gene of Arabidopsis thaliana encoding sterol glycosyltransferase was investigated during cold stress. T-DNA insertional sgt knockout mutants with significantly reduced SGs and ASGs levels, wild-type Col-0 and p35S:TTG15/UGT80B1 restored lines were used in the experiments. The p35S:TTG15/UGT80B1 restored lines were found to be better adapted to cold stress than TTG15/UGT80B1 knockout mutants during cold acclimated conditions. Cold acclimated conditions increased quantity of free sitosterol and sitosterol glycoside in Col-0 and p35S:TTG15/UGT80B1 restored lines, while the quantity of those compounds in TTG15/UGT80B1 knockout mutants decreased. Moreover, TTG15/UGT80B1 gene expression was induced during freeze conditions and appeared essential for survival of plants in those conditions (Mishra et al. 2015 ).

The predominant cold stress induced changes in sterol content presented in this review are summarized in Table  2 . Since the earlier symptoms of cold stress include changes in membrane fluidity and the phase transition of the membranes is determined by the relative proportions of constituent lipids, it can be expected that the content of sterols would be significantly altered in cold acclimation. The role of sterols in the plant adaptation to temperature is well documented. It has been suggested that the ability of plants to synthesize the 24-ethyl sterols, sitosterol and stigmasterol, may be a part of an evolutionary adaptation to stresses and maintenance of important membrane-associated metabolic processes (Dufourc 2008 ; Aboobucker and Suza 2019 ). The additional ethyl group branched on the alkyl chain of sitosterol and stigmasterol may reinforce van der Waals interactions with the alkyl chains of sphingolipids and phospholipids, leading to greater membrane cohesion and a lower temperature sensitivity. It also appears that the presence of membrane microdomains, with strictly regulated composition of sterols, can extend the temperature range in which membrane-associated processes can function properly (Dufourc 2008 ). The role of glycosylated forms of sterols, like SGs and ASGs, in defense mechanisms against cold stress was also demonstrated. The glycosylation of sterols significantly alters the biophysical properties of the membranes, indicating that the proportion of glycosylated versus free and acylated sterols may play a very important role in adaptation against adverse temperature conditions (Mishra et al. 2015 ).

Effect of drought stress on sterol content in plants

Many valuable crop plants are frequently exposed to drought stress, which is highly detrimental to the agricultural industry and has been an increasing problem in recent years due to global climate changes. Drought stress causes the destruction of cell membranes by disintegration of membrane lipids. Plants respond to drought stress by means of various physio-biochemical and molecular changes at cellular and molecular levels.

The role of sterols in response to drought stress due to water deprivation was investigated in seedlings of two rice ( Oryza sativa ) cultivars, one drought tolerant (cultivar N22) and one drought susceptible (cultivar IR64) (Kumar et al. 2015 , 2018 ). The drought tolerant cultivar exhibited a higher content of sterols and their corresponding steryl esters and this content increased approximately twofold in plants exposed to drought stress. This increase in sterols levels and their esters was proportional to the duration of dehydration stress. Levels of the major phytosterol, sitosterol, in drought tolerant rice seedlings increased gradually from 145 to 364 mg/g FW between days 3 and 12 of drought stress, while in the drought susceptible cultivar sitosterol levels increased from 137 to 287 mg/g FW. A similar pattern was observed with regard to campesterol levels, which increased from 103 to 219 mg/g FW and from 95 to 154 mg/g FW between days 3 and 12 of water deprivation in the drought tolerant and drought susceptible cultivars, respectively. Furthermore, an approximately twofold increase in the activity of HMG-CoA reductase (HMGR), a key limiting enzyme in the MVA pathway, was observed. A significant boost in the content of steryl esters (which constitute up to half of the total sterol accumulated pool), in a manner proportionate to the duration of water deprivation, was noticed, particularly in the drought tolerant cultivar. Taken together, these results indicated a significant increase in the content of sterols and their esters in plants exposed to water deprivation, which further implied that these compounds might play an important role in tolerance to drought stress by reinforcing the cell membranes. It would appear that the greater drought tolerance exhibited by the N22 rice cultivar may be due to its superior ability to accumulate sterols and their esters in comparison to the drought susceptible cultivar (Kumar et al. 2015 ).

In a subsequent study, the expression of HMGR and PSAT (phospholipid:sterol acyltransferase) genes was investigated in drought sensitive and drought tolerant rice cultivars under conditions of water deficit (Kumar et al. 2018 ). PSAT is involved in the conversion of sterols into steryl esters, thereby playing an important role in maintaining membrane homeostasis in response to drought stress. An increase in expression of both genes was observed, which was proportional to the level of severity (duration) of water deprivation. A threefold increase in the expression of HMGR transcript was observed between days 3 and 12 of drought stress in the drought tolerant cultivar, whereas in the drought sensitive cultivar only a twofold increase was observed. Simultaneously, PSAT gene expression exhibited a twofold increase in both the drought tolerant and the drought sensitive cultivars. Thus, this study demonstrated that the changes in sterol and steryl ester levels was accompanied by stimulation of respective gene expression in rice plants exposed to water deficit stress (Kumar et al. 2018 ).

The enzymes modifying sterol structures, including sterol desaturases and sterol acyltransferases, seem to be particularly involved in drought tolerance in plants. FvC5SD is a gene encoding a type of C-5 sterol desaturase isolated from the edible fungus Flammulina velutipes . It has been reported that FvC5SD overexpression in transgenic tomatoes ( L. esculentum ) leads to enhanced drought tolerance and pathogen resistance. FvC5SD is involved in ergosterol biosynthesis and the nutritional value of transgenic tomato fruits was improved due to increased polyunsaturated fatty acid (PUFA) level. However, no differences were observed in the levels of phytosterols and brassinosteroids between transgenic and wild type plants (Kamthan et al. 2012 ). In a study involving genetically modified, drought tolerant soybean Glycine max , transgenic plants were generated by insertion of FvC5SD gene by Agrobacterium -mediated transformation and these exhibited enhanced tolerance to dehydration and drought in comparison to wild type plants. In transgenic plants, diminished accumulation of ROS levels was also observed (Zhang et al. 2019 ). Unfortunately, in this study the sterol content was not determined.

The observed effects of drought stress on the content of sterols and their conjugated forms, particularly esters, in rice cultivars are shown in Table  3 . It would indeed appear that, as glycosylated forms of esters seem to be particularly involved in plant response to cold stress and cold acclimation, SEs may be crucial to survival during water deficit by strengthening the membranes in plant cells. Acylation of sterols is considered an important process in maintaining homeostasis of membrane lipids (Valitova et al. 2016 ). SEs can be found in lipid bodies in the cytoplasm of plant cells and they are present in substantial amounts in seeds, where they form a storage pool of sterols. Elevation of SE levels during senescence and aging has been well documented and it is considered to be a mechanism for reclaiming membrane lipids. Drought stress is linked with the metabolism of membrane lipids and the associated increase in SE levels seems to be involved in maintaining the integrity of plasma membrane during water deficit (Kumar et al. 2018 ).

Conclusions

Sterols are integral components of the membrane lipid bilayer in plants, where they regulate membrane fluidity and thereby influence its structure, properties and functions. Plant membranes are affected by various environmental conditions and sterols play a prominent role in plant response to abiotic stress. Diversity of sterols and their conjugated forms may allow sessile plants to adapt to environmental stress conditions.

Findings from studies presented in this review demonstrate that such abiotic stress factors as cold, drought and UV radiation have an inarguable impact on the biosynthesis and accumulation of various forms of sterols in plant tissues. Some reports correlate changes in the sterol profile, including the ratio of certain compounds (such as 24-methyl to ethyl sterols and sitosterol to stigmasterol, as well as the relative proportions of the conjugated sterols ASGs, SGs and SEs), with specific responses to different types of stress. However, sometimes it can be difficult to unambigously establish whether the increase or decrease in certain sterol forms is directly related to mechanisms of stress response, or merely a secondary product of disturbance or injury exerted by stress factor (Ferrer et al. 2017 ). Moreover, the pattern of changes observed in these studies cannot be regarded as universal and generalizing to all plants, since some species may have distinct adaptations to environmental conditions and their response to certain stress factors might not depend exclusively on modifications of sterol content in membranes, as was demonstrated in case of olive trees exposed to UV-B radiation stress (Dias et al. 2018 ).

A further limitation of the research approach utilized in the studies presented in this review is that they were each performed under a single stress factor. Plants are usually exposed to several types of abiotic stress in their natural environment or under field conditions. A recent study involving barley ( Hordeum vulgare ) showed that a combination of abiotic stressors significantly increased the sterol content, however, it also demonstrated discrepancies between the effect exerted in barley leaves exposed to multiple stressors, particularly for simultaneous drought and heat, and the effects exerted by a single factor (Kuczyńska et al. 2019 ). Therefore, the investigation on the effects of combinations of abiotic stressors should be considered in the future studies regarding the role of sterols in plant response to environmental cues, which present a major challenge to the contemporary agriculture and food industries as a result of global climate changes.

Abbreviations

Acyl steryl glycoside

C22-sterol desaturase

Fresh weight

3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase

2-C-methyl-d-erythritol 4-phosphate pathway

Mevalonic acid pathway

Phospholipid: sterol acyltransferase

Polyunsaturated fatty acid

Steryl ester

Steryl ferulate

Steryl glycoside

Sterol glucosyl transferase

C24-sterol methyltransferase 1

C24-sterol methyltransferase 2

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Rogowska, A., Szakiel, A. The role of sterols in plant response to abiotic stress. Phytochem Rev 19 , 1525–1538 (2020). https://doi.org/10.1007/s11101-020-09708-2

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Plant sterols and plant stanols in cholesterol management and cardiovascular prevention.

Graphical Abstract

1. Introduction

2. materials and methods, 3. dietary sources of intake, 4. biology and mechanism of action of plant sterols/stanols, 4.1. biology, 4.2. transport and circulation, 4.3. mechanism of cholesterol absorption inhibition, 5. effect of plant sterols/stanols on cvd risk factors, 5.1. effect on cholesterol, 5.2. effect on other lipid fractions, 5.3. effect on glucose metabolism, 6. effect of plant sterols/stanols on atherosclerosis and cvd clinical outcomes, 6.1. effect of plant sterols/stanols on atherosclerosis in animal studies, 6.2. effect of plant sterols/stanols on atherosclerosis in human studies, 6.3. effect of plant sterols/stanols on cardiovascular events, 6.3.1. randomized trials, 6.3.2. observational studies, 6.3.3. genetic studies, 7. clinical implications and practical issues, 7.1. official scientific guidelines, 7.2. data on consumption of foods enriched with plant sterols/stanols, 7.3. safety issues and concerns, 8. conclusions, author contributions, conflicts of interest.

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Barkas, F.; Bathrellou, E.; Nomikos, T.; Panagiotakos, D.; Liberopoulos, E.; Kontogianni, M.D. Plant Sterols and Plant Stanols in Cholesterol Management and Cardiovascular Prevention. Nutrients 2023 , 15 , 2845. https://doi.org/10.3390/nu15132845

Barkas F, Bathrellou E, Nomikos T, Panagiotakos D, Liberopoulos E, Kontogianni MD. Plant Sterols and Plant Stanols in Cholesterol Management and Cardiovascular Prevention. Nutrients . 2023; 15(13):2845. https://doi.org/10.3390/nu15132845

Barkas, Fotios, Eirini Bathrellou, Tzortzis Nomikos, Demosthenes Panagiotakos, Evangelos Liberopoulos, and Meropi D. Kontogianni. 2023. "Plant Sterols and Plant Stanols in Cholesterol Management and Cardiovascular Prevention" Nutrients 15, no. 13: 2845. https://doi.org/10.3390/nu15132845

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Stanols and sterols.

The use of foods containing added plant stanols or sterols is an option in conventional treatment for high cholesterol levels. Stanols and sterols are also available in dietary supplements. The evidence for the effectiveness of the supplements is less extensive than the evidence for foods containing stanols or sterols, but in general, studies show that stanol or sterol supplements, taken with meals, can reduce cholesterol levels. Some foods and dietary supplements that contain stanols or sterols are permitted to carry a health claim, approved by the U.S. Food and Drug Administration (FDA), saying that they may reduce the risk of heart disease when consumed in appropriate amounts.

What Does the Research Show?

• A  2022 network meta-analysis found that plant sterols supplementation can cause a modest reduction of low-density lipoprotein cholesterol (LDL-C) and total cholesterol with bergamot and red yeast rice being seemingly most effective.
• A  2023 single-center, prospective, randomized, single-blind clinical trial involving 190 participants compared the efficacy of a low-dose statin with placebo and six common supplements, including plant sterols, in impacting lipid and inflammatory biomarkers. The study found that none of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo.
• A  2013 systematic review and meta-analysis  of eight studies found that supplementation of plant sterols/stanols (in tablets and capsules) was associated with clinically significant reductions in LDL-C levels. Further analysis showed no significant difference between the LDL-C lowering action of plant sterol/stanol supplements compared with foods enriched with plant sterols/stanols.
• Plant sterols/stanols are generally safe for most healthy people. Side effects include diarrhea or fat in the stool.
• In people with sitosterolemia, high plant sterol levels have been associated with increased risk of premature atherosclerosis.

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Some soy products can have a small cholesterol-lowering effect. However, results from studies indicate that soy foods have more of a beneficial effect on cholesterol than soy protein supplements or isoflavones. 

• A  2015 meta-analysis  of 35 studies indicated that soy foods were more effective in lowering cholesterol than soy protein supplements and that isoflavones did not lower cholesterol. The effect of soy is much smaller than that of cholesterol-lowering drugs.
• A  2022 systematic review and meta-analysis of various effects of phytoestrogens on lipid profiles in postmenopausal women found that soy protein supplementation led to a significant decrease in total cholesterol levels, as well as a significant increase in high-density lipoprotein cholesterol (HDL-C) levels.
• Further, a  2023 review concluded that any beneficial effect of soy proteins is likely derived from a healthy diet in which soy proteins replace animal proteins rather than from the intrinsic properties of soy supplementation alone.
• Except for people with soy allergies, soy is believed to be safe when consumed in normal dietary amounts. However, the safety of long-term use of high doses of soy extracts has not been established.
• The most common side effects of soy are digestive upsets, such as stomach pain and diarrhea.
• Long-term use of soy isoflavone supplements might increase the risk of endometrial hyperplasia. Soy foods do not appear to increase the risk of endometrial hyperplasia.
• Current evidence indicates that it’s safe for women who have had breast cancer or who are at risk for breast cancer to eat soy foods. However, it’s uncertain whether soy isoflavone supplements are safe for these women.

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Studies of flaxseed preparations to lower cholesterol levels suggest possible beneficial effects for some types of flaxseed supplements, including whole flaxseed and flaxseed lignans but not flaxseed oil. The effects were stronger for women (especially postmenopausal women) than men and for people with higher initial cholesterol levels.

• Studies of flaxseed and flaxseed oil to lower cholesterol levels have had mixed results.
• A  2022 systematic review and meta-analysis found that different flaxseed products showed different effects in postmenopausal women. Whole flaxseed supplementation significantly reduced total cholesterol, while supplementation with lignans significantly reduced total cholesterol, LDL-C, and HDL-C. Flaxseed oil supplements had no lowering effect on lipids.
• A  2015 randomized controlled trial  of 110 participants with clinically significant cardiovascular disease found that milled flaxseed lowers total cholesterol and LDL-C in people with peripheral artery disease and may have additional LDL-C lowering capabilities when used in conjunction with cholesterol-lowering medications.
• Raw or unripe flaxseeds may contain potentially toxic compounds.
• Flaxseed and flaxseed oil supplements seem to be well tolerated in limited amounts. Few side effects have been reported.
• Flaxseed and flaxseed oil should be avoided during pregnancy as they may have mild hormonal effects. There’s little reliable information on whether it’s safe to use flaxseed when breastfeeding.
• Flaxseed, like any fiber supplement, should be taken with plenty of water, as it could worsen constipation or, in rare cases, cause an intestinal blockage. Both flaxseed and flaxseed oil can cause diarrhea.

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A recent review of the research on garlic supplements concluded that they can lower cholesterol if taken for more than 2 months, but their effect is modest in comparison with the effects of cholesterol-lowering drugs.

• A  2023 review found evidence that demonstrates mostly consistent total cholesterol reduction with garlic supplementation; however, its effect on LDL-C and HDL-C is variable.
• A  2016 meta-analysis and review  of 39 randomized controlled trials involving 2,300 participants treated for a minimum of 2 weeks found garlic to be effective in reducing total cholesterol and LDL-C by 10 percent if taken for more than 2 months by individuals with slightly elevated concentrations.
• Garlic is probably safe for most people in the amounts usually eaten in foods.
• Side effects include breath and body odor, heartburn, and upset stomach. These side effects can be more noticeable with raw garlic. Some people have allergic reactions to garlic.
• Taking garlic may increase the risk of bleeding.
• Garlic has been found to interfere with the effectiveness of some drugs, including saquinavir, a drug used to treat HIV infection.

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There is some limited evidence that suggests green tea may have a modest cholesterol-lowering effect.

• A  2023 review found evidence from several meta-analyses indicating that green tea is associated with small (2–5 percent) but significant reductions in total cholesterol and LDL-C; however, the effects on HDL-C are inconsistent.
• A  2020 meta-analysis of 31 trials involving a total of 3,321 participants found that green tea supplementation may lower LDL-C and total cholesterol, but not HDL-C or triglycerides in both normal weight subjects and those who were overweight or had obesity. However, the authors of the study noted the need for additional well-designed studies that include more diverse populations and longer duration.
• A  2018 meta-analysis  of 21 randomized controlled trials involving 1,704 overweight or obese participants found that green tea significantly decreased plasma total cholesterol and low-density lipoprotein cholesterol levels. The study found that green tea had no effect on high-density lipoprotein cholesterol levels.
• Green tea, when consumed as a beverage, is believed to be safe when used in moderate amounts.
• Liver problems have been reported in a small number of people who took concentrated green tea extracts. Although the evidence that the green tea products caused the liver problems is not conclusive, experts suggest that concentrated green tea extracts be taken with food and that people discontinue use and consult a health care provider if they have a liver disorder or develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice.
• Except for decaffeinated green tea products, green tea and green tea extracts contain substantial amounts of caffeine.
• Green tea has been shown to reduce blood levels of the drug nadolol, a beta-blocker used for high blood pressure and heart problems. It may also interact with other medicines.

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The FDA has determined that red yeast rice that contains more than trace amounts of a substance called monacolin K is an unapproved new drug and cannot be sold legally as a dietary supplement. Monacolin K is chemically identical to the cholesterol-lowering drug lovastatin, and some red yeast rice contains substantial amounts of this substance. Red yeast rice that contains monacolin K may lower blood cholesterol levels, but it can also cause the same types of side effects and drug interactions as lovastatin.

Researchers have not reported results of any studies of red yeast rice products that contain little or no monacolin K, so whether these products have any effect on blood cholesterol is unknown.

• In clinical trials of red yeast rice products that contained substantial amounts of monacolin K, the products lowered blood levels of total cholesterol and LDL-C. It is important to emphasize that all of these clinical trials used products that contained substantial amounts of monacolin K.
• A 2010 analysis showed that some of the red yeast rice products on the market contain very little monacolin K. These products may have little or no effect on blood cholesterol levels.
• Some red yeast rice products contain substantial amounts of monacolin K, which is chemically identical to the active ingredient in the cholesterol-lowering drug lovastatin. These products may lower blood cholesterol levels and can cause the same types of side effects and drug interactions as lovastatin.
• Red yeast rice products may be contaminated with citrinin, a substance that may cause kidney damage.

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Studies on the effects of red clover on cholesterol and other lipids have had inconsistent results.

• A  2020 systematic review and meta-analysis of 10 studies involving a total of 910 perimenopausal and postmenopausal women found that red clover extract was associated with a significant reduction in total cholesterol; however, its effects on HDL-C and LDL-C were not significant.
• A  2022 systematic review and meta-analysis found a significant reduction in total cholesterol levels after the use of red clover supplements and a significant increase in HDL-C levels.
• Red clover extracts have been used in clinical studies for as long as 3 years with apparent safety.
• Women should not take red clover supplements during pregnancy or while breastfeeding.

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There is some limited evidence suggesting that bergamot and bergamot-derived polyphenols may have lipid-lowering properties.

• A  2022 systematic review and meta-analysis suggested that bergamot supplementation significantly decreased serum levels of total cholesterol, triglycerides, and LDL-C and increased HDL-C. The results, however, are uncertain, due to the small number of studies in the analyses and low level of evidence.
• Oral use of bergamot extract at an appropriate dose appears safe over the short term.

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• Anderson JW, Bush HM. Soy protein effects on serum lipoproteins: a quality assessment and meta-analysis of randomized, controlled studies . Journal of the American College of Nutrition. 2011;30(2):79-91.
• Błaszczuk A, Barańska A, Kanadys W, et al. Role of phytoestrogen-rich bioactive substances ( Linum usitatissimum  L., Glycine max L., Trifolium pratense L.) in cardiovascular disease prevention in postmenopausal women: a systematic review and meta-analysis . Nutrients. 2022;14(12):2467.
• Edel AL, Rodriguez-Leyva D, Maddaford TG, et al. Dietary flaxseed independently lowers circulating cholesterol and lowers it beyond the effects of cholesterol-lowering medications alone in patients with peripheral artery disease . Journal of Nutrition. 2015;145(4):749-757.
• Giolo JS, Costa JG, da Cunha-Junior JP, et al. The effects of isoflavone supplementation plus combined exercise on lipid levels, and inflammatory and oxidative stress markers in postmenopausal women . Nutrients. 2018;10(4):424.
• Gordon RY, Cooperman T, Obermeyer W, et al. Marked variability of monacolin levels in commercial red yeast rice products: buyer beware! Archives of Internal Medicine . 2010;170(19):1722-1727.
• Kanadys W, Baranska A, Jedrych M, et al. Effects of red clover (Trifolium pratense) isoflavones on the lipid profile of perimenopausal and postmenopausal women—a systematic review and meta-analysis . Maturitas. 2020;132:7-16.
• Laffin LJ, Bruemmer D, Garcia M, et al. Comparative effects of low-dose rosuvastatin, placebo, and dietary supplements on lipids and inflammatory biomarkers . Journal of the American College of Cardiology. 2023;81(1):1-12.
• Mirzai S, Laffin LJ. Supplements for lipid lowering: what does the evidence show? Current Cardiology Reports. 2023;25(8):795-805.
• Onakpoya I, Spencer E, Heneghan C, et al. The effect of green tea on blood pressure and lipid profile: a systematic review and meta-analysis of randomized clinical trials . Nutrition, Metabolism, and Cardiovascular Diseases . 2014;24(8):823-836.
• Osadnik T, Goławski M, Lewandowaki P, et al. A network meta-analysis on the comparative effect of nutraceuticals on lipid profile in adults . Pharmacological Research. 2022;183:106402.
• Pan A, Yu D, Demark-Wahnefried W, et al. Meta-analysis of the effects of flaxseed interventions on blood lipids . American Journal of Clinical Nutrition . 2009;90(2):288-297.
• Reinhart KM, Talati R, White CM, et al. The impact of garlic on lipid parameters: a systematic review and meta-analysis . Nutrition Research Reviews . 2009;22(1):39-48.
• Ried K. Garlic lowers blood pressure in hypertensive individuals, regulates serum cholesterol, and stimulates immunity: an updated meta-analysis and review . Journal of Nutrition. 2016;146(2):389S-396S.
• Sadeghi-Dehsahraei H, Ghaleh HEG, Mirnejad R, et al. The effect of bergamot (KoksalGarry) supplementation on lipid profiles: a systematic review and meta-analysis of randomized controlled trials . Phytotherapy Research. 2022;36(12):4409-4424.
• Shaghaghi A, Abumweis SS, Jones PJH. Cholesterol-lowering efficacy of plant sterols/stanols provided in capsule and tablet formats: results of a systematic review and meta-analysis . Journal of the Academy of Nutrition and Dietetics. 2013;113(11):1494-1503.
• Tokede OA, Onabanjo TA, Yansane A, et al. Soya products and serum lipids: a meta-analysis of randomised controlled trials . British Journal of Nutrition . 2015;114(6):831-843.
• Xu R, Yang K, Li S, et al. Effect of green tea consumption on blood lipids: a systematic review and meta-analysis of randomized controlled trials . Nutrition Journal . 2020;19(1):48.
• Yuan F, Dong H, Fang K, et al. Effects of green tea on lipid metabolism in overweight or obese people: a meta-analysis of randomized controlled trials . Molecular Nutrition & Food Research . 2018;62(1).
• Zheng X-X, Xu Y-L, Li S-H, et al. Green tea intake lowers fasting serum total and LDL cholesterol in adults: a meta-analysis of 14 randomized controlled trials . American Journal of Clinical Nutrition . 2011;94(2):601-610.

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Clinical Digest Archive

The Best Plant Sterols For Lowering Cholesterol *

Over 100 clinical studies have demonstrated that plant sterols and stanols can significantly reduce blood cholesterol*, which is why physicians around the world recommend them. Plant sterols can reduce LDL (bad) cholesterol by 5-15% in as little as 4-6 weeks.*

Several medical guidelines recommend consuming at least 2 grams of plant sterols per day including those that are part of your regular diet and from dietary supplements or supplemented foods.

There are three primary ways to consume enough plants sterols to lower your cholesterol:

• Foods naturally high in plant sterols
• Foods with added plant sterols
• Dietary supplements

Reducing cholesterol with foods naturally high in plant sterols

Plant sterols are in the some of the foods you eat every day, including fruits, vegetables, vegetable oils, nuts and legumes. Consuming enough plant sterols in your diet can help decrease your blood cholesterol levels*.

Here are a few examples of plant sterol concentrations in food according to the European Atherosclerosis Society (expressed in mg of plant sterols/100 grams).

It can be challenging to get enough plant sterols through your regular diet alone. To consume a daily target of 2 grams (2000 mg) of plant sterols, you might need to eat 16 avocados or 123 bananas each day. This is why food with added plant sterols or a dietary supplement can help achieve the 2 grams per day goal.

Reducing cholesterol with foods supplemented with plant sterols

There are a few food products, including some margarines and orange juices that may have plant sterols added to them. Consuming these products may be an excellent way to progress towards the goal of consuming 2 grams of plant sterols each day. However, there are challenges.

Margarines may have significant fat and calories, so be sure to view the nutritional label. Orange juice has sugar and calories, and should be consumed in moderation. If you are already eating these foods, then a brand with added plant sterols may be a healthy and smart choice.

Reducing cholesterol with plant sterol tablets

Plant sterols and stanols are available in tablet format and are a good option for those people who are comfortable taking pills. Some people may find the size of the pills too large to take them over the long term, or have difficulty remembering to bring the bottle with them if they are eating out.

Lowering cholesterol* with plant sterol gummies from Piper Biosciences

Plant sterols are a clinically-proven, physician-recommended ingredient to reduce cholesterol*. Plant sterols are available in several formats, so you should choose a product that is enjoyable, convenient and manufactured by a trustworthy company. PIPER LDL Healthy Cholesterol* Gummies provides plant sterols in delicious, fruit flavored gummies, in convenient and portable daily pouches.

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How to reduce sugar intake to improve heart health, the glycemic index, carbohydrates: the good and bad news for protecting heart health, eating a heart healthy diet.

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Aggie Research Programs

Texas A&M University

Fall 2024: Bridging Arts and Science: Research Experiment & Academic Writing Training in Plant Sciences

Affiliations:	STEM EDUCATION Research Leadership
Project Leader:	Bin Wu Political Science
Faculty Mentor:	Hongmin Qin
	TBA
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	Participants in our project will have the opportunity to: 1) Gain a comprehensive understanding of plant physiology and specialize in woody plant tissue culture techniques. 2) Acquire skills in the strategic use of various plant growth regulators (PGRs) to achieve callus formation from stem or leaf sections, encourage bud differentiation from callus, and successfully root regenerated plantlets. 3) Master a range of practical plant tissue culture methods and other cutting-edge biological techniques. 4) Receive opportunities to present their research findings at prestigious scientific forums, including the TAMU Student Research Week and the Biology Undergraduate Research Symposium. 5) Access potential internship opportunities with leading nurseries throughout Texas, enhancing practical experience in the field. 6) Enhance writing skills in drafting scholarly documents and engage in the peer-reviewed manuscript preparation. An official website of the United States government The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site. The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. Publications Account settings My Bibliography Collections Citation manager Save citation to file Email citation, add to collections. Create a new collection Add to an existing collection Add to My Bibliography Your saved search, create a file for external citation management software, your rss feed. Search in PubMed Search in NLM Catalog Add to Search Cell polarity and PIN protein positioning in Arabidopsis require STEROL METHYLTRANSFERASE1 function Affiliation. 1 Developmental Genetics, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. PMID: 12615936 PMCID: PMC150017 DOI: 10.1105/tpc.008433 Plants have many polarized cell types, but relatively little is known about the mechanisms that establish polarity. The orc mutant was identified originally by defects in root patterning, and positional cloning revealed that the affected gene encodes STEROL METHYLTRANSFERASE1, which is required for the appropriate synthesis and composition of major membrane sterols. smt1(orc) mutants displayed several conspicuous cell polarity defects. Columella root cap cells revealed perturbed polar positioning of different organelles, and in the smt1(orc) root epidermis, polar initiation of root hairs was more randomized. Polar auxin transport and expression of the auxin reporter DR5-beta-glucuronidase were aberrant in smt1(orc). Patterning defects in smt1(orc) resembled those observed in mutants of the PIN gene family of putative auxin efflux transporters. Consistently, the membrane localization of the PIN1 and PIN3 proteins was disturbed in smt1(orc), whereas polar positioning of the influx carrier AUX1 appeared normal. Our results suggest that balanced sterol composition is a major requirement for cell polarity and auxin efflux in Arabidopsis. PubMed Disclaimer The orc Mutant Alters Plant… The orc Mutant Alters Plant Morphology. (A) Five-day-old wild-type (WT) seedling grown on… The orc Mutation Resides in… The orc Mutation Resides in the C-24 SMT1 Gene. (A) The orc between… Cell Polarity Defects in smt1… Cell Polarity Defects in smt1 orc . (A) and (B) In the wild… Quantification of Polarity Defects in… Quantification of Polarity Defects in smt1 orc . (A) Positions of nuclei in… Defective QC Marker Expression and… Defective QC Marker Expression and Organization of Columella Root Cap Cells in smt1… Development of smt1 orc Embryos.… Development of smt1 orc Embryos. (A) , (E) , and (I) Globular-stage embryos… Cotyledon Development and Tropic Responses… Cotyledon Development and Tropic Responses in smt1 orc . (A) DR5 - GUS… Localization of HA::AUX1 and Delocalized… Localization of HA::AUX1 and Delocalized Auxin Efflux Carriers in smt1 orc and smt1… Similar articles The sterol methyltransferases SMT1, SMT2, and SMT3 influence Arabidopsis development through nonbrassinosteroid products. Carland F, Fujioka S, Nelson T. Carland F, et al. Plant Physiol. 2010 Jun;153(2):741-56. doi: 10.1104/pp.109.152587. Epub 2010 Apr 23. Plant Physiol. 2010. PMID: 20421456 Free PMC article. PATELLINS are regulators of auxin-mediated PIN1 relocation and plant development in Arabidopsis thaliana . Tejos R, Rodriguez-Furlán C, Adamowski M, Sauer M, Norambuena L, Friml J. Tejos R, et al. J Cell Sci. 2018 Jan 29;131(2):jcs204198. doi: 10.1242/jcs.204198. J Cell Sci. 2018. PMID: 28687624 Sterol-dependent endocytosis mediates post-cytokinetic acquisition of PIN2 auxin efflux carrier polarity. Men S, Boutté Y, Ikeda Y, Li X, Palme K, Stierhof YD, Hartmann MA, Moritz T, Grebe M. Men S, et al. Nat Cell Biol. 2008 Feb;10(2):237-44. doi: 10.1038/ncb1686. Epub 2008 Jan 27. Nat Cell Biol. 2008. PMID: 18223643 Subcellular trafficking of PIN auxin efflux carriers in auxin transport. Friml J. Friml J. Eur J Cell Biol. 2010 Feb-Mar;89(2-3):231-5. doi: 10.1016/j.ejcb.2009.11.003. Epub 2009 Nov 26. Eur J Cell Biol. 2010. PMID: 19944476 Review. Recent developments in the understanding of PIN polarity. Marhava P. Marhava P. New Phytol. 2022 Jan;233(2):624-630. doi: 10.1111/nph.17867. Epub 2021 Dec 9. New Phytol. 2022. PMID: 34882802 Review. Changes in Gravitaxis and Gene-Expression in an Euglena gracilis Culture over Time. Krüger J, Richter P, Stoltze J, Prasad B, Strauch SM, Krüger M, Nasir A, Lebert M. Krüger J, et al. Biomolecules. 2024 Mar 9;14(3):327. doi: 10.3390/biom14030327. Biomolecules. 2024. PMID: 38540747 Free PMC article. Arabidopsis 3β-Hydroxysteroid Dehydrogenases/C4-Decarboxylases Are Essential for the Pollen and Embryonic Development. Pan J, Li W, Chen B, Liu L, Zhang J, Li J. Pan J, et al. Int J Mol Sci. 2023 Oct 25;24(21):15565. doi: 10.3390/ijms242115565. Int J Mol Sci. 2023. PMID: 37958553 Free PMC article. Advances and Challenges in Plant Sterol Research: Fundamentals, Analysis, Applications and Production. Evtyugin DD, Evtuguin DV, Casal S, Domingues MR. Evtyugin DD, et al. Molecules. 2023 Sep 8;28(18):6526. doi: 10.3390/molecules28186526. Molecules. 2023. PMID: 37764302 Free PMC article. Review. 3-Hydroxy-3-methylglutaryl coenzyme A reductase genes from Glycine max regulate plant growth and isoprenoid biosynthesis. Wang S, Feng Y, Lou Y, Niu J, Yin C, Zhao J, Du W, Yue A. Wang S, et al. Sci Rep. 2023 Mar 8;13(1):3902. doi: 10.1038/s41598-023-30797-4. Sci Rep. 2023. PMID: 36890158 Free PMC article. Roles of very long-chain fatty acids in compound leaf patterning in Medicago truncatula. Wang H, Lu Z, Xu Y, Zhang J, Han L, Chai M, Wang ZY, Yang X, Lu S, Tong J, Xiao L, Wen J, Mysore KS, Zhou C. Wang H, et al. Plant Physiol. 2023 Mar 17;191(3):1751-1770. doi: 10.1093/plphys/kiad006. Plant Physiol. 2023. PMID: 36617225 Free PMC article. Altmann, T. (1998). Recent advances in brassinosteroid molecular genetics. Curr. Opin. Plant Biol. 1, 378–383. - PubMed Athenstaedt, K., Zweytick, D., Jandrositz, A., Kohlwin, S.D., and Daum, G. (1999). Identification and characterization of major lipid particle proteins of the yeast Saccharomyces cerevisiae. J. Bacteriol. 181, 6441–6448. - PMC - PubMed Bagnat, M., and Simons, K. (2002). Cell surface polarization during yeast mating. Proc. Natl. Acad. Sci. USA 99, 14183–14188. - PMC - PubMed Bechtold, N., Ellis, J., and Pelletier, G. (1993). In planta Agrobacterium-mediated gene transfer by infiltration of adult Arabidopsis plants. C. R. Acad. Sci. Paris 316, 1194–1199. Bligh, E.G., and Dyer, W.J. (1959). A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 91–97. - PubMed Publication types Search in MeSH Related information PubChem Compound PubChem Compound (MeSH Keyword) PubChem Substance LinkOut - more resources Full text sources. PubMed Central Silverchair Information Systems Other Literature Sources Molecular biology databases. The Arabidopsis Information Resource Miscellaneous NCI CPTAC Assay Portal Citation Manager NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited. +1-866-353-3335 Custom Research Research Partners Enterprise Solution PUBLISHER: Persistence Market Research | PRODUCT CODE:  1539315 Sterols Market: Global Industry Analysis, Size, Share, Growth, Trends, and Forecast, 2024-2033 Add to Cart Description Table of contents. Persistence Market Research has recently published an extensive report on the global Sterols Market, offering a thorough analysis of essential market dynamics, including driving factors, emerging trends, opportunities, and challenges. This report provides a comprehensive understanding of the current market landscape. Key Insights: Sterols Market - Report Scope: Sterols are compounds found in plant-based foods that have been shown to lower cholesterol levels and support cardiovascular health. These compounds are utilized in various applications, including dietary supplements, functional foods, and pharmaceuticals. The market for sterols is driven by increasing health awareness, rising incidences of cardiovascular diseases, and growing demand for natural and plant-based ingredients. Technological advancements in extraction processes and the rising adoption of functional foods are also contributing to the market's expansion. Market Growth Drivers: The global Sterols Market is primarily driven by the growing focus on preventive healthcare and the rising prevalence of heart disease. The increasing consumption of health-enhancing products and the heightened awareness of the benefits of sterols in reducing cholesterol levels are fueling market growth. Additionally, advancements in extraction technologies and the integration of sterols into a wide range of consumer products are supporting the market's upward trajectory. Market Restraints: Despite its potential, the Sterols Market faces several challenges, including regulatory hurdles and the high cost of extraction and production. Stringent regulations surrounding health claims and the varying quality standards across regions can impact market growth. Moreover, the relatively high cost of sterol-based products compared to conventional alternatives may hinder broader market adoption. Addressing these challenges requires effective regulatory compliance strategies and cost-efficient production methods. Market Opportunities: The Sterols Market offers significant opportunities driven by increasing consumer interest in natural health solutions and the expansion of the functional foods sector. Innovations in product formulations and the development of new applications for sterols in dietary supplements and pharmaceuticals present growth prospects. Strategic partnerships and collaborations with key stakeholders, investment in research and development, and the exploration of new market segments are crucial for capitalizing on these opportunities and fostering market expansion. Key Questions Answered in the Report: Competitive Intelligence and Business Strategy: Key players in the global Sterols Market, such as Cargill, BASF, and DuPont, are focusing on innovation, technological advancements, and strategic partnerships to enhance their market presence. These companies invest significantly in R&D to develop advanced sterol products and expand their application range. Collaborations with research institutions, food manufacturers, and pharmaceutical companies facilitate market access and promote the adoption of sterol-based solutions. Emphasizing sustainable sourcing, product differentiation, and consumer education are critical strategies for maintaining a competitive edge in the evolving Sterols Market landscape. Key Companies Profiled: Sterols Industry Research by Category By End Use: 1. Executive Summary 2. market overview, 3. key market trends, 4. key success factors, 5. global market demand analysis 2019-2023 and forecast, 2024-2033, 6. global market - pricing analysis, 7. global market demand (in value or size in us$ mn) analysis 2019-2023 and forecast, 2024-2033, 8. market background, 9. global market analysis 2019-2023 and forecast 2024-2033, by form, 10. global market analysis 2019-2023 and forecast 2024-2033, by source, 11. global market analysis 2019-2023 and forecast 2024-2033, by end use, 12. global market analysis 2019-2023 and forecast 2024-2033, by region, 13. north america market analysis 2019-2023 and forecast 2024-2033, 14. latin america market analysis 2019-2023 and forecast 2024-2033, 15. europe market analysis 2019-2023 and forecast 2024-2033, 16. south asia & pacific market analysis 2019-2023 and forecast 2024-2033, 17. east asia market analysis 2019-2023 and forecast 2024-2033, 18. middle east and africa market analysis 2019-2023 and forecast 2024-2033, 19. country wise market analysis, 2024, 20. market structure analysis, 21. competition analysis, 22. assumptions and acronyms used, 23. research methodology. Jeroen Van Heghe Manager - EMEA +32-2-535-7543 Christine Sirois Manager - Americas +1-860-674-8796 An official website of the United States government The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site. The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. Publications Account settings Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now . Advanced Search Journal List Front Pharmacol Phytosterols: From Preclinical Evidence to Potential Clinical Applications Bahare salehi. 1 Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Cristina Quispe 2 Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile Javad Sharifi-Rad 3 Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran 4 Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador Natália Cruz-Martins 5 Faculty of Medicine, University of Porto, Porto, Portugal 6 Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal 7 Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Porto, Portugal Manisha Nigam 8 Department of Biochemistry, H. N. B. Garhwal (A Central) University, Srinagar Garhwal, India Abhay Prakash Mishra 9 Adarsh Vijendra Institute of Pharmaceutical Sciences, School of Pharmacy, Shobhit University, Gangoh, India Dmitryi Alexeevich Konovalov 10 Department of Pharmacognosy, Botany and Technology of Phytopreparations, Pyatigorsk Medical-Pharmaceutical Institute, Branch of Volgograd State Medical University, Ministry of Health of Russia, Pyatigorsk, Russia Valeriya Orobinskaya 11 Institute of Service, Tourism and Design (Branch) of North-Caucasus Federal University in Pyatigorsk, Pyatigorsk, Russia Ibrahim M. Abu-Reidah 12 Department of Environmental Science/Boreal Ecosystem Research Initiative, Memorial University of Newfoundland, Corner Brook, NL, Canada 13 Department of Analytical and Food Chemistry, Faculty of Pharmacy, Al-Andalus University for Medical Sciences, Tartous, Syria Farukh Sharopov 14 “Chinese-Tajik Innovation Center for Natural Products”, Academy of Sciences of the Republic of Tajikistan, Dushanbe, Tajikistan Tommaso Venneri 15 Department of Pharmacy, University of Napoli Federico II, Napoli, Italy Raffaele Capasso 16 Department of Agricultural Sciences, University of Naples Federico II, Portici, Italy Wirginia Kukula-Koch 17 Department of Pharmacognosy, Medical University of Lublin, Lublin, Poland Anna Wawruszak 18 Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland Wojciech Koch 19 Chair and Department of Food and Nutrition, Medical University of Lublin, Lublin, Poland Magdalena Rudzińska , Poznan University of Life Sciences, Poland Phytosterols (PSs) are plant-originated steroids. Over 250 PSs have been isolated, and each plant species contains a characteristic phytosterol composition. A wide number of studies have reported remarkable pharmacological effects of PSs, acting as chemopreventive, anti-inflammatory, antioxidant, antidiabetic, and antiatherosclerotic agents. However, PS bioavailability is a key issue, as it can be influenced by several factors (type, source, processing, preparation, delivery method, food matrix, dose, time of administration into the body, and genetic factors), and the existence of a close relationship between their chemical structures (e.g., saturation degree and side-chain length) and low absorption rates has been stated. In this sense, the present review intends to provide in-depth data on PS therapeutic potential for human health, also emphasizing their preclinical effects and bioavailability-related issues. Introduction Consumer awareness for healthy lifestyles, seeking optimal health and longevity, has moved primary attention toward nutrition that offers health potentialities beyond staple food. In fact, bioactive-rich diets at appropriate amounts are invaluable for health maintenance ( Floros et al., 2010 ), where the impact of a balanced diet is crucial. Often conceived as providing a proper variety of distinct types of food and concomitantly adequate amounts of the required nutrients to ensure good health and maintain health vitality, welfare, and proper body function ( Shao et al., 2017 ), a balanced diet has been increasingly adopted by consumers worldwide. There is a wide variety of plant-derived bioactive molecules that have been increasingly consumed by human beings given their renowned health benefits ( Salehi et al., 2018 ; Sharifi-Rad et al., 2018 ; Imran et al., 2019 ). These molecules, often called phytochemicals, include phenolic compounds, organic acids, carotenoids, alkaloids, and sterols. Broadly, plant sterols are functional ingredients solely obtained from plant resources ( Piironen et al., 2003 ). Phytosterols (PSs) are plant-derived fatty compounds (steroids) representing the greatest portion of unsaponifiable matter in plant lipids ( Piironen et al., 2003 ), while cholesterol is present in animals. They consist of a steroid skeleton characterized by a saturated bond between C-5 and C-6 of the sterol moiety. They have an aliphatic side chain attached to the C-17 atom and a hydroxyl group attached to the C-3 atom ( Figure 1 ). Cholesterol and plant sterols are originally found as nonesterified and esterified forms of cinnamic acid/fatty acids (FA) or as glycosides. The bound form is usually hydrolyzed in the small intestine by pancreatic enzymes. Free dietary cholesterol absorption in human gut has been estimated at up to 50%, depending on variations of PS structure and molecular weight ( Fassbender et al., 2008 ). The steroid skeleton. All plant species have its characteristic PS composition (Ogbe et al., 2015), with more than 250 PS being recognized so far. Although PS are found in all plant foods, unrefined plant oils, including vegetable, nuts and olive oils, such as sesame, safflower, soybeans, peas, macadamia, and almonds are extremely rich sources; however, nuts, seeds, whole grains, and legumes are also good dietary sources of PS (Sharifi-Rad et al., 2018; Piironen et al., 2003; (Wadikar et al., 2017). They are classified into sterols and stanols, representing the unsaturated and saturated molecules, respectively (Piironen et al., 2000). Beta-sitosterol, 4 of 47 campesterol, and stigmasterol ( Figure 2 ) are the most common plant–derived sterols in human diet. All contain a core skeleton of cholesterol but possess a different side chain. Betasitosterol and stigmasterol have an ethyl group at C-24, whereas campesterol is equipped with a C24-methyl group. Stigmasterol derives from sitosterol by the action of sterol C-22 desaturases. Brassicasterol, and D-7-avenasterol are minor constituents. Stanols are also found in plants, although they form only 10% of total dietary phytosterol (PS) (Jones and AbuMweis, 2009). The structure of the most occurring plant-originated sterols in human diet. Briefly, PSs are biologically active molecules with multiple health applications, and increasing evidence has shown that PS activity depends on various criteria, such as formulation and solubility in the food matrix ( Schiepers et al., 2009 ; Poudel et al., 2019 ). Nonetheless, as humans cannot synthetize PSs, they should obtain them from diet ( Cabral and Klein, 2017 ). There is increasing scientific evidence supporting the idea that PSs and their derivatives have multiple pharmacological properties, including human-wellness-promoting abilities. These health benefits include a great ability to reduce total and low-density lipoprotein (LDL) cholesterol levels, thus decreasing the risk of many diseases ( Plat et al., 2019 ). Moreover, PSs also modulate inflammation; have antioxidant, antiulcer, immunomodulatory, antibacterial, and antifungal effects; and also intervene in wound healing promotion and platelet aggregation inhibition ( Dutta, 2003 ; Ogbe et al., 2015 ). To what concerns to PS health effects and given its long history of safe consumption, they have been targeted of an increasingly specific and highly regulated labeling to ensure consumers protection and safety. So far, the authorized health claims for PS consumption, when consumed as part of a healthy diet and lifestyle, are directly related to its ability to help maintain or reduce the low-density lipoprotein cholesterol (LDL-C) level, with marked reductions in blood cholesterol of 7–12.5% for intakes of 1.5–3 g/day ( Shortt, 2015 ). In addition, issues related to plant sterols and stanols safety have already been declared by international agencies, such as the Food and Drug Administration (FDA) and the European Union Scientific Committee (EUSC) ( Dutta, 2003 ), which clearly reveals their promissory potential at the same time that denotes the huge attention paid to this class of biomolecules. In this sense, the present review is aimed at providing detailed information on PS therapeutic potential for human health, moving from preclinical to clinical pharmacological effects, and bioavailability issues. Preclinical Pharmacological Activities of Phytosterols Experiments in animals and cell manners have shown that PSs may confer a wide number of biological effects, including chemopreventive, antioxidant, anti-inflammatory, antidiabetic, antiatherosclerotic, and cardioprotective agents ( Table 1 ). Preclinical phytosterol (PS) bioactive effects and the respective mechanisms of action. Bioactive effects Mechanism of action Reference Anticancer Decrease the number of aberrant crypt and crypt multiplicity. Attenuate -catenin and PCNA expression. Trigger apoptosis, through increasing Fas protein expression, caspase 8, TRAIL, BAD dephosphorylation, mitochondrial depolarization and caspase 3-dependent PARP cleavage, intracellular Ca2+ influx, rise in ROS levels, cell cycle arrest at phase G0/G1 and S, and cell necrosis Decrease mammary hyperplastic lesions and total tumor burden Cell cycle arrest at G2/M phase Interfere in DNA fragmentation ; ; ; ; ; ; Antioxidant Free radical scavenger Cell membranes stabilizer Antioxidant enzyme booster Anti-inflammatory Macrophage- and neutrophil-mediated inflammatory process Evoke Th1 cell response Decrease edema Decrease proinflammatory cytokine levels Interfere in matrix degradation mediators Increase the remission periods in GI tract diseases, improving colon shortening and blocking mucosal colonic damage ; ; ; Antidiabetic Glucose metabolism modulation Interfere with AMPK and peroxisome proliferator-activated receptors Antiatherosclerotic/effects on lipid profile Cholesterol absorption blockage Decrease LDL-C and VLDL secretion and accumulation Decrease plasma and hepatic TG levels Neuroactive effects Reduce Aβ plaque formation, counteract memory deficits, increase the acetylcholine levels in brain, and increase Aβ clearance Antieryptotic and antihemolytic effects Prevent eryptosis; reduce Ca influx, ROS overproduction, GSH depletion, and hemolysis Microbiota modulation effects Promoters of beneficial species abundance, affecting the Erysipelotrichaceae and Eubacterium family proportions AMPK, adenosine monophosphate (AMP)-activated kinase; DNA, deoxyribonucleic acid; GI, gastrointestinal; LDL-c, low-density lipoprotein cholesterol; PCNA, proliferating cell nuclear antigen; PSs, phytosterols; TG, triglycerides; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; VLDL-C, very-low-density lipoprotein cholesterol. Chemopreventive Effects Several studies have reported that PSs possess anticancer properties through interaction with various cell targets and pathways. Βeta-sitosterol isolated from Asclepias curassavica L. was reported to be effective in colorectal cancer in a dose-related approach. ß -sitosterol supplementation decreased the number of aberrant crypts and crypt multiplicities in 1,2 dimethylhydrazine (DMH)-initiated rats without exerting toxic effects and also attenuated ß -catenin and proliferating cell nuclear antigen (PCNA) expression in human intestinal carcinoma cells ( Baskar et al., 2010 ). Various experiments have also revealed that ß -sitosterol supplementation is effective in MCF-7 and MDA-MB-231 breast cancer cells, triggering apoptosis by increasing Fas protein expression, caspase 8, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) ( Daniel et al., 2001 ; Awad et al., 2007 ; Herbst et al., 2010 ). Awad et al. (2000) observed that ß -sitosterol stimulated apoptosis in MDA-MB-231 cells and reduced tumor size through an estrogen-signaling-independent process. In another study, dietary PS supplementation decreased mammary hyperplastic lesions and total tumor burden in female mice fed with a high-fat diet but not in those with a low-fat diet. This was partly explained by the preventative lipoprotein oxidation/inflammation properties of PSs, which was found to be crucial for tumor expansion ( Llaverias et al., 2013 ). ß -sitosterol and daucosterol identified in Grewia tiliaefolia , alone or in combination, had the potential to promote apoptotic death of A549 lung cancer cells by arresting the cell cycle at the G2/M phase ( Rajavel et al., 2017 ). ß -sitosterol was also found to significantly induce cell viability reduction in cervical cancer cells (HeLa) in a dose-related approach, interfering on DNA fragmentation through the appearance of a sub-G1 cell population ( Alvarez-Sala et al., 2019 ). Cilla and colleagues ( Cilla et al., 2015 ) in a study performed on Caco-2 cells stated that PSs and ß -Cx, used alone or combined, markedly decreased cell viability through mitochondrial pathway-induced apoptosis. As main triggers, the authors reported BAD dephosphorylation, mitochondrial depolarization, and caspase 3-dependent PARP cleavage, along with intracellular Ca 2+ influx and ROS level raise. Similar findings were stated by López-García and colleagues ( López-García et al., 2017 ), who found that PSs trigger cell cycle arrest in phase G0/G1 and cell necrosis in Caco-2 cells. In a similar way, Alvarez-Sala and colleagues ( Alvarez-Sala et al., 2018a ), addressing the PS impact in colon cancer cells (Caco-2 and HT-29 cell lines) used in combination with 5-fluorouracil, stated a pronounced cell cycle arrest at S phase, induction of apoptosis, and rise in caspases activation. Antioxidant and Anti-Inflammatory Activities Several reports have indicated that PSs possess interesting antioxidant and anti-inflammatory effects. In vitro studies indicated that PSs reduced lipid peroxidation in platelet membranes in the presence of iron ( Van Rensburg et al., 2000 ), with PS antioxidant effects being increasingly related to their high ability to act as free radicals scavenger and stabilizer of cell membranes and even act as a boost for antioxidant enzymes ( Van Rensburg et al., 2000 ; Nashed et al., 2005 ; Brüll and Mensink, 2009 ). In addition, the inflammatory process is increasingly related to oxidative stress and reactive oxygen species (ROS) overproduction, so bioactive molecules with pronounced antioxidant effects also have interesting anti-inflammatory potential, and PSs are not an exception. A study performed by López-García and coworkers ( López-García et al., 2020 ) found that a PS-enriched milk-based fruit beverage with/without galactooligosaccharides blocked cholesterol oxidation products oxidation-induced oxidative stress, besides reducing the levels of interleukin (IL)-8 and IL-6 following IL-1β-induction. Indeed, PSs have also been revealed to be able to decrease macrophage- and neutrophil-mediated inflammatory reaction. In vivo studies in mice have indicated that PSs can evoke a 1Th response and decrease edema and proinflammatory cytokine concentrations ( Nashed et al., 2005 ; Brüll and Mensink, 2009 ). The effectiveness of PSs in inflammatory bowel disease has also been tested in mice, where PSs feeding did not obstruct colitis onset but considerably decreased the disorder intensity and enhanced clinical remission ( Vilahur et al., 2019 ). A potent antioxidant action was also seen, almost restoring colon, ileal, and gallbladder motility ( Aldini et al., 2014 ). Additionally, PSs were proved to allow homeostatic stability restoration of hepatic and colon metabolism in an experimental colitis mice model ( Iaccarino et al., 2019 ). Similar findings were stated by López-García and colleagues ( López-García et al., 2019 ) following administration of a PS-enriched milk-based fruit beverage in a murine chronic colitis model, where a marked reduction in ulcerative colitis-associated symptoms was stated along with an improvement in colon shortening and mucosal colonic damage. In vivo studies proved that stigmasterol could inhibit various proinflammatory and matrix degradation mediators involved in triggering osteoarthritis-induced cartilage degrading, at least in part through nuclear factor kappa B (NF-kB) pathway inhibition ( Gabay et al., 2010 ). Antidiabetic Effects Some studies have identified PSs as key modulators of glucose metabolism, through acting on AMP-activated kinase (AMPK) activation or peroxisome proliferator-activated receptors (PPARs) to transcriptional regulation pathways ( Zakłos-Szyda, 2015 ). Hwang et al. have indicated that ß -sitosterol (20 µM) handling of L6 muscle cells increases glucose intake across increased GLUT4 translocation to the plasma membrane ( Hwang et al., 2008 ). A limited rise in blood glucose scale after oral administration of high glucose concentration and increased insulin response was observed in Zucker diabetic fatty rats supplemented with 5-campestenone (0.6%) ( Konno et al., 2005 ). A prominent decrease in blood glucose levels with concurrent glucose elimination inhibition in urine was reported in db/db mice fed with 0.3% 5-campestenone after eight weeks ( Suzuki et al., 2002 ). Effects on Lipoprotein Metabolism In accordance with various surveys, PS administration led to a reduction in total cholesterol (TC) and LDL-C levels by blocking dietary cholesterol absorption and further impacting its hepatic/intestinal biotransformation ( Moghadasian, 2000 ). Male C57BL/6 J mice with high-fat diet supplementation together with 3.1% PS administration for three weeks presented a decrease in very-low-density lipoprotein (VLDL) secretion, while no distinction was found in chylomicron secretion ( Schonewille et al., 2014 ). Epidemiological and experimental data have affirmed that a high-cholesterol diet is detrimental to cognitive performance in animal models. Rui et al. proved that rats fed with a high-cholesterol diet supplemented with 2% g/100 g PS for 6 months maintained body mass match, reduced serum lipid levels, improved cognitive performance, triggered an increase in pyramidal cells number, and had an obvious reduction in the number of astrocytes ( Rui et al., 2017 ). Several studies have emphasized the role of PSs in plasma and hepatic triglycerides (TG) levels modulation ( Rideout et al., 2015b ). Rideout et al. assessed the effect of diet supplemented with 2% w/w PSs on Syrian golden hamsters fed with a high-fat diet for 6 weeks ( Rideout et al., 2014 ). Curiously, the decrease in blood TG in the PS group was similar to that using ezetimibe ( Rideout et al., 2014 ). Similar results were found in other animal studies, considering that some factors, such as the type of diet applied, PS dosage, test period, and diurnal regulation of lipid levels, could contribute to the differences observed in TG-lowering level and associated mechanisms ( Pan et al., 2010 ; Schonewille et al., 2014 ). Thus, given the main findings from animal experiments, it was proposed that PSs are able to lower circulating TG levels through mechanisms involving the reduction of TG and FA uptake, a rise in fecal FA excretion, a decrease in duodenal bile acid excretion, and modulation of hepatic FA and TG metabolism ( Rideout et al., 2015a ). Some in vivo studies with different animal models have delivered conflicting results, such as the case of Brufau et al., who investigated the effect of 2.45% g/100 g PS supplementation on guinea pigs with a high-saturated fat diet for 4 weeks ( Brufau et al., 2007 ). The authors did not state changes in medium chain FAs excretion, but medium/short-chain FA excretion decreased, while an increase in long-chain FA excretions was detected ( Brufau et al., 2007 ). In addition, although total saturated FA fecal excretions did not change, the shift toward greater excretion of longer chain and more hydrophobic saturated FA suggest a reduction in intestinal lipid solubilizing potential, and the study period selected for this experiment may have also affected the obtained results. Antiatherosclerotic Effects Antiatherosclerotic properties of plant sterols are properly developed in several animal models and directly associated with their cholesterol-lowering effects ( Jessup et al., 2008 ). Shariq et al. (2015) studied the antiatherosclerotic effect of virgin coconut oil reported to contain increased levels of PSs on male Wistar rats. The findings revealed a considerable decrease in body weight, TC, TG, LDL, and VLDL and a significant increase in high-density lipoprotein (HDL) levels correlated with antiatherosclerotic effects. Various investigations have also explained a modulatory role for PSs on atherosclerosis due to their anti-inflammatory effects ( Nashed et al., 2005 ; Calpe-Berdiel et al., 2007 ). PSs were found to reduce proinflammatory cytokine generation, namely, IL-6 and tumor necrosis factor (TNF)-α, and increase the Th1/Th2 ratio and the level of Treg cytokine IL-10 in splenocytes of ApoE −/− mice ( Nashed et al., 2005 ; Calpe-Berdiel et al., 2007 ). Increased serum IL-10 levels have also been correlated with a severe reduction in atherosclerotic lesion size ( Pinderski et al., 2002 ; Nashed et al., 2005 ). A marked reduction in atherosclerotic lesions size was also linked to a prominent reduction in other constituents, such as the number of foam cells and cholesterol clefts, extracellular matrix amounts, and the extent of apparently proliferative smooth muscle cells ( Moghadasian, 2000 ). ApoE-deficient mice fed on a diet supplementation with 2% PS for 14 weeks led to changes in the expression of 132 genes, with particular emphasis on hepatic genes involved in sterol biotransformation regulation ( Xu et al., 2008 ). All these changes allow a better understanding of how PSs mechanistically exert their cardioprotective action. Other Effects Besides the above listed biological activities of PSs, some recently published studies have also underlined interesting effects, namely, to what concerns to its antieryptotic and antihemolytic effects and neuroprotective and even microbiota modulatory abilities. In an in vitro study, Alvarez-Sala and colleagues used a selected PS mixture, composed of ß -sitosterol, campesterol, stigmasterol, or ß -cryptoxanthin (β-Cx), and observed that the use of ß -Cx led to an increase in eryptotic cell number and volume, hemolysis, and glutathione depletion (GSH) without ROS overproduction and intracellular Ca 2+ influx ( Alvarez-Sala et al., 2018d ). On the other side, PSs prevented eryptosis, reduced Ca 2+ influx, ROS overproduction, GSH depletion, and hemolysis. However, when both bioactive compounds were coincubated, they completely prevented hemolysis, prevented eryptosis and GSH depletion, and thus may be considered promissory candidates for eryptosis-associated disease healing. In another study, Cuevas-Tena et al. (2018) assessed the plant sterol influence on gut microbiota and vice versa. As main findings, the authors stated that both Erysipelotrichaceae and Eubacterium family proportions were affected by high-dose plant sterols, at the same time that sitosterol and stigmasterol decreased while its metabolites increased. Concomitantly, low TC conversion was stated under plant sterols presence. Thus, plant sterols may be viewed as promoters of beneficial species abundance ( Cuevas-Tena et al., 2018 ). More recently, Schepers et al. (2020) highlighted in a review article prominent neuroactive effects of PSs derived from marine origin. As main statements, the authors clearly highlighted the ability of fucosterol, 24(S)-saringosterol, sitosterol, and stigmasterol to reduce Aβ plaque formation; the ability of fucosterol and 24(S)-saringosterol to counteracts memory deficits; the ability of fucosterol to increase the acetylcholine levels in the brain; and the ability of 24(S)-saringosterol to increase Aβ clearance ( Schepers et al., 2020 ). Adverse Effects Specifically addressing the possible adverse effects related to PSs, first, it is worth noting that in vitro studies have shown that high ß -sitosterol amounts can trigger human umbilical vein endothelial cells shrinking ( Rubis et al., 2008 ). Second, particularly addressing in vivo studies, it should be highlighted that some animal species, such as rodents, may not represent a proper prototype due to the remarkable variations between them and humans in sterol metabolic process ( Dietschy and Turley, 2002 ), although several animal studies have indicated possible undesirable adverse effects of PSs. For example, Chen et al. reported that WKY inbred rats consuming diets containing PSs or phytostanol had a notable rise in systolic and diastolic blood pressure correlated with increased renal angiotensinogen mRNA levels ( Chen et al., 2010 ). Wild-type mice fed with PS or phytostanol diets also showed impaired endothelium-dependent vasorelaxation and grown cerebral lesion area after middle cerebral artery occlusion ( Weingartner et al., 2008 ). In addition, high PS concentrations in plasma of both male and female laboratory animals may have adverse effects on their generative organs ( Malini and Vanithakumari, 1990 ). In rats, both testosterone and estradiol levels in males and females, respectively, were also raised due to ß -sitosterol intake ( Ryokkynen et al., 2005 ). On the other hand, it is also convenient to highlight that plants often accommodate traceable amounts of oxidized derivatives of PSs (oxyPS). These compounds are noticeable in atheromatous plaque, and this may demonstrate their engagement in atherosclerosis expansion ( Patel and Thompson, 2006 ). However, the number of investigations conducted so far is not acceptable to assess the exact metabolic action of oxyPS. In such a way, a recent study published by Alvarez-Sala and colleagues ( Alvarez-Sala et al., 2018b ) measured both the level of oxidized sterols formed and its bioaccessibility in a plant sterol-enriched milk-based fruit beverage with milk fat globule membrane at 0-, 3-, and 6-month storage. As main findings, the authors did not state considerable changes during storage, meaning that such formulation was maintained stable over the studied period, without an increase in oxidized sterols’ contents and bioaccessibility, and thus may be considered as a suitable PS-enriched food matrix for extended shelf-life, in addition of being safe for consumers ( Alvarez-Sala et al., 2018b ). Nonetheless, the authors just assessed a single preparation, and thus further studies are still needed in such a way. Phytosterols in Clinical Trials Phytosterols and cardiovascular risk. A plethora of studies have explored distinct aspects of the clinical efficacy of plant sterols/stanols in lowering LDL-C levels. There have been more than five decades of research on PSs to prove its efficacy in decreasing cholesterol levels. It was shown that PSs inhibit cholesterol intake via cholesterol displacement from micelles ( Ling and Jones, 1995 ), thus reducing the risk of CV diseases ( Vahouny et al., 1983 ; Ikeda et al., 1988 ) ( Figure 3 ). Mechanism of action of phytosterols in reducing cardiovascular diseases. A survey of 46 patients ( Lees et al., 1977 ) with type II hyperlipoproteinemia was conducted to evaluate the effect of plant sterols preparations from two distinct sources and in two physical forms in lowering plasma TC levels, administered along with appropriate diet therapy. The PS hypocholesterolemic potential was also assessed in seven patients by a sterol balance technique, revealing inhibition of TC intake. The maximal mean TC lowering was 12%, which suggests the PS potential value as a dietary therapy adjunct in mild hypercholesterolemic patients ( Lees et al., 1977 ). A clinical trial performed in 153 mild hypercholesterolemic patients revealed that substituting sitostanol-ester margarine as part of the normal daily dietary fat is effective in lowering serum TC and LDL-C, thus having favorable effects ( Miettinen et al., 1995 ). Another report summarizing information from a meta-analysis of 41 trials on sterols and stanols efficacy and safety profile demonstrated that consumption of 2 g/d of stanols or sterols decreased LDL-C by 10% ( Katan et al., 2003 ). Epidemiological studies with TC-lowering drugs showed that its long-term use in the first five years reduces the CV disease risk by 12%–20%, whereas lifetime use reduces it by 20%. Additionally, the adverse effects of plant sterols intake into blood circulation were found to be hypothetical in adults. This study agrees with another meta-analysis of 59 clinical trials ( Abumweis et al., 2008 ), where plant sterols (and stanols)-containing product use when compared to placebo was linked to a reduction in LDL-C levels. An investigation performed to evaluate the PS role in changing plasma lipid levels, when incorporated into nonfat or low-fat beverages on moderately hypercholesterolemic men and women ( Jones et al., 2003 ), revealed that PS absorption in the low-fat beverage format is not effective in changing the lipid levels, namely, HDL-C and triacylglycerol (TAG). While earlier no significant changes in TG levels were documented with the use of stanols and sterols, some meta-analyses have reported a small, but statistically significant decrease in TAG levels ( Gupta et al., 2011 ). Moreover, it has been found that the daily use of 1.6–3 g of esterified PS in the first month of therapy reduces LDL-C levels by 4.1–15% when compared to placebo ( O'neill et al., 2005 ). In a clinical study assessing the effects of plant stanol and sterol esters on serum PS levels in individuals with familial hypercholesterolemia, a reduction in serum TC levels was documented, although the clinical role of increased plant sterol contents was not known ( Ketomaki et al., 2004 ). In a nine-week trial with metabolic syndrome patients receiving a daily dose of 2 g stanol esters, a remarkable decline in non-HDL-C and TAG levels was documented ( Plat et al., 2009 ). Moreover, the TAG effects were also present in combination with a low dose (10 mg) simvastatin treatment, thus depicting the additional benefit of stanol esters use in individuals with CV disease risk. In another study, the effects of the absorption of three phytosterols on whole-body TC metabolic pathway were determined in 18 adults receiving a phytosterol-deficient diet (50 mg PS/2000 kcal) plus beverages supplemented with 0, 400, or 2000 mg PS/day for four weeks each in a random order ( Racette et al., 2010 ). Dietary PS, at moderate (459 mg/day) and high (2059 mg/day) dosages, dose-dependently improved biliary and dietary TC excretion and decreased the efficiency of intestinal TC absorption. In another study, this group of researchers also reported a significant reduction in intestinal TC absorption and an increased fecal TC excretion during ezetimibe administration plus plant sterols (2 g/day) when compared to ezetimibe alone ( Lin et al., 2011 ). This data indicates that PS combination with ezetimibe notably improved the ezetimibe effects, thus emphasizing the dietary importance of PS as adjunctive therapy for hypercholesterolemia. In addition, it has been reported that the effective daily dose range of PS is between 1 g and 3 g, beyond which it offers no additional benefits and fully effective therapy can take up to eight weeks ( Malinowski and Gehret, 2010 ). Another clinical study with 41 men and women designed to explore the activity of PS capsules on circulating LDL-C levels in patients with mild-to-moderate hypercholesterolemia revealed that daily PS intake in capsules (2 g) did not decline TC or LDL-C levels ( Ottestad et al., 2013 ). These findings emphasize the need for choosing a suitable dose delivery system to reach optimal TC-lowering effects. A clinical trial with 182 hypercholesterolemic adults was performed to assess the long-term effectiveness of 2 g/day of plant stanols for 12 months in reducing LDL-C levels ( Parraga-Martinez et al., 2015 ). As main findings, >10% reduction in plasma LDL-C levels was stated from baseline at both three months and one year of consumption, hinting its role in reducing CV disease risk. As plant sterols have been reported to reduce plasma LDL-C, a double-blind randomized placebo-controlled parallel-group study was performed in hypercholesterolemic patients ( Ras et al., 2013 ). Healthy men and women used low-fat spreads without or with added PS (3 g/d) for 12 weeks after a four-week run-in period ( Ras et al., 2013 ). The time curves of changes in plasma PS for 12 weeks of PS intake and the impact of TC synthesis and absorption in plasma PS were also exploited. The authors stated a plasma PS levels stabilization within four weeks of PS intervention, which were not impacted by basal TC synthesis or absorption efficiency. Due to the high prevalence of lactose intolerance in China, a study was designed to evaluate if PS-rich milk is effective in lowering serum LDL-C ( Cheung et al., 2017 ). Other participants ( n = 221) without TC-lowering drugs or diabetes mellitus were assigned to a daily intake of PS-rich low-fat milk, containing 1.5 g PS/day or conventional low-fat milk for three weeks. Blood profile and physical examination were also performed. As compared to control, the treated group depicted a remarkable decline in serum LDL-C and TC levels and diastolic blood pressure; thus, it can be used as part of a healthy diet. A three-arm, double-blind, randomized clinical trial in mildly hypercholesterolemic subjects was conducted to analyze the effects of PSs, red yeast rice, or both nutraceuticals on lipid pattern over an 8-week treatment period, as well as their tolerability ( Cicero et al., 2017 ). It was documented that the additive lipid-lowering effect of PSs and red yeast rice enhanced lipid parameters with good short-term tolerability as depicted by a significant reduction in LDL-C and apolipoprotein B levels comparing with individual treatments of these two nutraceuticals. In addition, a double-blind randomized placebo-controlled crossover intervention study was performed with healthy volunteers (without or mild hypercholesteremia) to assess the activity of plant sterol esters supplemented margarine on TC, non-TC sterols, and oxidative stress in serum and monocytes ( Weingartner et al., 2017 ). The authors stated that plant sterol ester consumption supplemented margarine led to a rise in plant sterol contents and TC synthesis markers, without affecting serum TC and activating circulating monocytes or redox state ( Weingartner et al., 2017 ). Considering the high occurrence of nonalcoholic fatty liver, the role of dietary cholesterol in liver inflammation, and the PS action on TC metabolism, the PS therapeutic potential against nonalcoholic fatty liver disease has also been explored ( Javanmardi et al., 2018 ). It has been documented that, as compared to the placebo, PS additive remarkably enhanced LDL-C, aspartate aminotransferase, alanine aminotransferase, and TNF-α levels. However, no remarkable differences were stated between the two groups with regard to TC, TG, HDL-C, VLDL-C, LDL-C/HDL-C, and TC/HDL-C ratios, gamma-glutamyl transferase, IL-6, high-sensitivity C-reactive protein (hs-CRP), adiponectin, and leptin levels. The effect of dietary intervention with PSs, with or without curcumin, on blood lipids in hypercholesterolemic individuals was also investigated in a double-blind, randomized, placebo-controlled, 2 × 2 factorial trial ( Ferguson et al., 2018 ). The authors documented that curcumin addition to PS therapy led to a complementary TC-lowering effect, larger than PS therapy alone without adverse effects. Another study assessed the TC-lowering activity of 2 g of plant sterols from sterol-rich cereals through the form of a whole grain wheat biscuit, in 50 volunteers with a TC > 5.5 mmol/L in a randomized crossover trial with two four-week periods ( Clifton and Keogh, 2018 ). It was observed that the LDL-C lowering effect of the whole grain wheat biscuit did not vary from other foodstuff delivering 2–2.5 g of plant sterols daily. Recently, a study assessed the gender differences in LDL-C lowering activity post-PS intervention ( San Mauro-Martín et al., 2018 ), where milk intake with 2.2 g/day of added PSs significantly lowered LDL-C levels in men. In studies on prepubertal children with familial hypercholesterolemia, dietary plant sterol/stanol consumption did not ameliorate endothelial function despite the significant decrease in LDL-C levels ( De Jongh et al., 2003 ; Jakulj et al., 2006 ). Interestingly, some early reports have documented that the mildly elevated plant sterol levels are positively impacted with vascular disease ( Sudhop et al., 2002 ; Assmann et al., 2006 ), whereas others referred to an inverse or even lack of association between circulating plant sterols and CV disease risk ( Windler et al., 2009 ; Escurriol et al., 2010 ). Such variations in PS effects have been increasingly exploited in a tentative way of clarifying the different findings obtained by different authors ( Borel and Desmarchelier, 2018 ). Some recent studies have found variations in both PS absorption and consequent bioavailability, attributed to genetic polymorphisms, namely, that of ABCG5/G8, as other proteins/genes directly or indirectly involved in PS transportation to enterocyte, blood, and even other tissues. Moreover, variations in both Niemann-Pick C1 Like 1 transporter (NPC1L1) and apolipoprotein E (APOE) have also been reported as having a great impact on PS bioavailability ( Borel and Desmarchelier, 2018 ). More detailed attention is given in the section PS bioavailability. Phytosterols and Cancer Risk Dietary and lifestyle factors play a critical role in cancer etiology. PSs are well recognized for their role in maintaining blood TC levels, but their potential in the area of anticancer research is still unexplored, with case-control studies showing no causal effect ( Figure 4 ). For example, a randomized, double-blind, placebo-controlled multicenter trial in patients with benign prostatic hyperplasia (BPH) was performed over 6 months, using β-sitosterol (which contains a mixture of PSs) three times/day or placebo ( Berges et al., 1995 ). Although no relevant decline in prostatic volume was observed in the ß -sitosterol and placebo group, a remarkable improvement was seen in symptoms and urinary flow parameters, revealing the ß -sitosterol effectiveness. Similar results were reported in another clinical study, using the ß -sitosterol for the treatment of BPH, where results demonstrated slightly more rapid changes than that stated by Berges et al., (1995) with a difference of 2.6 points over placebo after four weeks ( Klippel et al., 1997 ). A case-control study was also performed to determine the protective role of plant sterols in lung carcinogenesis in 463 subjects ( Mendilaharsu et al., 1998 ). It was concluded that the highest quartile intake of PSs led to a 50% reduction in lung cancer risk. Another case-control study found that the highest PS intake is inversely related to gastric cancer risk ( De Stefani et al., 2000 ). Anticancer effects of phytosterols. Looking at ovarian cancer, a case-control study was conducted in 124 confirmed ovarian cancer cases to determine the impact of food diet, via a detailed food frequency questionnaire ( Mccann et al., 2003 ). As compared with women in the lowest quintile of intake, a lower risk was documented for women in the highest quintile of stigmasterol intake, thus supporting the assumption that phytoestrogen intake exerts a protective action on ovarian cancer ( Mccann et al., 2003 ). Conversely, in a cohort study on 3,123 subjects with colon and rectal cancer risks, no association was observed between PS intake and a lower risk of colon and rectal cancers ( Normen et al., 2001 ). Moreover, a recently published meta-analysis aiming to provide a comprehensive synopsis on PS intake and cancer risk highlighted a linear association for campesterol and a nonlinear association for total PS intake and cancer risk. Such findings support that high PS intake is inversely related to cancer risk, although further and more in-depth studies are needed, particularly of prospective design to more clearly know the PS contribution to anticancer effects ( Jiang et al., 2019 ). Phytosterols and Gestational Diabetes Gestational diabetes mellitus (GDM) is a rapidly growing serious health complication over pregnancy. A clinical study designed to assess the action of a PS-rich margarine spread daily consumed on insulin resistance and lipid profile in GDM women revealed that, after 16 weeks, TAG, TC, and LDL-C levels were remarkably reduced, while HDL-C increased when compared to baseline ( Li and Xing, 2016 ). Additionally, fasting plasma glucose and serum insulin levels, insulin check index, and ß -cell function were also remarkably improved. In another clinical study, the effect of PS-rich margarine spreads consumed daily was assessed on both maternal and neonatal outcomes of GDM patients ( Gao et al., 2017 ). It was observed that the daily consumption of the PS-rich spread led to remarkable benefits on maternal diabetic symptoms, namely, in improving lipid composition and glucose metabolism and decreasing the incidence of neonatal complications. Phytosterols and Immunomodulation Although the role of PSs in immunomodulation has not yet been extensively exploited, studies have suggested their impact on the immune system, via T cells ( Bouic, 2001 ) ( Figure 5 ). Thus, to assess the effects of acute plant stanol esters intake on gene profile expression of the upper small intestine in healthy volunteers, a double-blind crossover design was performed in 14 healthy subjects ( De Smet et al., 2015 ). Microarray analysis showed that the acute plant stanol esters intake did not change genes profiles expression. Nevertheless, T-cell function-involved pathways were consistently downregulated in the jejunum. In vitro and ex vivo investigations have demonstrated that plant sterols and stanols can shift the T helper (Th) 1/Th2 balance toward a Th1-type immune response, which may be beneficent in Th2-dominant conditions, such as asthma and allergies. In another study, the effects of plant stanol esters on the immune response of asthma patients were assessed ( Brüll et al., 2016 ). For that, 58 asthmatic patients were recruited, with half of them receiving plant stanol-rich soy-based yogurts (4.0 g plant stanols/day), while the others consumed control yogurts ( Brüll et al., 2016 ). It was found that asthmatic patients receiving plant stanol-rich soy-based yogurts had higher antibody titers against hepatitis A virus (3 and 4 weeks after vaccination) and marked reductions in plasma total Ig-E, IL-1β, and TNF-α levels ( Brüll et al., 2016 ); thus, plant stanol ester consumption was able to improve the immune function in asthmatic patients. More recently, Alvarez-Sala et al. (2018a) assessed the impact of a milk-based fruit beverage with a milk fat globule membrane on the levels of cholesterol and cholesterol precursors, serum biomarkers, and cytokines in postmenopausal women. As main findings, the authors stated a marked decrease in TC and LDL levels and a marked increase in the precursor lanosterol with a concomitant decrease in the proinflammatory cytokine IL-1β; such observations clearly underline that this beverage may promote the CV health in postmenopausal women given its impact on both inflammatory status and CV risk factors ( Alvarez-Sala et al., 2018c ). Immunomodulatory effects of phytosterols. Phytosterols and Osteoporosis A clinical trial analyzed the effect of ß -Cx plus PSs on CV risk and bone turnover markers in postmenopausal women, who are at higher risk of CV disease and bone demineralization ( Granado-Lorencio et al., 2014 ). Interestingly, it was observed that ß -Cx enhances the TC-lowering action of PSs when simultaneously supplied with this combination providing benefits in reducing the risk of osteoporosis. The clinical trials of PSs performed on CV risk, cancer risk, gestational diabetes, immunomodulation, and osteoporosis are summarized in Table 2 . Clinical studies with PS effects in humans. Disease/reference Type of study and subjects Treatment Outcomes Cardiovascular risk  Lees et al. CT type II hyperlipoproteinemic patients ( = 46). Duration: 7 years Plant sterols preparations from two distinct sources and in 2 physical forms (soy sterols suspension (18 g/day) and powder (18 g/day) and tail oil sterols suspension (3 and 6 g/day) and powder (3 g/day)) Decrease in plasma TC (12%, = 0.001) and LDL-C (17%, < 0.001) levels  Miettinen et al. RCT mild hypercholesterolemic patients ( = 153). Duration: one year Sitostanol-ester margarine ( = 102; 1.8 and 2.6 g/day) and margarine without sitostanol ( = 51) 10.2% and 14.1% decrease in serum TC and LDL-C levels in the sitostanol group and 0.1% and 1.1% in the control group, respectively ( < 0.001)  Jones et al. CT moderately hypercholesterolemic patients (men and women; = 15). Duration: 21 days Nonfat placebo and nonfat and low-fat beverages with added PS PS absorption in the low-fat and nonfat beverages was not effective in changing HDL-C and triacylglycerol levels  Ketomaki et al. CT family with familial hypercholesterolemia. Duration: 3-4 weeks Plant stanol and sterol esters on serum PS levels Reduction in serum TC (14%) and LDL-c (17%) levels ( < 0.001)  Plat et al. RCT metabolic syndrome patients ( = 36). Duration: 9 weeks Placebo ( = 9), simvastatin + placebo drink ( = 10), placebo + stanol drink ( = 9), and simvastatin + stanol drink ( = 8) Stanol esters (2 g/day), simvastatin, or the combination decreased non-HDL-C ( < 0.001) and TAG ( < 0.01) levels; additional benefits were also seen when stanol esters were combined with simvastatin  Racette et al. CT adults receiving a PS-deficient diet (50 mgPS/200 kcal), supplemented with different PS doses ( = 18). Duration: 4 weeks Three PS doses (59, 459, 2059 mg PS/day) Moderate (459 mg/day) and high (2059 mg/day) dosages, dose-dependently improved biliary and dietary TC excretion ( < 0.01), and decreased intestinal TC absorption efficiency ( < 0.01)  Lin et al. RCT mildly hypercholesterolemic subjects ( = 21). Duration: 3 weeks PS-controlled diet plus (1) ezetimibe placebo + PS placebo, (2) 10 mg ezetimibe/day + PS placebo, and (3) 10 mg ezetimibe/day +2.5 g PS/day Reduction in intestinal TC absorption ( < 0.0001) and an increased fecal TC excretion ( < 0.0001) during ezetimibe administration plus PS, when compared to ezetimibe alone  Ottestad et al. RCT mild-to-moderate hypercholesterolemic patients ( = 41 men and women). Duration: 2 × 4 weeks Soft gel capsules containing either PS (2.0 g/d) or sunflower oil Daily PS intake in capsules did not decline TC ( = 0.74) or LDL-C ( = 0.32) levels  Parraga-Martinez et al. RCT hypercholesterolemic adult patients ( = 182). Duration: 12 months Plant stanols (2 g/day) group and control group (receiving unsupplemented yogurt) >10% reduction in plasma LDL-C levels was stated ( = 0.011) from baseline at both three months and one year of plant stanols consumption  Cheung et al. RCT adults ( = 221) without TC-lowering drugs or diabetes mellitus (41 men and 180 women). Duration: 3 weeks PS-rich low-fat milk, containing 1.5 g PS/day ( = 110) or a conventional low-fat milk ( = 111) PS group revealed a marked decline in serum LDL-C (−9.5%, < 0.001), TC levels ( < 0.001), and diastolic blood pressure ( = 0.01)  Cicero et al. RCT mild-to-moderate hypercholesterolemic subjects ( = 90). Duration: 8 weeks PS (800 mg), red yeast rice (5 mg monacolins), or both combined nutraceuticals Additive lipid-lowering effect of PS and red yeast rice enhanced lipid parameters with a marked reduction in LDL-C (−20.5%, < 0.001) and apolipoprotein B (−14.4%, < 0.001) levels compared with individual treatments of these two nutraceuticals  Weingartner et al. RCT healthy volunteers, with no or mild hypercholesterolemia ( = 16). Duration: 4 weeks Plant sterols (3 g/day) via a supplementedmargarine Plant sterols led to a rise in serum levels of plant sterols (campesterol, = 0.005; sitosterol, < 0.001) and of TC synthesis (desmosterol, = 0.006; lathosterol, = 0.012) markers, without affecting serum TC and activating circulating monocytes or redox state  Javanmardi et al. RCT nonalcoholic fatty liver disease patients ( = 38). Duration: 8 weeks PS group ( = 19, received 1.6 g PS supplement) and control group ( = 19, 1.6 g starch daily) Compared to placebo, PS group remarkably enhanced LDL-C ( = 0.030), AST ( = 0.010), ALT ( = 0.001), and TNF-α ( = 0.006) levels. No differences were stated between the two groups with regard to TC, TG, HDL-C, VLDL-C, LDL-C/HDL-C, and TC/HDL-C ratios, gamma-glutamyl transferase, IL-6, hs-CRP, adiponectin, and leptin levels  Ferguson et al. RCT hypercholesterolemic individuals ( = 70). Duration: four weeks Placebo ( = 18, no PS or curcumin), PS ( = 17, 2 g/day), curcumin ( = 18, 200 mg/day), and PS + curcumin (2 g/day + 200 mg/day) Curcumin addition to PS led to a complementary TC-lowering effect, larger than PS therapy alone ( < 0.0001), with no adverse effects  Clifton et al. RCT volunteers with a TC > 5.5 mmol/L ( = 50). Duration: 2 × 4 weeks Breakfast wheat biscuit (2 g PS) and standard wholegrain wheat breakfast cereal biscuit LDL-C lowering effect between wholegrain wheat biscuits and plant sterol-enriched wholegrain wheat breakfast cereal biscuit was 0.23 mmol/L (5.6%, = 0.001)  San Mauro-Marín et al. RCT gender differences in LDL-C lowering activity of PS ( = 30 women and 24 men). Duration: 2 × 3 weeks 2.2 g/day of added PS in 700 ml milk PS-enriched milk intake led to a decrease in LDL-C levels in men Cancer  Berges et al. RCT patients with benign prostatic hyperplasia ( = 200). Duration: 6 months Β-sitosterol (20 mg, which contains a mixture of PS), three times/day or placebo Remarkable improvement ( < 0.01) in symptoms score and urinary flow parameters, thus revealing the -sitosterol effectiveness  Klippel et al. RCT patients with benign prostatic hyperplasia ( = 177). Duration: 6 months β-sitosterol (130 mg) and placebo Marked improvements ( < 0.01) in symptoms score and quality of life index and an increase in Qmax and a decrease in postvoid residual urinary volume  Mendilaharsu et al. CCS lung cancer cases ( = 463) and hospitalized controls ( = 465). Duration: 3 years Plant sterols intake, through food frequency questionnaire Highest quartile intake of PS led to a 50% reduction in lung cancer risk (OR 0.29, 95% CI, 0.14–0.63)  De Stefani et al. CCS gastric cancer cases ( = 120) and controls ( = 360). Duration: 2 years Plant sterols, through food frequency questionnaire Highest PS intake was inversely related to gastric cancer risk (OR 0.09, 95% CI, 0.02–0.32)  McCann et al. CCS Ovarian cancer cases ( = 124) and controls ( = 696). Duration: 2 years Impact of food diet, via detailed food frequency questionnaire A lower risk was documented for women in the highest quintile of stigmasterol intake (OR 0.42, 95% CI, 0.20–0.87)  Normen et al. CS colon ( = 620) and rectal ( = 344) cancer cases. Duration: 6.3 years No association was found between PS intake and a lower cancer risk  Li et al. RCT women with gestational diabetes mellitus ( = 206). Duration: 16 weeks Margarine spread with ( = 102) or without ( = 104) PS In PS-rich margarine spread, TAG ( = 0.017), TC ( = 0.032), and LDL-C ( = 0.027) levels were remarkably reduced, while HDL-C ( = 0.041) increased compared to baseline; also, fasting plasma glucose ( = 0.021) and serum insulin ( = 0.018) levels, insulin check index ( = 0.035), and -cell function ( = 0.029) were also remarkably improved  Gao et al. RCT women with gestational diabetes mellitus ( = 244). Duration: 13 weeks Margarine spread with ( = 123) or without ( = 1 21) PS PS-rich margarine spread had benefits on maternal diabetic symptoms, namely, in improving lipid composition (TC, = 0.03; LDL, = 0.02; HDL, = 0.03) and glucose metabolism ( = 0.03), decreasing the incidence of neonatal complications  De Smet et al. CT healthy subjects ( = 14). Duration: 4 h Snake with or without plant stanol esters (4 g/day) No changes in genes profiles expression; T-cell function-involved pathways were downregulated in the jejunum  Brull et al. RCT asthmatic patients ( = 58). Duration: 2 + 8 weeks Plant stanol-rich soy-based yogurts (4 g stanols/day) or control yogurts Higher antibody titers against hepatitis A virus (three and four weeks postvaccination, = 0.037 and = 0.030, respectively) and marked reductions in plasma total Ig-E, IL-1β ( < 0.05), and TNF-α ( < 0.05) levels in treated group  Granado-Lorencio et al. RCT postmenopausal women ( = 38). Duration: 4 weeks β-cryptoxanthin (0.75 mg/day) and PS (1.5 g/day), single or combined β-cryptoxanthin combined with PS led to marked changes in TC ( = 0.0047), HDL-C ( = 0.0057), and LDL-C ( = 0.0014) levels and bone turnover markers AST, aspartate aminotransferase; ALT, alanine aminotransferase; CT, clinical trial; CS, cohort study; CCS, case–control study; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; LDL-c, low-density lipoprotein cholesterol; PSs, phytosterols; RCT, randomized controlled trial; TC, total cholesterol; TAG, triacylglycerol; VLDL-C, very-low-density lipoprotein cholesterol. Bioavailability of Phytosterols PSs are absorbed from food in the proximal small bowel and incorporated into micelles ( Salen et al., 2006 ; Miras-Moreno et al., 2016 ). At the same time, the PS absorption is lesser than that of cholesterol, because of intestinal lumen selectivity and return, through an ABC-transporter–mediated process. Only a small amount of PSs administered with food is absorbed and reaches the systemic circulation ( Ostlund et al., 2002 ). In addition, PSs are not produced in the human organism, and the concentration of PSs circulating in the human body is two hundred times less than that of cholesterol in subjects with the usual type of nutrition ( Chan et al., 2006 ; Ras et al., 2013 ). According to Miettinen et al. (1990) , the content of plant sterols in human blood is only 0.1–0.14% of TC level. In a healthy human, sitosterol/cholesterol ratio on a molar basis is around 1 to 800–1,000 ( Shahzad et al., 2017 ). Mellies et al. (1976) found that 300–900 mg/day of plant sterol consumption with food led to a significant amassing in plasma (0.44 μM) of children ( Mellies et al., 1976 ). In some studies, it appeared that plant sterol conversion to stanols significantly reduces LDL-C serum levels ( Ikeda and Sugano, 1978 ; Sugano et al., 1978 ; Becker et al., 1993 ). Since nonesterified stanols may have restricted bioavailability to block cholesterol intake ( Denke, 1995 ), a trial was made to increase their bioavailability by converting nonesterified bioavailable stanols into FA stanol esters ( Heinemann et al., 1986 ). Plant stanols esters can easily dissolve in oils or margarine. They suffer intestinal hydrolysis, releasing nonesterified stanols bioavailable to block cholesterol absorption in the intestine. In Vitro Phytosterol Bioavailability Baldi and Pinotti reported that milk fat is an effective delivery system for highly hydrophobic compounds, such as PSs ( Baldi and Pinotti, 2008 ). In addition, the occurrence of lecithin or unsaturated FA (oleic, linoleic, and a -linolenic acids) ( Brown et al., 2010 ) may improve cholesterol and/or PS inclusion in a micelle-mixed bile model. Some studies have also focused on sterols solubility assessment after digestion product imitation containing orange juice enriched with PS or multivitamin/multimineral tablets dissolved in orange juice ( Bohn et al., 2007 ), PS-rich commercially available fermented milk beverages ( Vaghini et al., 2016 ), and skimmed milk and/or fruit beverages. Data show that both matrix and component composition of PSs present in food have a key effect on their bioavailability. For example, Alvarez-Sala et al. developed a functional milk-based fruit drink with PSs modified with lipid components/emulsifiers to increase PS bioavailability. The authors found that the content of the sum and individual PSs, fat, type of emulsifier, and homogeneity in beverages differed ( Alvarez-Sala et al., 2016 ). Individual PSs in one and the same beverage showed a similar bioavailability, except the beverage without fat addition, where the highest bioavailability corresponded to campestanol. In the beverage, with olive oil and soy lecithin inclusion (where there was less homogeneity), stigmasterol had the lowest bioavailability. Beverages with higher fat content (2.4%) revealed higher PS bioavailability (31.4% and 28.2%, respectively) compared to those where the fat content was 1.1% (8.7%). According to the authors, the fat content in the food matrix may contribute to mixed micelles formation during gastrointestinal (GI) digestion. In general, data showed that PS bioavailability is influenced by both fat type/amount and the type of emulsifier used ( Alvarez-Sala et al., 2016 ). In addition, milk fat and whey proteins addition increase the bioavailability of both the sum and individual PSs, in particular, campestanol, and stigmasterol ( Alvarez-Sala et al., 2016 ). Nik et al. found in a simulated digestion model in the duodenum that ß -sitosterol, campesterol, and stigmasterol bioavailability (transfer to the aqueous micellar phase) ranged from 72 to 93% ( Nik et al., 2011 ). These data were higher than that reported in another study ( Alvarez-Sala et al., 2016 ), possibly due to a less complex food matrix. Vaghini et al. and colleagues investigated the bioavailability of both selected plant sterols and stanols from four (A–D) commercial fermented milk drinks using in vitro GI digestion, including mixed micelles formation. PS amount in beverage samples ranged from 1.5% to 2.9% (w/w). ß -sitosterol was present in all samples but prevailed in samples A and B (about 80% of the total PS number) ( Vaghini et al., 2016 ). Campesterol concentration in the samples was as follows: C (22%) > A (7%) > B (5%). Sitosterol was the most common in sample D (85%), while stigmasterol was only present in sample C (33%). The highest degree of bioavailability in the PS sum was related to samples A and B (16–17%), followed by D (11%) and C (9%). The PS sum bioavailability was not related to protein, lipids, or PS content in beverages, while in samples with higher carbohydrates and fiber content, bioavailability was lower. The individual PS bioavailability differed relatively to the sample and was not related to sample’s PS profile, indicating a high dependence on food matrix composition. Studies searching for mutations that cause sitosterolemia were original research aiming to identify genetical variations associated with PS bioavailability. Findings from these studies allowed us to associate this disorder with mutations in ABCG5 and ABCG8 genes, encoding 2 ATP-binding cassettes (sterolin-1 and -2) acting as hemitransporters ( Borel and Desmarchelier, 2018 ). These proteins are responsible for PS removal from enterocytes into enteral lumen and hepatocytes from bile. This finding indicates that genetic polymorphisms in these genes may modulate PS bioavailability, although probably less; therefore, it is asymptomatic. This has been confirmed by several associative studies ( Borel and Desmarchelier, 2018 ). However, these results do not present definitive evidence that single nucleotide polymorphisms in these transporters affect the intestinal PS absorption. It seems feasible that the observed associations may be due to the PS effects on hepatocyte excretion but not on enterocytes. Other authors also showed that single nucleotide polymorphisms in ABCG8 can modulate changes in PS content in the blood, thus affecting their bioavailability ( Borel and Desmarchelier, 2018 ). PS bioavailability is not only controlled by ABCG5/G8, as other proteins/genes directly or indirectly participate in PS transportation through the enterocyte, as well as into the blood and other tissues. For instance, at enterocytes level, it has been shown that PSs are absorbed, at least partially, by a Niemann-Pick 1C Like 1 transporter (NPC1L1)-mediated process ( Borel and Desmarchelier, 2018 ). Thus, genetic variations in other genes, other than ABCG5/G8, may be involved in PS bioavailability modulation. The search for candidate gene associations was only focused on NPC1L1 and apolipoprotein E (APOE). First, it was confirmed that NPC1L1 is the single nucleotide polymorphisms that modulate PS bioavailability ( Borel and Desmarchelier, 2018 ). In two studies, it was observed that, in subjects with apoE 3/4 or 4/4 alleles, the PS bioavailability was higher than in subjects with the apoE 3/3 allele. However, no biological mechanism has been proposed to explain how APOE can modulate PS absorption. This requires further research ( Borel and Desmarchelier, 2018 ). Blanco-Morales et al. ( Blanco-Morales et al., 2018 ) studied the action of adding galactooligosaccharides on sterols bioavailability in milk-fruit–based beverages, enriched with three plant sterols, after micellar GI digestion, and found that galactooligosaccharides addition did not affect the overall PS bioavailability. In Vivo Phytosterol Bioavailability Plant sterols are absorbed by many animals, with dogs, pigs, mice, rats, and sheep having approximately 10–20 times more sitosterol in serum and tissues than humans (∼5 µM) ( D'Hollander and Chevallier, 1969 ; Kuksis et al., 1976 ; Sugano et al., 1978 ; Strandberg et al., 1989 ; Miettinen et al., 1990 ; Morton et al., 1995 ; Shahzad et al., 2017 ). In spite of structural similarities between cholesterol and PSs, their intake in the intestines of mammals is low. Overall, the PS absorption rates are 0.5%, 1.9%, 0.04%, and 0.16% for ß -sitosterol, campesterol, sitostanol, and campestanol, respectively, compared to that of cholesterol (56%) ( Ostlund et al., 2002 ; Ostlund, 2007 ). The low PS absorption when compared to cholesterol is attributed to their quick resecretion from intestinal cells back into the GI lumen through ABC G5 and ABC G8 transporters ( Berge et al., 2000 ). Comparison of Preclinical and Clinical Findings Garcia-Llatas et al. ( Garcia-Llatas et al., 2015 ) investigated for the first time preclinical and clinical PS bioavailability. Two fruit beverages based on milk were used; they were enriched with plant sterols and ß -Cx, and their suitability was compared as phytosterol-rich food matrices and feasible effects on PS absorption ( Garcia-Llatas et al., 2015 ). As main findings, the authors concluded that both in vitro (bioaccessibility determined from simulated gastrointestinal digestion) and in vivo (response in serum from individuals of an interventional study) models give similar results. In 36 postmenopausal women, Garcia-Llatas et al. (2015) stated that serum campesterol concentrations were notably raised (within 0.3–0.4 μg/ml) one month after beverage intake (1.5 g of PS/day). Thus, the authors concluded that the duration of PS-rich foods intake may affect serum levels and, consequently, their absorption. In the studies of Garcia-Llatas et al. (2015) , Plana et al. (2008) , and Casas-Agustench et al. (2012) , with a duration of 28–42 days, it was established that the composition of bioavailable PS consumed with food included ß -sitosterol (≥ 70%) and campesterol (≤ 10%). A longer investigation (up to 90 days) suggested that the bioavailability of both PS was equalized. After three months, the authors established lesser contents of ß -sitosterol (37–50%) and higher contents of campesterol (20–30%) in the subject's serum ( Hernandez-Mijares et al., 2010 ). Phytosterol Bioavailability in Humans Ostlund et al. (2002) assessed the systemic intake of lecithin-emulsified ∆ 5 -PS and phytosterols consumed with food and having isotopic labeling. The absorption of 600 mg of soybean Δ 5 sterols added to subject's standard breakfast was 0.512 ± 0.038% for sitosterol, 1.89 ± 0.27% for campesterol, 0.0441 ± 0.004% for sitostanol, and 0.155 ± 0.017% for campestanol. The authors also stated that the lack of a double bond in position five of the sterol cycle reduced absorption by more than eightfold. Indeed, the plasma concentration (t½) for stanols was achieved faster than that for delta5-sterols. Thus, it was stated that PS absorption proficiency is lower than previously stated. Indeed, both campestanol and sitostanol absorption were solely ∼10% of the absorption of the corresponding ∆ 5 sterols, which indicates the dominant effect of the double bond saturation on absorption. Several investigations have tested the serum PS concentrations after consuming PS-rich foods. These low-fat products included dairy products, such as low-fat milk and yogurt or fermented milk. All these studies were published by Ras et al., (2013) in a meta-analysis, including data from 41 studies, with a total of 2084 patients. The average PS dose added to food was 1.6 g/day (range: 0.3–3.2 g/day). Plasma sitosterol and campesterol concentrations were raised by on average 2.24 μmol/L (31%) and 5.00 μmol/L (37%), respectively, compared to control. The increase in both sitosterol and campesterol concentrations was due to the total PS and baseline doses used and the composition of the tested products. For PS doses of 2.0 g/day and 3.2 g/day, the increase for sitosterol and campesterol averaged 3.56 μmol/L and 7.64 μmol/L, respectively. Baseline plasma sitosterol (6.9 μmol/L) and campesterol (13.1 μmol/L) concentrations stated by Ras et al., (2013) were also comparable to that previously published by Chan et al., (2006) , who included data from 45 studies, where the average baseline concentrations of sitosterol and campesterol in the general population were 7.9 μmol/L and 14.2 μmol/L, respectively. According to Ras et al., (2013) , changes in plasma PS concentration were linked to the PS dose daily consumed, and it was also established that the higher the dose, the greater the increase in both sitosterol and campesterol concentrations. The authors also reported that an even greater increase in plasma PS may be at doses >3.2 g/day. Davidson et al. ( Davidson et al., 2001 ) also assessed the PS content in the blood serum when 3, 6, and 9 g PS/day were added to food and found that the increase in serum PSs differed slightly between the three doses used. However, even at the highest dose (9 g/day), the total absolute PS doses remained < 2 mg/dl (∼50 μmol/L). Another work showed an increase in PS intake (1.25, 2.5, and 5 g/day) along with a minerals’ mixture over three consecutive five-week periods ( Tuomilehto et al., 2009 ). Serum sitosterol contents were raised dose-dependently, while campesterol did not. These results do not allow clear conclusions regarding dose-response relationships for plasma PS at higher doses when consumed with food (> 3 g/day). The PS mixture composition and the source type also affected the magnitude of sitosterol and campesterol concentration increase in plasma. In separate studies, plasma PS concentrations were determined at different time points ( De Jong et al., 2008 ), and differences in plasma concentrations of both sterols appeared to stabilize over time. For example, in the study of De Jong et al. (2008) , the plasma concentrations of sitosterol and campesterol were the same after 45 and 85 weeks. Salen et al. (1970) also found that oral PS bioavailability is extremely low (0.5–5%), depending on the sterols structure. In their study, ß -sitosterol metabolism was compared with that of cholesterol in 12 patients who consumed ß -sitosterol from a typical American diet. Plasma ß -sitosterol concentration ranged from 0.30 mg/100 ml to 1.02 mg/100 ml, and plasma levels increased only slightly when the intake of ß -sitosterol was significantly increased. With the consumption of food devoid of plant sterols, plasma and feces were quickly released from ß -sitosterol. The concentration of esterified ß -sitosterol in plasma was similar to that of cholesterol. However, the ß -sitosterol esterification rate was lower than that of cholesterol ( Salen et al., 1970 ). Thus, as studied patients do not have an endogenous ß -sitosterol synthesis, the daily ß -sitosterol turnover was equal to its daily intake after a meal. ß -sitosterol absorption was 5% (or less) of daily intake, while that of cholesterol was 45–54%. Around 20% of ß -sitosterol absorbed is metabolized to cholic and chenodeoxycholic acid, while the exceeding is excreted in the bile as a free sterol, with its elimination being faster than that of cholesterol ( Salen et al., 1970 ). Metabolic turnover, absolute oral bioavailability, clearance, and distribution volume of ß -sitosterol were tested by Duchateau et al. in healthy volunteers ( Duchateau et al., 2012 ) using [ 14 C] β-sitosterol as an isotopic indicator at doses ranging from 3 µg to 4 μg, which was low enough as not to disturb diet-derived ß -sitosterol kinetics. The absolute ß -sitosterol bioavailability was extremely low (0.41%), with its metabolites not being detected in plasma ( Duchateau et al., 2012 ). Thus, given the generally low PS bioavailability noticed in consumed food, several factors can influence this indicator ( Racette et al., 2015 ) including the following: (1) PS type (i.e., plant sterol or stanol, esterified against nonesterified, steryl glycosides, and PS solubility). A direct correlation between chemical structure (saturation degree of the sterol ring and side-chain length) and low absorption rate has been stated. Campesterol (with a methyl group) has higher absorption rates than β-sitosterol (with an ethyl group) ( Bradford and Awad, 2007 ; Miras-Moreno et al., 2016 ). (2) Chemical structure of PSs (e.g., sitosterol, campesterol, stigmasterol, brassicasterol, Δ-5-avenasterol, sitostanol, or campestanol). PS source (e.g., soybean oil, corn oil, or shea nut oil). (3) Processing (e.g., refining or hydrogenation). Refining and hydrogenation of vegetable oils reduce both the content of free sterols and sterols amount in oils ( Phillips et al., 2002 ; Racette et al., 2015 ). (4) Food preparation (e.g., boiling) ( Normen et al., 1999 ; Racette et al., 2015 ). (5) Other nutrients (e.g., fiber) and aspects related to the food item (i.e., food matrix, injected dose, administration frequency and time, delivery method (emulsifiers use soy lecithin), and surfactants) ( Berger et al., 2004 ). (6) Genetic factors ( Berger et al., 2004 ). Conclusions PSs are plant-derived steroids. Over 250 PSs have been isolated, and each plant species contains a characteristic phytosterol composition. A wide number of researches have reported that PSs possess a wide variety of interesting pharmacological properties, including anti-inflammatory, antioxidant, antidiabetic, chemopreventive, and antiatherosclerotic effects. Nonetheless, PS bioavailability is a limiting aspect that may be affected by multiple factors, such as the type, source, processing, preparation, delivery method, food matrix, dose, time of administration into the body, and genetic factors, and there exists an intercorrelation between low absorption rates and their chemical structure. Thus, further studies are needed to ensure a more in-depth understanding of the multiple potentialities of PSs and to design upcoming strategies to overcome the currently identified bioavailability-related gaps. Author Contributions All authors contributed equally to this work. 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This review summarizes the recent findings and deliberations of 31 experts in the field who participated in a scientific meeting in Winnipeg, Canada, on the health effects of plant sterols and stanols. Plant Sterols and Plant Stanols in Cholesterol Management and Plant sterols are steroidal alkaloids that differ from cholesterol in their side chain at C-24 (methyl or ethyl group) or with an additional double bond in C-22, while plant stanols are 5α-saturated derivatives of plant sterols ( Figure 1) [ 7 ]. Figure 1. Biochemical structure of plant sterols and stanols. 4.2. LDL-Cholesterol Lowering of Plant Sterols and Stanols—Which Factors The LDL-cholesterol (LDL-C) lowering effect of plant sterols/stanols (PSS) is summarized in several meta-analyses showing a dose-response relationship with intakes of 1.5 to 3 g/day lowering LDL-C by 7.5% to 12%. This review summarizes evidence for the ... Efficacy and Safety of Plant Stanols and Sterols in the Management of Foods with plant stanol or sterol esters lower serum cholesterol levels. We summarize the deliberations of 32 experts on the efficacy and safety of sterols and stanols. A meta-analysis of 41 trials showed that intake of 2 g/d of stanols or sterols reduced low-density lipoprotein (LDL) by 10%; higher intakes added little. Efficacy is similar for sterols and stanols, but the food form may ... Advances and Challenges in Plant Sterol Research: Fundamentals ... Plant sterols (PS) are cholesterol-like terpenoids widely spread in the kingdom Plantae. Being the target of extensive research for more than a century, PS have topped with evidence of having beneficial effects in healthy subjects and applications in food, cosmetic and pharmaceutical industries. However, many gaps in several fields of PS's research still hinder their widespread practical ... Advances and Challenges in Plant Sterol Research: Fundamentals ... Plant sterols (PS) are cholesterol-like terpenoids widely spread in the kingdom Plantae. Being the target of extensive research for more than a century, PS have topped with evidence of having beneficial effects in healthy subjects and applications in food, cosmetic and pharmaceutical industries. How … The role of sterols in plant response to abiotic stress Sterols are integral components of the membrane lipid bilayer and they are involved in many processes occurring in plants, ranging from regulation of growth and development to stress resistance. Maintenance of membrane homeostasis represents one of the principal functions of sterols in plant cells. Plant cell membranes are important sites of perception of environmental abiotic factors ... Plant sterols and plant stanols in the management of ... This EAS Consensus Panel critically appraised evidence relevant to the benefit to risk relationship of functional foods with added plant sterols and/or plant stanols, as components of a healthy lifestyle, to reduce plasma low-density lipoprotein-cholesterol (LDL-C) levels, and thereby lower cardiovascular risk. Plant Sterols: Diversity, Biosynthesis, and Physiological ... Plant sterols have diverse composition; they exist as free sterols, sterol esters with higher fatty acids, sterol glycosides, and acylsterol glycosides, which are absent in animal cells. This diversity of types of phytosterols determines a wide spectrum of functions they play in plant life. Plant-based sterols and stanols in health & disease: "Consequences of Highlights • Dietary plant sterols and stanols lower low density lipoprotein cholesterol, a causal risk factor for cardiovascular diseases • Although plant sterols and stanols are poorly absorbed they are taken up by various organs, which may affect health and disease. • Plant sterols and stanols may play a crucial role in functioning of immune cells and have beneficial effects beyond ... Diversity of Plant Sterols Metabolism: The Impact on Human Health In overwhelming majority, the great variability in plant sterols effect is explained by differences of individual phenotypes and gut microbiota composition that participates in transformation of sterols into secondary metabolites, with potentially higher activity and impact on health [ 6, 7, 8 ]. Progress and perspectives in plant sterol and plant stanol research Current evidence indicates that foods with added plant sterols or stanols can lower serum levels of low-density lipoprotein cholesterol. This review summarizes the recent findings and deliberations of 31 experts in the field who participated in a scientific meeting in Winnipeg, Canada, on the health effects of plant sterols and stanols. Plant Sterols and Plant Stanols in Cholesterol Management and ... Functional foods enriched with plant sterols/stanols have become the most widely used nonprescription cholesterol-lowering approach, despite the lack of randomized trials investigating their long-term safety and cardiovascular efficacy. High Cholesterol and Natural Products: What the Science Says Stanols and Sterols The use of foods containing added plant stanols or sterols is an option in conventional treatment for high cholesterol levels. Stanols and sterols are also available in dietary supplements. The evidence for the effectiveness of the supplements is less extensive than the evidence for foods containing stanols or sterols, but in general, studies show that stanol or sterol ... The Best Plant Sterols For Lowering Cholesterol Over 100 clinical studies have demonstrated that plant sterols and stanols can significantly reduce blood cholesterol*, which is why physicians around the world recommend them. Plant sterols can reduce LDL (bad) cholesterol by 5-15% in as little as 4-6 weeks.* Several medical guidelines recommend consuming at least 2 grams of plant sterols per day including those that are part of your regular ... What Is the Portfolio Diet? What to Know About the Cholesterol ... The authors established a Portfolio Diet Score (PDS) that ranked plant protein, nuts and seeds, viscous fiber sources, plant sterols, and monounsaturated fat sources. After looking at the diet ... Biosynthesis and the Roles of Plant Sterols in Development and Stress These studies provide better knowledge on the synthesis and regulation of sterols, and the review also aimed to provide new insights for the global role of sterols, which is liable to benefit future research on the development and abiotic stress tolerance in plant. What You Should Know About Plant-Based Diets A plant-based diet refers to eating entirely or mostly plant foods. Veganism, on the other hand, goes beyond just what you eat — it's a way of living . Most vegans avoid using, consuming or ... The role of sterols in plant growth and development Abstract. Sterols found in all eukaryotic organisms are membrane components which regulate the fluidity and the permeability of phospholipid bilayers. Certain sterols in minute amounts, such as campesterol in Arabidopsis thaliana, are precursors of oxidized steroids acting as growth hormones collectively named brassinosteroids. H5N1 and Safety of U.S. Meat Supply Research: H5N1 Beef Safety Studies. To verify the safety of the meat supply in the context of H5N1, FSIS, APHIS, and USDA's Agricultural Research Service (ARS) have completed three separate beef safety studies related to avian influenza in meat from dairy cattle. Beef Muscle Sampling of Cull Dairy Cows. On May 30, 2024, FSIS announced the final results of its beef muscle sampling of cull dairy ... Fall 2024: Bridging Arts and Science: Research Experiment & Academic This project aims to enhance undergraduate education in plant sciences by integrating a hands-on research experiment in plant tissue culture with academic writing training. The dual focus on practical experimentation and effective communication will prepare students for future endeavors in both research and professional contexts. 2. Research ... Phytosterols and Cardiovascular Disease However, the German Cardiac Society (DGK) is more critical of food supplementation with plant sterols and calls for randomized controlled trials investigating hard cardiovascular outcomes. An increasing body of evidence suggests that plant sterols per se are atherogenic. Greta Thunberg, Activists Block Parts of Norwegian Gas Processing Plant US News is a recognized leader in college, grad school, hospital, mutual fund, and car rankings. Track elected officials, research health conditions, and find news you can use in politics ... Cell polarity and PIN protein positioning in Arabidopsis require STEROL Plants have many polarized cell types, but relatively little is known about the mechanisms that establish polarity. The orc mutant was identified originally by defects in root patterning, and positional cloning revealed that the affected gene encodes STEROL METHYLTRANSFERASE1, which is required for the appropriate synthesis and composition of major membrane sterols. smt1(orc) mutants displayed ... A rare orchid survives on a few tracts of prairie. Researchers want to "They're sort of like the canary in the coal mine for the rest of our ecosystems," McGuinness said. Graduate students from North Dakota State University in Fargo are hoping to learn more about the pollinators and reproduction of the western prairie fringed orchid.Their work includes logging the GPS coordinates of orchids at 20 various sites in Minnesota, North Dakota and Manitoba, Canada ... Plant sterols and cardiovascular disease: a systematic review and meta The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols ... Sterols Market: Global Industry Analysis, Size, Share, Growth, Trends Sterols Market: Global Industry Analysis, Size, Share, Growth, Trends, and Forecast, 2024-2033 - Persistence Market Research has recently published an extensive report on the global Sterols Market, offering a thorough analysis of essential market dynamics, including driving factors, emerging trends, opportunities, and challenges. This report provides a comprehensive understanding of the ... Plant sterols/stanols as cholesterol lowering agents: A meta-analysis Objectives To more precisely quantify the effect of plant sterol enriched products on LDL cholesterol concentrations than what is reported previously, and to identify and quantify the effects of subjects' characteristics, food carrier, frequency and time of intake on efficacy of plant sterols as cholesterol lowering agents. Phytosterols: From Preclinical Evidence to Potential Clinical Phytosterols (PSs) are plant-originated steroids. Over 250 PSs have been isolated, and each plant species contains a characteristic phytosterol composition. A wide number of studies have reported remarkable pharmacological effects of PSs, acting as chemopreventive, anti-inflammatory, antioxidant, antidiabetic, and antiatherosclerotic agents. essay homework paper phd review speech study thesis