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Special Issue "Chemical Biology of Sterols, Triterpenoids and Other Natural Products: A Themed Issue in Honor of Professor W. David Nes on the Occasion of His 65th Birthday"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (1 October 2018).

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Assoc. Prof. Dr. Wenxu Zhou
E-Mail Website
Guest Editor
Department of Chemistry and Biochemistry, Center for Chemical Biology (CCB), Texas Tech University, Lubbock, TX 79409, USA
Interests: sterol; antifungal; sterol biosynthesis; sterol auxotrophy; metabolomics
Prof. Dr. De-an Guo
E-Mail Website
Guest Editor
Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
Interests: natural products chemistry; phytochemical analysis; herbal quality control; biotransformation; pharmacokinetics

Special Issue Information

Dear Colleagues,

Dr. W. David Nes is an eminent sterol biochemist who has made seminal contributions to the areas of chemical analysis, biosynthesis, and mechanistic enzymology. His fundamental research has led to the isolation and synthesis of over 300 sterols and triterpenoids, to a greater understanding of sterol diversity and function across kingdoms, and new knowledge for catalytic competence and three-dimensional structures of sterol biosynthesis enzymes. He developed significant collaborations in the US and abroad to advance steroidal inhibitors for the treatment of fungal and protozoan diseases. Dr. W. David Nes is currently a Paul Whitfield Horn Professor of Chemistry & Biochemistry at Texas Tech University, Lubbock, Texas. He received his BA from Gettysburg College (1975), MS from Drexel University (1977), and PhD from the University of Maryland, College Park (1979). He completed post-doctoral studies at the University of California, Berkeley and at the ARS-USDA regional laboratory in Albany CA during years 1979 to 1982. He continued on in the Plant Physiology and Chemistry Research Unit in Albany and then in the Microbial Products Research Unit at the USDA laboratory in Athens, GA until 1993 as Lead Research Chemist. In 1993, he moved to the Department of Chemistry & Biochemistry and was promoted to Horn professor in 2007. From 1999 to 2016, he was Division Chair of Biochemistry, and from 2012 to 2016, Director of the Center for Chemical Biology at Texas Tech University. He took a two-year leave of absence from the university during the period 2003–2005 to be Program Director of Molecular Biochemistry in the Division of Molecular and Cellular Biosciences at the National Science Foundation.

Professor Nes has received several awards for research excellence while at the USDA and at Texas Tech University, including the Barnie E. Rushing Jr. Award for Research Excellence. He has received an Honorable Guest Professorship (Peking University, China, 1995), Advanced Distinguished Lectureship (Kansas State University, 2010), DAAD fellowship from Germany (1982), and was sponsored by several members of the National Academy of Sciences and Royal Society to publish papers in PNAS and Proc. R. Soc. and contributed papers to special issues honoring members of the US National Academy of Sciences. During his career, he has held adjunct professor positions in the chemistry department at Auburn University (1988–1993) and the Natural Product Institute at the University of Georgia (1991–1993). He has held Visiting Professorships at the Institute for Chemical Ecology (Max Planck Institute, Jena, Germany 2007) and Centre for Cytochrome P-450 Biodiversity (College of Medicine, Swansea University, Wales, 2013) and Professorship in the Department of Immunology and Molecular Microbiology (Texas Tech Health Sciences Center School of Medicine, 2013–2017) and has served on the editorial boards of high-impact journals and on a range of federal panels, including the National Institutes of Health and National Science Foundation. He has been funded by USDA, NIH, NSF, Welch Foundation and Industry, including AstraZeneca Pharmaceuticals, Norvatis, Monsanto, and Bayer Crops, and mentored 30 MS and PhD students and 43 Post-doctoral fellows and Visiting Scientists. His high H-index is reflective of his >200 publications and eight books, many of which are among some of the highly cited or considered classics.

Molecules is highly pleased to host a Special Issue, and invites scientists to submit original contributions to “Chemical Biology of Sterols, Triterpenoids and Other Natural Products: A Themed Issue in Honor of Professor W. David Nes on the Occasion of His 65th Birthday”.

Assoc. Prof. Dr. Wenxu Zhou
Prof. Dr. De-an Guo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sterol
  • sterol biosynthesis
  • natural products
  • isoprenoids
  • cholesterol
  • phytosterol
  • lipidomics
  • enzymology/enzyme mechanisms
  • ergosterol biosynthesis inhibitors
  • drug therapy
  • CYP51
  • sterol C24-methyltransferase
  • suicide substrate
  • transition state analog
  • antifungal
  • anti-parasite drugs
  • sparking function
  • chemical analysis
  • eukaryotic pathogen
  • sterol evolution
  • sterol auxotroph

Published Papers (17 papers)

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Editorial

Jump to: Research, Review

Open AccessEditorial
More than 40 Years Active in Steroid and Isoprenoid Research—A Personal Note on W. David Nes’ Career and His Multiple Achievements in this Field
Molecules 2019, 24(5), 901; https://doi.org/10.3390/molecules24050901 - 05 Mar 2019
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Research

Jump to: Editorial, Review

Open AccessCommunication
Developing an Enzyme-Assisted Derivatization Method for Analysis of C27 Bile Alcohols and Acids by Electrospray Ionization-Mass Spectrometry
Molecules 2019, 24(3), 597; https://doi.org/10.3390/molecules24030597 - 07 Feb 2019
Abstract
Enzyme-assisted derivatization for sterol analysis (EADSA) is a technology designed to enhance sensitivity and specificity for sterol analysis using electrospray ionization–mass spectrometry. To date it has only been exploited on sterols with a 3β-hydroxy-5-ene or 3β-hydroxy-5α-hydrogen structure, using bacterial cholesterol oxidase enzyme to [...] Read more.
Enzyme-assisted derivatization for sterol analysis (EADSA) is a technology designed to enhance sensitivity and specificity for sterol analysis using electrospray ionization–mass spectrometry. To date it has only been exploited on sterols with a 3β-hydroxy-5-ene or 3β-hydroxy-5α-hydrogen structure, using bacterial cholesterol oxidase enzyme to convert the 3β-hydroxy group to a 3-oxo group for subsequent derivatization with the positively charged Girard hydrazine reagents, or on substrates with a native oxo group. Here we describe an extension of the technology by substituting 3α-hydroxysteroid dehydrogenase (3α-HSD) for cholesterol oxidase, making the method applicable to sterols with a 3α-hydroxy-5β-hydrogen structure. The 3α-HSD enzyme works efficiently on bile alcohols and bile acids with this stereochemistry. However, as found by others, derivatization of the resultant 3-oxo group with a hydrazine reagent does not go to completion in the absence of a conjugating double bond in the sterol structure. Nevertheless, Girard P derivatives of bile alcohols and C27 acids give an intense molecular ion ([M]+) upon electrospray ionization and informative fragmentation spectra. The method shows promise for analysis of bile alcohols and 3α-hydroxy-5β-C27-acids, enhancing the range of sterols that can be analyzed at high sensitivity in sterolomic studies. Full article
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Open AccessFeature PaperArticle
Phytosterol Composition of Arachis hypogaea Seeds from Different Maturity Classes
Molecules 2019, 24(1), 106; https://doi.org/10.3390/molecules24010106 - 29 Dec 2018
Cited by 2
Abstract
The seeds of cultivated peanut, Arachis hypogaea, are an agronomically important crop produced for human nutrition, oilseed and feed stock. Peanut seed is the single most expensive variable input cost and thus producers require seed with excellent performance in terms of germination [...] Read more.
The seeds of cultivated peanut, Arachis hypogaea, are an agronomically important crop produced for human nutrition, oilseed and feed stock. Peanut seed is the single most expensive variable input cost and thus producers require seed with excellent performance in terms of germination efficiency. During the maturation process, triglycerides are stored in oil bodies as an energy resource during germination and seedling development. The stability of oil body membranes is essential for nutrient mobilization during germination. This study focused on evaluating the phytosterol composition in seed components including the kernel, embryo (heart), and seed coat or skin. Samples of different maturity classes were analyzed for macronutrient and phytosterol content. The three biosynthetic end products in the phytosterol pathway, β-sitosterol, campesterol and stigmasterol, comprised 82.29%, 86.39% and 94.25% of seed hearts, kernels and seed coats, respectively. Stigmasterol concentration was highest in the seed kernel, providing an excellent source of this sterol known to have beneficial effects on human health. Peanut hearts contained the highest concentration of sterols by mass, potentially providing protection and resources for the developing seedling. The amount of α-tocopherol increases in peanut hearts during the maturation process, providing protection from temperature stress, as well as stability required for seedling vigor. These results suggest that phytosterols may play a significant role in the performance of seeds, and provide a possible explanation for the poor germination efficiency of immature seeds. Full article
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Open AccessArticle
Leishmanicidal Activity of Withanolides from Aureliana fasciculata var. fasciculata
Molecules 2018, 23(12), 3160; https://doi.org/10.3390/molecules23123160 - 30 Nov 2018
Abstract
Leishmaniasis is the generic denomination to the neglected diseases caused by more than 20 species of protozoa belonging to the genus Leishmania. The toxic and parenteral-delivered pentavalent antimonials remain to be the first-line treatment. However, all the current used drugs have restrictions. [...] Read more.
Leishmaniasis is the generic denomination to the neglected diseases caused by more than 20 species of protozoa belonging to the genus Leishmania. The toxic and parenteral-delivered pentavalent antimonials remain to be the first-line treatment. However, all the current used drugs have restrictions. The species Aureliana fasciculata (Vell.) Sendtner var. fasciculata is a native Brazilian species parsimoniously studied on a chemical point of view. In this study, the antileishmanial activity of A. fasciculata was evaluated. Among the evaluated samples of the leaves, the dichloromethane partition (AFfDi) showed the more pronounced activity, with IC50 1.85 µg/ml against promastigotes of L. amazonensis. From AFfDi, two active withanolides were isolated, the Aurelianolides A and B, with IC50 7.61 μM and 7.94 μM, respectively. The withanolides also proved to be active against the clinically important form, the intracellular amastigote, with IC50 2.25 μM and 6.43 μM for Aurelianolides A and B, respectively. Furthermore, withanolides showed results for in silico parameters of absorption, distribution, metabolism, excretion, and toxicity (ADMET) similar to miltefosine, the reference drug, and were predicted as good oral drugs, with the advantage of not being hepatotoxic. These results suggest that these compounds can be useful as scaffolds for planning drug design. Full article
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Open AccessArticle
Cytotoxic and Membrane Cholesterol Effects of Ultraviolet Irradiation and Zinc Oxide Nanoparticles on Chinese Hamster Ovary Cells
Molecules 2018, 23(11), 2979; https://doi.org/10.3390/molecules23112979 - 15 Nov 2018
Abstract
Zinc Oxide (ZnO) nanoparticles are suspected to produce toxic effects toward mammalian cells; however, discrepancies in the extent of this effect have been reported between different cell lines. Simultaneously, high levels of ultraviolet (UV-C) radiation can have carcinogenic effects. The mechanism of this [...] Read more.
Zinc Oxide (ZnO) nanoparticles are suspected to produce toxic effects toward mammalian cells; however, discrepancies in the extent of this effect have been reported between different cell lines. Simultaneously, high levels of ultraviolet (UV-C) radiation can have carcinogenic effects. The mechanism of this effect is also not well understood. Due to similarities in phenotype morphology after cell exposure to ZnO nanoparticles and UV-C irradiation, we emit the hypothesis that the toxicity of both these factors is related to damage of cellular membranes and affect their sterol content. Wild-type Chinese Hamster Ovary (CHO-K1) cells were exposed to ZnO nanoparticles or UV-C radiation. The amount of absorbed ZnO was determined by UV-visible spectroscopy and the changes in sterol profiles were evaluated by gas chromatography. Cell viability after both treatments was determined by microscopy. Comparing morphology results suggested similarities in toxicology events induced by ZnO nanoparticles and UV exposure. UV-C exposure for 360 min disrupts the sterol metabolic pathway by increasing the concentration of cholesterol by 21.6-fold. This increase in cholesterol production supports the hypothesis that UV irradiation has direct consequences in initiating sterol modifications in the cell membrane. Full article
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Open AccessArticle
Lupeol, a Pentacyclic Triterpene, Promotes Migration, Wound Closure, and Contractile Effect In Vitro: Possible Involvement of PI3K/Akt and p38/ERK/MAPK Pathways
Molecules 2018, 23(11), 2819; https://doi.org/10.3390/molecules23112819 - 30 Oct 2018
Cited by 4
Abstract
Skin wound healing is a dynamic and complex process involving several mediators at the cellular and molecular levels. Lupeol, a phytoconstituent belonging to the triterpenes class, is found in several fruit plants and medicinal plants that have been the object of study in [...] Read more.
Skin wound healing is a dynamic and complex process involving several mediators at the cellular and molecular levels. Lupeol, a phytoconstituent belonging to the triterpenes class, is found in several fruit plants and medicinal plants that have been the object of study in the treatment of various diseases, including skin wounds. Various medicinal properties of lupeol have been reported in the literature, including anti-inflammatory, antioxidant, anti-diabetic, and anti-mutagenic effects. We investigated the effects of lupeol (0.1, 1, 10, and 20 μg/mL) on in vitro wound healing assays and signaling mechanisms in human neonatal foreskin keratinocytes and fibroblasts. Results showed that, at high concentrations, Lupeol reduced cell proliferation of both keratinocytes and fibroblasts, but increased in vitro wound healing in keratinocytes and promoted the contraction of dermal fibroblasts in the collagen gel matrix. This triterpene positively regulated matrix metalloproteinase (MMP)-2 and inhibited the NF-κB expression in keratinocytes, suggesting an anti-inflammatory effect. Lupeol also modulated the expression of keratin 16 according to the concentration tested. Additionally, in keratinocytes, lupeol treatment resulted in the activation of Akt, p38, and Tie-2, which are signaling proteins involved in cell proliferation and migration, angiogenesis, and tissue repair. These findings suggest that lupeol has therapeutic potential for accelerating wound healing. Full article
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Open AccessCommunication
Arginine in the FARM and SARM: A Role in Chain-Length Determination for Arginine in the Aspartate-Rich Motifs of Isoprenyl Diphosphate Synthases from Mycobacterium tuberculosis
Molecules 2018, 23(10), 2546; https://doi.org/10.3390/molecules23102546 - 06 Oct 2018
Cited by 1
Abstract
Isoprenyl chains are found in many important metabolites. These are derived from precursors of the appropriate length produced by isoprenyl diphosphate synthases (IDSs). The human pathogen Mycobacterium tuberculosis makes various isoprenoids/terpenoids, with important roles in their biosynthesis played by two closely related IDSs, [...] Read more.
Isoprenyl chains are found in many important metabolites. These are derived from precursors of the appropriate length produced by isoprenyl diphosphate synthases (IDSs). The human pathogen Mycobacterium tuberculosis makes various isoprenoids/terpenoids, with important roles in their biosynthesis played by two closely related IDSs, encoded by grcC1 (Rv0562) and grcC2 (Rv0989c), with Rv0989c generating the 10-carbon precursor (E)-geranyl diphosphate (GPP), and Rv0562 the 20-carbon precursor (E,E,E)-geranylgeranyl diphosphate (GGPP). Intriguingly, while Rv0562 contains the prototypical trans-IDS first and second aspartate-rich (DDxxD) motifs (FARM and SARM, respectively), Rv0989c uniquely contains arginine in place of the second Asp in the FARM and first Asp in the SARM. Here site-directed mutagenesis of the corresponding residues in both Rv0562 and Rv0989c reveals that these play a role in determination of product chain length. Specifically, substitution of Asp for the Arg in the FARM and SARM of Rv0989c leads to increased production of the longer 15-carbon farnesyl diphosphate (FPP), while substitution of Arg for the corresponding Asp in Rv0562 leads to increased release of shorter products, both FPP and GPP. Accordingly, while the primary role of the FARM and SARM is known to be chelation of the divalent magnesium ion co-factors that assist substrate binding and catalysis, the Arg substitutions found in Rv0989c seem to provide a novel means by which product chain length is moderated, at least in these M. tuberculosis IDSs. Full article
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Open AccessArticle
Squalene Cyclases and Cycloartenol Synthases from Polystichum polyblepharum and Six Allied Ferns
Molecules 2018, 23(8), 1843; https://doi.org/10.3390/molecules23081843 - 24 Jul 2018
Abstract
Ferns are the most primitive of all vascular plants. One of the characteristics distinguishing them from flowering plants is its triterpene metabolism. Most cyclic triterpenes in ferns are hydrocarbons derived from the direct cyclization of squalene by squalene cyclases (SCs). Both ferns and [...] Read more.
Ferns are the most primitive of all vascular plants. One of the characteristics distinguishing them from flowering plants is its triterpene metabolism. Most cyclic triterpenes in ferns are hydrocarbons derived from the direct cyclization of squalene by squalene cyclases (SCs). Both ferns and more complex plants share sterols and biosynthetic enzymes, such as cycloartenol synthases (CASs). Polystichum belongs to Dryopteridaceae, and is one of the most species-rich of all fern genera. Several Polystichum ferns in Japan are classified as one of three possible chemotypes, based on their triterpene profiles. In this study, we describe the molecular cloning and functional characterization of cDNAs encoding a SC (PPH) and a CAS (PPX) from the type species Polystichum polyblepharum. Heterologous expression in Pichia pastoris revealed that PPH and PPX are hydroxyhopane synthase and CAS, respectively. By using the PPH and PPX sequences, we successfully isolated SC- and CAS-encoding cDNAs from six Polystichum ferns. Phylogenetic analysis, based on SCs and oxidosqualene cyclase sequences, suggested that the Polystichum subclade in the fern SC and CAS clades reflects the chemotype—but not the molecular phylogeny constructed using plastid molecular markers. These results show a possible relation between triterpenes and their biosynthetic enzymes in Polystichum. Full article
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Open AccessArticle
Sterol Composition of Clinically Relevant Mucorales and Changes Resulting from Posaconazole Treatment
Molecules 2018, 23(5), 1218; https://doi.org/10.3390/molecules23051218 - 19 May 2018
Cited by 3
Abstract
Mucorales are fungi with increasing importance in the clinics. Infections take a rapidly progressive course resulting in high mortality rates. The ergosterol biosynthesis pathway and sterol composition are of interest, since they are targeted by currently applied antifungal drugs. Nevertheless, Mucorales often exhibit [...] Read more.
Mucorales are fungi with increasing importance in the clinics. Infections take a rapidly progressive course resulting in high mortality rates. The ergosterol biosynthesis pathway and sterol composition are of interest, since they are targeted by currently applied antifungal drugs. Nevertheless, Mucorales often exhibit resistance to these drugs, resulting in therapeutic failure. Here, sterol patterns of six clinically relevant Mucorales (Lichtheimia corymbifera, Lichtheimia ramosa, Mucor circinelloides, Rhizomucor pusillus, Rhizopus arrhizus, and Rhizopus microsporus) were analysed in a targeted metabolomics fashion after derivatization by gas chromatography-mass spectrometry. Additionally, the effect of posaconazole (POS) treatment on the sterol pattern of R. arrhizus was evaluated. Overall, fifteen different sterols were detected with species dependent variations in the total and relative sterol amount. Sterol analysis from R. arrhizus hyphae confronted with sublethal concentrations of posaconazole revealed the accumulation of 14-methylergosta-8,24-diene-3,6-diol, which is a toxic sterol that was previously only detected in yeasts. Sterol content and composition were further compared to the well-characterized pathogenic mold Aspergillus fumigatus. This work contributes to a better understanding of the ergosterol biosynthesis pathway of Mucorales, which is essential to improve antifungal efficacy, the identification of targets for novel drug design, and to investigate the combinatorial effects of drugs targeting this pathway. Full article
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Open AccessArticle
Improved Synthesis of N-Methylcadaverine
Molecules 2018, 23(5), 1216; https://doi.org/10.3390/molecules23051216 - 19 May 2018
Abstract
Alkaloids compose a large class of natural products, and mono-methylated polyamines are a common intermediate in their biosynthesis. In order to evaluate the role of selectively methylated natural products, synthetic strategies are needed to prepare them. Here, N-methylcadaverine is prepared in 37.3% [...] Read more.
Alkaloids compose a large class of natural products, and mono-methylated polyamines are a common intermediate in their biosynthesis. In order to evaluate the role of selectively methylated natural products, synthetic strategies are needed to prepare them. Here, N-methylcadaverine is prepared in 37.3% yield in three steps. The alternative literature two-step strategy resulted in reductive deamination to give N-methylpiperidine as determined by the single crystal structure. A straightforward strategy to obtain the mono-alkylated aliphatic diamine, cadaverine, which avoids potential side-reactions, is demonstrated. Full article
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Open AccessArticle
Ursolic Acid Attenuates Atherosclerosis in ApoE−/− Mice: Role of LOX-1 Mediated by ROS/NF-κB Pathway
Molecules 2018, 23(5), 1101; https://doi.org/10.3390/molecules23051101 - 07 May 2018
Cited by 12
Abstract
Atherosclerosis, a chronic inflammatory disease, is a major contributor to cardiovascular diseases. Ursolic acid (UA) is a phytonutrient with widely biological effects including anti-oxidative, anti-inflammatory, and so on. At present, the effect of UA on atherosclerosis and the mechanism of action are still [...] Read more.
Atherosclerosis, a chronic inflammatory disease, is a major contributor to cardiovascular diseases. Ursolic acid (UA) is a phytonutrient with widely biological effects including anti-oxidative, anti-inflammatory, and so on. At present, the effect of UA on atherosclerosis and the mechanism of action are still obscure. This study focused on investigating the effects of UA on atherosclerosis both in vivo and in vitro. We first selected LOX-1 as our target, which was reckoned as a new promising receptor for treating atherosclerosis. The evaluation in vitro suggested that UA significantly decreased endothelial LOX-1 expression induced by LPS both in mRNA and protein levels. Pre-treatment of UA also inhibited TLR4/MyD88 signaling activated by LPS. Moreover, UA reduced ROS production and suppressed the activation of NF-κB stimulated by LPS. Particularly, the evaluation in vivo further verified the conclusion obtained in vitro. In ApoE−/− mice fed with an atherogenic diet, both UA (100 mg/kg/day) and simvastatin significantly attenuated atherosclerotic plaque formation and shrunk necrotic core areas. The enhanced expression of LOX-1 in atherosclerotic aorta was also dramatically decreased by administration of UA. Taken together, these results suggested that UA, with anti-atherosclerotic activity through inhibition of LOX-1 mediated by ROS/NF-κB signaling pathways, may become a valuable vascular protective candidate for the treatment of atherosclerosis. Full article
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Open AccessArticle
The Effects of Plant-Derived Oleanolic Acid on Selected Parameters of Glucose Homeostasis in a Diet-Induced Pre-Diabetic Rat Model
Molecules 2018, 23(4), 794; https://doi.org/10.3390/molecules23040794 - 29 Mar 2018
Cited by 9
Abstract
Prolonged exposure to high energy diets has been implicated in the development of pre-diabetes, a long-lasting condition that precedes type 2 diabetes mellitus (T2DM). A combination of pharmacological and dietary interventions is used to prevent the progression of pre-diabetes to T2DM. However, poor [...] Read more.
Prolonged exposure to high energy diets has been implicated in the development of pre-diabetes, a long-lasting condition that precedes type 2 diabetes mellitus (T2DM). A combination of pharmacological and dietary interventions is used to prevent the progression of pre-diabetes to T2DM. However, poor patient compliance leads to negligence of the dietary intervention and thus reduced drug efficiency. Oleanolic acid (OA) has been reported to possess anti-diabetic effects in type 1 diabetic rats. However, the effects of this compound on pre-diabetes have not yet been established. Consequently, this study sought to evaluate the effects OA on a diet-induced pre-diabetes rat model. Pre-diabetic male Sprague Dawley rats were treated with OA in both the presence and absence of dietary intervention for a period of 12 weeks. The administration of OA with and without dietary intervention resulted in significantly improved glucose homeostasis through reduced caloric intake, body weights, plasma ghrelin concentration and glycated haemoglobin by comparison to the pre-diabetic control. These results suggest that OA may be used to manage pre-diabetes as it was able to restore glucose homeostasis and prevented the progression to overt type 2 diabetes. Full article
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Open AccessArticle
Nine New Gingerols from the Rhizoma of Zingiber officinale and Their Cytotoxic Activities
Molecules 2018, 23(2), 315; https://doi.org/10.3390/molecules23020315 - 02 Feb 2018
Cited by 6
Abstract
Nine new gingerols, including three 6-oxo-shogaol derivatives [(Z)-6-oxo-[6]-shogaol (1), (Z)-6-oxo-[8]-shogaol (2), (Z)-6-oxo-[10]-shogaol (3)], one 6-oxoparadol derivative [6-oxo-[6]-paradol (4)], one isoshogaol derivative [(E)-[4]-isoshogaol (5)], and four [...] Read more.
Nine new gingerols, including three 6-oxo-shogaol derivatives [(Z)-6-oxo-[6]-shogaol (1), (Z)-6-oxo-[8]-shogaol (2), (Z)-6-oxo-[10]-shogaol (3)], one 6-oxoparadol derivative [6-oxo-[6]-paradol (4)], one isoshogaol derivative [(E)-[4]-isoshogaol (5)], and four paradoldiene derivatives [(4E,6Z)-[4]-paradoldiene (8), (4E,6E)-[6]-paradoldiene (9), (4E,6E)-[8]-paradoldiene (10), (4E,6Z)-[8]-paradoldiene (11)], together with eight known analogues, were isolated from the rhizoma of Zingiber officinale. Their structures were elucidated on the basis of spectroscopic data. It was noted that the isolation of 6-oxo-shogaol derivatives represents the first report of gingerols containing one 1,4-enedione motif. Their structures were elucidated on the basis of spectroscopic and HRESIMS data. All the new compounds were evaluated for their cytotoxic activities against human cancer cells (MCF-7, HepG-2, KYSE-150). Full article
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Review

Jump to: Editorial, Research

Open AccessFeature PaperReview
Metabolism and Biological Activities of 4-Methyl-Sterols
Molecules 2019, 24(3), 451; https://doi.org/10.3390/molecules24030451 - 27 Jan 2019
Abstract
4,4-Dimethylsterols and 4-methylsterols are sterol biosynthetic intermediates (C4-SBIs) acting as precursors of cholesterol, ergosterol, and phytosterols. Their accumulation caused by genetic lesions or biochemical inhibition causes severe cellular and developmental phenotypes in all organisms. Functional evidence supports their role as meiosis activators or [...] Read more.
4,4-Dimethylsterols and 4-methylsterols are sterol biosynthetic intermediates (C4-SBIs) acting as precursors of cholesterol, ergosterol, and phytosterols. Their accumulation caused by genetic lesions or biochemical inhibition causes severe cellular and developmental phenotypes in all organisms. Functional evidence supports their role as meiosis activators or as signaling molecules in mammals or plants. Oxygenated C4-SBIs like 4-carboxysterols act in major biological processes like auxin signaling in plants and immune system development in mammals. It is the purpose of this article to point out important milestones and significant advances in the understanding of the biogenesis and biological activities of C4-SBIs. Full article
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Open AccessFeature PaperReview
Microbial Sterolomics as a Chemical Biology Tool
Molecules 2018, 23(11), 2768; https://doi.org/10.3390/molecules23112768 - 25 Oct 2018
Cited by 2
Abstract
Metabolomics has become a powerful tool in chemical biology. Profiling the human sterolome has resulted in the discovery of noncanonical sterols, including oxysterols and meiosis-activating sterols. They are important to immune responses and development, and have been reviewed extensively. The triterpenoid metabolite fusidic [...] Read more.
Metabolomics has become a powerful tool in chemical biology. Profiling the human sterolome has resulted in the discovery of noncanonical sterols, including oxysterols and meiosis-activating sterols. They are important to immune responses and development, and have been reviewed extensively. The triterpenoid metabolite fusidic acid has developed clinical relevance, and many steroidal metabolites from microbial sources possess varying bioactivities. Beyond the prospect of pharmacognostical agents, the profiling of minor metabolites can provide insight into an organism’s biosynthesis and phylogeny, as well as inform drug discovery about infectious diseases. This review aims to highlight recent discoveries from detailed sterolomic profiling in microorganisms and their phylogenic and pharmacological implications. Full article
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Open AccessReview
Oxysterols and Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome: Implications for an Improved Therapeutic Intervention
Molecules 2018, 23(10), 2720; https://doi.org/10.3390/molecules23102720 - 22 Oct 2018
Cited by 2
Abstract
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive human disease caused by mutations in the gene encoding 7-dehydrocholesterol (7DHC) reductase (DHCR7), resulting in abnormal accumulation of 7DHC and reduced levels of cholesterol in bodily tissues and fluids. A rat model of the disease has [...] Read more.
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive human disease caused by mutations in the gene encoding 7-dehydrocholesterol (7DHC) reductase (DHCR7), resulting in abnormal accumulation of 7DHC and reduced levels of cholesterol in bodily tissues and fluids. A rat model of the disease has been created by treating normal rats with the DHCR7 inhibitor, AY9944, which causes progressive, irreversible retinal degeneration. Herein, we review the features of this disease model and the evidence linking 7DHC-derived oxysterols to the pathobiology of the disease, with particular emphasis on the associated retinal degeneration. A recent study has shown that treating the rat model with cholesterol plus suitable antioxidants completely prevents the retinal degeneration. These findings are discussed with regard to their translational implications for developing an improved therapeutic intervention for SLOS over the current standard of care. Full article
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Open AccessReview
Synthesis and Biological Activity of Sterol 14α-Demethylase and Sterol C24-Methyltransferase Inhibitors
Molecules 2018, 23(7), 1753; https://doi.org/10.3390/molecules23071753 - 17 Jul 2018
Cited by 2
Abstract
Sterol 14α-demethylase (SDM) is essential for sterol biosynthesis and is the primary molecular target for clinical and agricultural antifungals. SDM has been demonstrated to be a valid drug target for antiprotozoal therapies, and much research has been focused on using SDM inhibitors to [...] Read more.
Sterol 14α-demethylase (SDM) is essential for sterol biosynthesis and is the primary molecular target for clinical and agricultural antifungals. SDM has been demonstrated to be a valid drug target for antiprotozoal therapies, and much research has been focused on using SDM inhibitors to treat neglected tropical diseases such as human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis. Sterol C24-methyltransferase (24-SMT) introduces the C24-methyl group of ergosterol and is an enzyme found in pathogenic fungi and protozoa but is absent from animals. This difference in sterol metabolism has the potential to be exploited in the development of selective drugs that specifically target 24-SMT of invasive fungi or protozoa without adversely affecting the human or animal host. The synthesis and biological activity of SDM and 24-SMT inhibitors are reviewed herein. Full article
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