Sulfated Sterols Research Articles

Sea cucumber derived sulfated sterols alter glucose metabolism by promoting gluconeogenesis and reducing glycogenesis in healthy mice

Sea cucumber derived sulfated sterols alter glucose metabolism by promoting gluconeogenesis and reducing glycogenesis in healthy mice

Comprehensive metabolomics of Philippine Stichopus cf. horrens reveals diverse classes of valuable small molecules for biomedical applications.

Stichopus cf. horrens is an economically important sea cucumber species in Southeast Asia due to their presumed nutritional and medicinal benefits. However, compared to other sea cucumbers such as Apostichopus japonicus, there are no biochemical studies on which compounds contribute to the purported bioactivities of S. cf. horrens. To address this, a high-throughput characterization of the global metabolite profile of the species was performed through LC-MS/MS experiments and utilizing open-access platforms such as GNPS, XCMS, and metaboAnalyst. Bioinformatics-based molecular networking and chemometrics revealed the abundance of phospholipids such as phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidylinositols (PIs), and phosphatidylserines (PSs) in the crude samples. Body wall extracts were observed to have higher levels of structural, diacylated PCs, while the viscera have higher relative abundance of single-tail PCs and PEs that could be involved in digestion via nutrient absorption and transport for sea cucumbers. PEs and sphingolipids could also be implicated in the ecological response and morphological transformations of S. cf. horrens in the presence of predatory and other environmental stress. Interestingly, terpenoid glycosides and saponins with reported anti-cancer benefits were significantly localized in the body wall. The sulfated alkanes and sterols present in S. cf. horrens bear similarity to known kairomones and other signaling molecules. All in all, the results provide a baseline metabolomic profile of S. cf. horrens that may further be used for comparative and exploratory studies and suggest the untapped potential of S. cf. horrens as a source of bioactive molecules.

Preparation and properties of fucoxanthin-loaded liposomes stabilized by sea cucumber derived cholesterol sulfate instead of cholesterol

The preparation of steady-state phospholipid liposomes requires cholesterol as a stabilizer, but excessive intake of cholesterol may increase the risk of cardiovascular disease. The sulfated sterols extracted from sea cucumber, mainly including sulfated 24-methylene cholesterol and cholesterol sulfate, have been reported to have a variety of physiological activities. Sulfated sterols are similar to cholesterol in structure and have the potential to replace cholesterol to prepare novel stable multifunctional liposomes, allowing the liposomes to act as carriers for the delivery of less bioavailable nutrients while allowing sulfated sterols in the lipid bilayer to exert physiologically active effects. This study aimed to prepare a novel multifunctional nanoliposome stabilized with sulfated sterols from sea cucumber instead of cholesterol by ultrasound-assisted thin-film dispersion method. The results showed that stable and uniformly dispersed nanoliposomes could be formed when the substitution ratio of sea cucumber-derived cholesterol sulfate was 100% and the ratio of lecithin to cholesterol sulfate was 3:1. Fucoxanthin encapsulated liposome with egg yolk lecithin/sea cucumber-derived cholesterol sulfate/fucoxanthin mass ratio of 6:2:3 was successfully prepared, with an average particle size of 214 ± 3nm, polydispersity index (PDI) value of 0.297 ± 0.006, the zeta potential of-57.2 ± 1.10mV, and the encapsulation efficiency of 85.5 ± 0.8%. The results of digestion and absorption invitro and invivo showed that liposomes could significantly improve the bioavailability of fucoxanthin and prolong its residence time in serum. As an efficient multifunctional carrier, this novel liposome has great potential for applications in functional foods and biomedicine.

Oxysterol misbalance critically contributes to Wilson disease pathogenesis.

Wilson disease (WD) is a metabolic disorder caused by inactivation of the copper-transporting ATPase 2 (ATP7B) and copper (Cu) overload in tissues. Excess Cu causes oxidative stress and pathologic changes with poorly understood mechanistic connections. In Atp7b−/− mice with established liver disease, Cu overload activates the stress-sensitive transcription factor Nrf2 (nuclear factor erythroid-derived 2-like 2). Nrf2 targets, especially sulfotransferase 1e1 (Sult1e1), are strongly induced and cause elevation of sulfated sterols, whereas oxysterols are decreased. This sterol misbalance results in inhibition of the liver X receptor (LXR) and up-regulation of LXR targets associated with inflammatory responses. Pharmacological inhibition of Sult1e1 partially reverses oxysterol misbalance and LXR inhibition. Contribution of this pathway to advanced hepatic WD was demonstrated by treating mice with an LXR agonist. Treatment decreased inflammation by reducing expression of proinflammatory molecules, diminished fibrosis by down-regulating the noncanonical transforming growth factor–β signaling pathway, and improved liver morphology and function. Thus, the identified pathway is an important driver of WD.

Preparation and Characterization of Astaxanthin-loaded Liposomes Stabilized by Sea Cucumber Sulfated Sterols Instead of Cholesterol.

Liposomes are widely used as carrier system for bioactive ingredients and usually need to be stabilized by cholesterol. However, the relationship between cholesterol intake and human health has been controversial. The objective of this study was to develop novel multifunctional nanoliposomes stabilized by sea cucumber sulfated sterols via the thin-film hydration method. The liposomes obtained from this study were obviously stable for more than 27 days at 4°C. Astaxanthin was successfully encapsulated by a novel uniform liposome prepared with a mass ratio of egg yolk lecithin to sea cucumber sulfated sterols at 3:1. The mean particle size was 109.53±0.30 nm with 0.241±0.005 polydispersity index and zeta potential value of -21.13±1.01 mV. Astaxanthin-loaded liposome stabilized by sea cucumber sulfated sterols exhibited significantly higher antioxidant activities in terms of DPPH radical-scavenging activity and reducing power than the mixture of astaxanthin and blank sea cucumber sulfated sterols liposome during storage of 6 and 12 days, respectively. The in vivo digestion and absorption results showed that the bioavailability of dietary astaxanthin encapsulated in liposomes could significantly be improved. Being an efficient carrier with multifunctions, the novel liposome stabilized by sea cucumber sulfated sterols had great potential in functional food development and biomedical applications.

Absorption, Pharmacokinetics, Tissue Distribution, and Excretion Profiles of Sea Cucumber-Derived Sulfated Sterols in Mice.

Sea cucumber-derived sulfated sterols exhibited more significant bioactivities compared to plant sterols due to the distinctive structure of the sulfate group at the C-3 position; however, their absorption, pharmacokinetics, tissue distribution, and excretion profiles are unknown, which limits the analysis of molecular mechanisms related to their unique activities. In this study, the absorption characteristics of sea cucumber sterols were determined by oral gavage administration, and their pharmacokinetics, excretion, and tissue distribution were studied by tail vein injection. The results showed that SS1 and SS2 reached the peak at 3 h (20.14 ± 1.2 μg/mL) and 4 h (13.32 ± 0.9 μg/mL) in serum, respectively, after oral gavage administration, suggesting the faster absorption rate of SS1 than SS2 due to the difference in the side-chain groups. Besides, lipid-containing food media improved the digestion and absorption rates of sea cucumber sterols. Moreover, SS1 exhibited a relatively longer duration of efficacy than SS2, and they were almost completely excreted within 9 h through urine. Additionally, sea cucumber sterols were found to be mainly accumulated in the liver (P < 0.05), followed by the kidney and spleen. These findings might provide a theoretical basis for the research and development of functional foods and nutraceuticals associated with sea cucumber sterols.

Antioxidant and Signal-Modulating Effects of Brown Seaweed-Derived Compounds against Oxidative Stress-Associated Pathology.

The biological and therapeutic properties of seaweeds have already been well known. Several studies showed that among the various natural marine sources of antioxidants, seaweeds have become a potential source of antioxidants because of their bioactive compounds. Most of the metabolic diseases are caused by oxidative stress. It is very well known that antioxidants have a pivotal role in the treatment of those diseases. Recent researches have revealed the potential activity of seaweeds as complementary medicine, which have therapeutic properties for health and disease management. Among the seaweeds, brown seaweeds (Phaeophyta) and their derived bioactive substances showed excellent antioxidant properties than other seaweeds. This review focuses on brown seaweeds and their derived major bioactive compounds such as sulfated polysaccharide, polyphenol, carotenoid, and sterol antioxidant effects and molecular mechanisms in the case of the oxidative stress-originated disease. Antioxidants have a potential role in the modification of stress-induced signaling pathways along with the activation of the oxidative defensive pathways. This review would help to provide the basis for further studies to researchers on the potential antioxidant role in the field of medical health care and future drug development.

Sea cucumbers-derived sterol sulfate alleviates insulin resistance and inflammation in high-fat-high-fructose diet-induced obese mice

Sea cucumbers are widely consumed in traditional medicine and food. Sea cucumbers-derived sulfated sterol exhibits a sulfate group at C-3 position, which is different from phytosterol with a hydroxyl group. However, the effect of sterol sulfate on metabolic syndrome remains unknown. The purpose of the present study is to investigate the alleviation of sterol sulfate on high-fat-high-fructose diet (HFFD)-induced insulin resistance and inflammation. After 2 weeks feeding with HFFD, male C57BL/6J mice were continuously fed with HFFD plus 0.4 % (w/w) sterol sulfate or phytosterol for 6 weeks. The OGTT was carried out at 7 weeks. At the end of the experimental period, the changes of glycogen, circulating glucose, insulin, pro-inflammatory cytokine and adiponectin were measured. H&E staining was used to observe the morphological changes in adipose tissue. Furthermore, the underlying molecular mechanisms were investigated. Dietary sterol sulfate was superior to phytosterol in reducing body weight gain, adipocyte hypertrophy, and levels of circulating glucose and insulin, as well as increasing the glycogen content of tissues. Furthermore, sterol sulfate ameliorated insulin resistance mainly due to the inhibition of gluconeogenesis, the promotion of glycogen synthesis and GLUT4 translocation by activating PI3K/Akt signaling pathway. Additionally, sterol sulfate effectively attenuated inflammation by increasing serum adiponectin and reducing pro-inflammatory cytokine release. Sterol sulfate exhibited a more significant effect than phytosterol in alleviating HFFD -induced insulin resistance and inflammation, which might be closely related to the sulfate group. The results might provide insights into the prevention and alleviation of metabolic syndrome.

Phallusiasterol C, A New Disulfated Steroid from the Mediterranean Tunicate Phallusia fumigata.

A new sulfated sterol, phallusiasterol C (1), has been isolated from the Mediterranean ascidian Phallusia fumigata and its structure has been determined on the basis of extensive spectroscopic (mainly 2D NMR) analysis. The possible role in regulating the pregnane X receptor (PXR) activity of phallusiasterol C has been investigated; although the new sterol resulted inactive, this study adds more items to the knowledge of the structure-PXR regulating activity relationships in the case of sulfated steroids.

Is GERD a Factor in Osteonecrosis of the Jaw? Evidence of Pathology Linked to G6PD Deficiency and Sulfomucins

Osteonecrosis of the jaw (ONJ), a rare side effect of bisphosphonate therapy, is a debilitating disorder with a poorly understood etiology. FDA's Adverse Event Reporting System (FAERS) provides the opportunity to investigate this disease. Our goals were to analyze FAERS data to discover possible relationships between ONJ and specific conditions and drugs and then to consult the scientific literature to deduce biological explanations. Our methodology revealed a very strong association between gastroesophageal reflux and bisphosphonate-induced ONJ, suggesting acidosis as a key factor. Overgrowth of acidophilic species, particularly Streptococcus mutans, in the oral microbiome in the context of insufficient acid buffering due to impaired salivary glands maintains the low pH that sustains damage to the mucosa. Significant associations between ONJ and adrenal insufficiency, vitamin C deficiency, and Sjögren's syndrome were found. Glucose 6 phosphate dehydrogenase (G6PD) deficiency can explain much of the pathology. An inability to maintain vitamin C and other antioxidants in the reduced form leads to vascular oxidative damage and impaired adrenal function. Thus, pathogen-induced acidosis, hypoxia, and insufficient antioxidant defenses together induce ONJ. G6PD deficiency and adrenal insufficiency are underlying factors. Impaired supply of adrenal-derived sulfated sterols such as DHEA sulfate may drive the disease process.

Shotgun lipidomic analysis of chemically sulfated sterols compromises analytical sensitivity: Recommendation for large‐scale global lipidome analysis

Recommended sequence of MS analyses for global lipidome analysis using shotgun lipidomics.

Phallusiasterols A and B: Two New Sulfated Sterols from the Mediterranean Tunicate Phallusia fumigata and Their Effects as Modulators of the PXR Receptor

Purification of the apolar extracts of the marine ascidian Phallusia fumigata, afforded two new sulfated sterols, phallusiasterols A (1) and B (2). The structures of the new compounds have been elucidated using mass spectrometry and NMR experiments. The effects of phallusiasterols A and B as modulators of pregnane-X-receptor (PXR) have been investigated. These studies revealed that phallusiasterol A induces PXR transactivation in HepG2 cells and stimulates the expression of the PXR target genes CYP3A4 and MDR1 in the same cell line. Molecular docking calculations suggested the theoretical binding mode of phallusiasterol A with hPXR and revealed that phallusiasterol A fitted well in the LBD of PXR.

Discovery of Sulfated Sterols from Marine Invertebrates as a New Class of Marine Natural Antagonists of Farnesoid-X-Receptor

We report the biochemical characterization of sulfated polyhydroxysterols isolated from marine invertebrates as potent antagonists of farnesoid-X-receptor (FXR), a ligand-regulated transcription factor involved in the regulation of lipid and glucose homeostasis in mammals. Molecular characterization of a library of sulfated polyhydroxysteroids resulted in the identification of a first FXR antagonist. In contrast to partial antagonists, this compound was endowed with an antagonistic activity on the expression of a subset of FXR-regulated genes in liver cells and abrogated the release of nuclear coreceptor from the promoter of these genes. The putative binding mode to FXR, obtained through docking calculations, suggested the crucial role played by the bent shape of the molecule as well as the presence of one hydroxyl group in its side chain. This compound is a major tool to explore the effect of FXR inhibition in pharmacological settings.

Solomonsterols A and B fromTheonella swinhoei. The First Example of C-24 and C-23 Sulfated Sterols from a Marine Source Endowed with a PXR Agonistic Activity

The finding of new PXR modulators as potential leads for treatment of human disorders characterized by dysregulation of innate immunity and with inflammation is of wide interest. In this paper, we report the identification of the first example of natural marine PXR agonists, solomonsterols A and B, from a Theonella swinhoei sponge. The structures were determined by interpretation of NMR and ESIMS data, and the putative binding mode to PXR has been obtained through docking calculations.

Fibrosterol sulfates from the Philippine sponge Lissodendoryx (Acanthodoryx) fibrosa: sterol dimers that inhibit PKCzeta.

Three new sulfated sterol dimers, fibrosterol sulfates A-C (1-3), have been isolated from the sponge Lissodendoryx (Acanthodoryx) fibrosa, collected in the Philippines. The structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1 and 2 inhibited PKCzeta with IC(50) values of 16.4 and 5.6 microM, respectively.

Reversal of Fluconazole Resistance by Sulfated Sterols from the Marine Sponge Topsentia sp.

Bioassay-guided fractionation of the extract of Topsentia sp. led to the identification of two new sulfated sterols, geodisterol-3-O-sulfite (1) and 29-demethylgeodisterol-3-O-sulfite (2), the active constituents reversing efflux pump-mediated fluconazole resistance. Both compounds enhanced the activity of fluconazole in a Saccharomyces cerevisiae strain overexpressing the Candida albicans efflux pump MDR1, as well as in a fluconazole-resistant Candida albicans clinical isolate known to overexpress MDR1. These results provide insight into the clinical utility of combining efflux pump inhibitors with current antifungals to combat the resistance associated with opportunistic fungal infections caused by C. albicans.

Amaroxocanes A and B: Sulfated Dimeric Sterols Defend the Caribbean Coral Reef Sponge Phorbas amaranthus from Fish Predators

Two new dimeric steroids, amaroxocanes A (1) and B (2), were isolated from Phorbas amaranthus collected on shallow coral reefs off Key Largo, Florida. The two compounds are comprised of two sulfated sterol cores bridged by an oxocane formed by different oxidative side-chain fusions. The structures were characterized by interpretation of MS and NMR spectroscopic data. The compounds are the primary components of a fraction that deters feeding of the bluehead wrasse, Thalassoma bifasciatum, in aquarium assays. When the pure compounds were assayed at eight times the natural concentration, amaroxocane B (2) was found to be an effective antifeedant, but A (1) was not.

Biosynthesis of leukotriene B4 in human polymorphonuclear leukocytes: regulation by cholesterol and other lipids

Leukotriene B4 (LTB4) is one of the most potent chemotactic compounds produced in macrophages and neutrophils. LTB4 is a product of arachidonic acid oxygenation by 5-lipoxygenase pathway. We present here the data on regulation of LT synthesis in human polymorphonuclear leukocytes by cholesterol, cholesterol sulfate and cholesterol phosphate. The addition of Pseudomonas aeruginosa lipopolysaccharides (LPS) with lipid vesicles containing phosphatidylcholine or phosphatidylcholine/cholesterol (70:30) showed that omitting cholesterol abolished the effect of LPS on LT synthesis. We show here the capacity of cholesterol sulfate, the most abundant sulfated sterol in human blood, to suppress LT production in human neutrophils and to neutralize the effect of P. aeruginosa LPS on LT synthesis. We suggest that sulfated lipids serve as specific endogenous regulators of LT synthesis in neutrophils, and anti-inflammatory therapy may be based on modification of cholesterol level and its conversion to anionic derivatives.

Cholesterol and its anionic derivatives inhibit 5‐lipoxygenase activation in polymorphonuclear leukocytes and MonoMac6 cells

5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes (LTs), biological mediators of host defense reactions and of inflammatory diseases. While the role of membrane binding in the regulation of 5-LO activity is well established, the effects of lipids on cellular activity when added to the medium has not been characterized. Here, we show such a novel function of the most abundant sulfated sterol in human blood, cholesterol sulfate (CS), to suppress LT production in human polymorphonuclear leukocytes (PMNL) and Mono Mac6 cells. We synthesized another anionic lipid, cholesterol phosphate, which demonstrated a similar capacity in suppression of LT synthesis in PMNL. Cholesteryl acetate was without effect. Cholesterol increased the effect of CS on 5-LO product synthesis. CS and cholesterol also inhibited arachidonic acid (AA) release from PMNL. Addition of exogenous AA increased the threshold concentration of CS required to inhibit LT synthesis. The effect of cholesterol and its anionic derivatives can arise from remodeling of the cell membrane, which interferes with 5-LO activation. The fact that cellular LT production is regulated by sulfated cholesterol highlights a possible regulatory role of sulfotransferases/sulfatases in 5-LO product synthesis.

Arenicolsterol A, a Novel Cytotoxic Enolic Sulfated Sterol from a Marine Annelid Arenicola cristata

AbstractMarine organisms are the important source of the bioactive metabolites. A novel enolic sulfated sterol, arenicolsterol A, has been isolated from a marine annelid Arenicola cristata collected in the coast of Mainland of China. The structure was elucidated using all sorts of spectroscopic data including ESIMS, 1D and 2D NMR etc. The cytotoxic bioactivity of this sterol was evaluated by MTT assay. It could inhibit the growth of human cervix cancer cell line (Hela) and human non‐small cell lung cancer cell line (NCI‐h6) with IC50 of (3.1±0.6) µg/mL and (7.6±0.8) µg/mL.