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Ndoj K, Meurs A, Papaioannou D, Bjune K, Zelcer N. The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms. Atherosclerosis 2025; 401:119082. [PMID: 39700747 DOI: 10.1016/j.atherosclerosis.2024.119082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/11/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024]
Abstract
Cholesterol is a vital component of cellular membranes and is an essential molecule in mammalian physiology. Yet dysregulation of hepatic cholesterol metabolism and an increase in plasma cholesterol is linked to development of atherosclerotic cardiovascular disease. Maintaining tight regulation of cholesterol homeostasis is therefore essential, elegantly highlighted by the control of hepatic low-density lipoprotein receptor (LDLR) abundance and associated lipoprotein clearance. The LDLR was discovered in the 1970's in the seminal work of Brown and Goldstein. This was followed by the development of statins, which promote hepatic clearance of LDL via the LDLR pathway. The discovery two decades ago of Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9), a secreted protein that binds to the LDLR ectodomain and promotes its degradation, and the clinical development of PCSK9 inhibitors has ushered an effort to uncover additional mechanisms that govern the function and abundance of the LDLR. In recent years this has led to the identification of novel post-transcriptional and post-translational mechanisms that govern the LDLR. This review focuses on these emerging regulatory mechanisms and specifically discusses: (1) Regulation of the LDLR mRNA by RNA-binding proteins and microRNAs, (2) Ubiquitin-dependent degradation of the LDLR protein by the E3 ubiquitin ligases inducible degrader of the LDLR (IDOL) and GOLIATH (RNF130), (3) Control of the LDLR pathway by the asialoglycoprotein receptor 1 (ASGR1), and (4) The role of LDLR ectodomain shedding mediated by membrane-type 1 matrix metalloprotease (MT1-MMP), Bone morphogenetic protein 1 (BMP1), and γ-secretase. Understanding the contribution of these emerging mechanisms to regulation of the LDLR is important for the development of novel LDLR-focused lipid-lowering strategies.
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Affiliation(s)
- Klevis Ndoj
- Department of Medical Biochemistry, Amsterdam UMC Location AMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands
| | - Amber Meurs
- Department of Medical Biochemistry, Amsterdam UMC Location AMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands
| | - Dimitra Papaioannou
- Department of Medical Biochemistry, Amsterdam UMC Location AMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands
| | - Katrine Bjune
- Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Noam Zelcer
- Department of Medical Biochemistry, Amsterdam UMC Location AMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands.
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Zio S, Tarnagda B, Tapsoba F, Zongo C, Savadogo A. Health interest of cholesterol and phytosterols and their contribution to one health approach: Review. Heliyon 2024; 10:e40132. [PMID: 39583830 PMCID: PMC11584608 DOI: 10.1016/j.heliyon.2024.e40132] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 09/29/2024] [Accepted: 11/04/2024] [Indexed: 11/26/2024] Open
Abstract
Plants and animals are potential sources of food, particularly lipids. They are sources of nutrients for humans, and are used in various applications in food industries. Foods whose lipids consumed, have benefits for animal and human health. Sterols are among the compounds essential to the well-being of living beings. Phytosterols are derived from plants and algae, and zoosterols from animals dominated by cholesterol. Cholesterol is found in small quantities in some plant lipids. Also, cholesterol is produced by herbivorous insects by metabolizing phytosterols. Oilseeds and vegetable oils contain sterols and are the richest natural sources of phytosterols. Vegetables and fruit also contain small quantities. These compounds play an undeniable role in our diet. Foods, particularly vegetable oils, when produced, preserved and used according to established prescriptions, help to ensure consumer health and prevent certain pathologies. Sterols, and in particular phytosterols, play a number of roles in the pharmaceutical field (therapeutic steroids), nutrition (anti-cholesterol, anti-cancer properties). These natural molecules with their nutritional and therapeutic properties have a positive impact on human and animal health, and possibly on vegetative growth (development cycle of plants). The same is true for cholesterol, which has multiple functions in humans and animals. Also, a diet based on plants or their by-products with positive effects on human and animal health is closely in line with the objectives of the 'One health approach'. Indeed, sterols can have adverse effects on health when established standards are not respected. As a result, the health benefits of sterols (cholesterol and phytosterols) require particular attention, given their contribution to the public health problems facing our countries. The aim of the present research is to highlight the health benefits of cholesterol and phytosterols for living organisms, particularly humans, and their contribution to the One Health approach.
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Affiliation(s)
- Souleymane Zio
- Université Joseph KI-ZERBO, Laboratoire de Biochimie et d’Immunologie Appliquées, 03 BP 7021, Ouagadougou 03, Burkina Faso
| | - Bakary Tarnagda
- Université Joseph KI-ZERBO, Laboratoire de Biochimie et d’Immunologie Appliquées, 03 BP 7021, Ouagadougou 03, Burkina Faso
- Centre Universitaire de Banfora, Université Nazi BONI, 01 BP, Bobo Dioulasso 01, Burkina Faso
| | - François Tapsoba
- Université Joseph KI-ZERBO, Laboratoire de Biochimie et d’Immunologie Appliquées, 03 BP 7021, Ouagadougou 03, Burkina Faso
| | - Cheikna Zongo
- Université Joseph KI-ZERBO, Laboratoire de Biochimie et d’Immunologie Appliquées, 03 BP 7021, Ouagadougou 03, Burkina Faso
| | - Aly Savadogo
- Université Joseph KI-ZERBO, Laboratoire de Biochimie et d’Immunologie Appliquées, 03 BP 7021, Ouagadougou 03, Burkina Faso
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Chandramouli A, Kamat SS. A Facile LC-MS Method for Profiling Cholesterol and Cholesteryl Esters in Mammalian Cells and Tissues. Biochemistry 2024; 63:2300-2309. [PMID: 38986142 DOI: 10.1021/acs.biochem.4c00160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Cholesterol is central to mammalian lipid metabolism and serves many critical functions in the regulation of diverse physiological processes. Dysregulation in cholesterol metabolism is causally linked to numerous human diseases, and therefore, in vivo, the concentrations and flux of cholesterol and cholesteryl esters (fatty acid esters of cholesterol) are tightly regulated. While mass spectrometry has been an analytical method of choice for detecting cholesterol and cholesteryl esters in biological samples, the hydrophobicity, chemically inert nature, and poor ionization of these neutral lipids have often proved a challenge in developing lipidomics compatible liquid chromatography-mass spectrometry (LC-MS) methods to study them. To overcome this problem, here, we report a reverse-phase LC-MS method that is compatible with existing high-throughput lipidomics strategies and capable of identifying and quantifying cholesterol and cholesteryl esters from mammalian cells and tissues. Using this sensitive yet robust LC-MS method, we profiled different mammalian cell lines and tissues and provide a comprehensive picture of cholesterol and cholesteryl esters content in them. Specifically, among cholesteryl esters, we find that mammalian cells and tissues largely possess monounsaturated and polyunsaturated variants. Taken together, our lipidomics compatible LC-MS method to study this lipid class opens new avenues in understanding systemic and tissue-level cholesterol metabolism under various physiological conditions.
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Affiliation(s)
- Aakash Chandramouli
- Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Siddhesh S Kamat
- Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
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Lee JH, Kim YJ, Kim K, Kweon H, Kim HB, Kim SR, Kim SW, Park JW, Kang SK. Antioxidant and cholesterol regulatory effect of flavonoid-rich silk sericin. Food Sci Biotechnol 2024; 33:2623-2630. [PMID: 39144192 PMCID: PMC11319555 DOI: 10.1007/s10068-024-01527-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/13/2023] [Accepted: 01/10/2024] [Indexed: 08/16/2024] Open
Abstract
Cholesterol is a component of cell membranes and a precursor of hormones, and excess levels are associated with disease development; therefore, it must be maintained within the normal range. Silkworm cocoons are known to contain bioactive substances. Therefore, we compared the bioactivities of pigmented and white silkworm cocoons. Sericin extract of the Yeonnokjam (YN) variety, which contained a high flavonoid content, showed the highest antioxidant activity and inhibited cholesterol biosynthetic enzyme activity. YN-fed mice showed a 26% reduction in serum low-density lipoprotein cholesterol level. In addition, a 27% decrease in cholesterol accumulation in the liver was observed. Mechanistically, YN reduced the expression of 3-hydroxy-3-methylglutaryl-CoA reductase and acetyl-CoA acetyltransferase 2 proteins by 34 and 13%, respectively. In conclusion, YN suppresses cholesterol synthesis in the liver and stimulates bile acid secretion, which contributes to reduction in cholesterol levels, suggesting its potential as a cholesterol-lowering agent.
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Affiliation(s)
- Ji Hae Lee
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, 55365 South Korea
| | - Yeon-Ji Kim
- Korean Medicine-Application Center, Korea Institute of Oriental Medicine, Daegu, South Korea
| | - Kyungho Kim
- Korean Medicine-Application Center, Korea Institute of Oriental Medicine, Daegu, South Korea
| | - HaeYong Kweon
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, 55365 South Korea
| | - Hyun-bok Kim
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, 55365 South Korea
| | - Seong Ryul Kim
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, 55365 South Korea
| | - Seong-Wan Kim
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, 55365 South Korea
| | - Jong Woo Park
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, 55365 South Korea
| | - Sang Kuk Kang
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, 55365 South Korea
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Skeyni A, Pradignac A, Matz RL, Terrand J, Boucher P. Cholesterol trafficking, lysosomal function, and atherosclerosis. Am J Physiol Cell Physiol 2024; 326:C473-C486. [PMID: 38145298 DOI: 10.1152/ajpcell.00415.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 12/26/2023]
Abstract
Despite years of study and major research advances over the past 50 years, atherosclerotic diseases continue to rank as the leading global cause of death. Accumulation of cholesterol within the vascular wall remains the main problem and represents one of the early steps in the development of atherosclerotic lesions. There is a complex relationship between vesicular cholesterol transport and atherosclerosis, and abnormalities in cholesterol trafficking can contribute to the development and progression of the lesions. The dysregulation of vesicular cholesterol transport and lysosomal function fosters the buildup of cholesterol within various intracytoplasmic compartments, including lysosomes and lipid droplets. This, in turn, promotes the hallmark formation of foam cells, a defining feature of early atherosclerosis. Multiple cellular processes, encompassing endocytosis, exocytosis, intracellular trafficking, and autophagy, play crucial roles in influencing foam cell formation and atherosclerotic plaque stability. In this review, we highlight recent advances in the understanding of the intricate mechanisms of vesicular cholesterol transport and its relationship with atherosclerosis and discuss the importance of understanding these mechanisms in developing strategies to prevent or treat this prevalent cardiovascular disease.
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Affiliation(s)
- Alaa Skeyni
- UMR-S INSERM 1109, University of Strasbourg, Strasbourg, France
| | - Alain Pradignac
- UMR-S INSERM 1109, University of Strasbourg, Strasbourg, France
| | - Rachel L Matz
- UMR-S INSERM 1109, University of Strasbourg, Strasbourg, France
| | - Jérôme Terrand
- UMR-S INSERM 1109, University of Strasbourg, Strasbourg, France
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Kojima M, Degawa M. Causes of Sex Differences in Serum Cholesterol and Triglyceride Levels in Meishan Pigs. Biol Pharm Bull 2024; 47:606-610. [PMID: 38462492 DOI: 10.1248/bpb.b23-00895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
To clarify the causes of sex differences (male < female) in the serum total cholesterol (TCHO) and triglyceride (TG) levels in Meishan pigs, we examined the sex differences in mRNA levels of key hepatic enzymes involved in the biosynthesis/metabolism of cholesterol and TG using real-time RT-PCR. There were no sex differences in mRNA levels of 3-hydroxy-3-methylglutaryl-CoA reductase and CYP51A1 for cholesterol biosynthesis, or of the rate-limiting enzyme CYP7A1 for bile acid synthesis from cholesterol. By contrast, sex differences (male < female) were observed in mRNA levels of glycerol-3-phosphate acyltransferase 1 (GPAT1), a rate-limiting enzyme for TG biosynthesis. However, the sex differences in mRNA levels of carnitine palmitoyltransferase 1A (CPT1A) and acyl-CoA dehydrogenase long chain (ACADL), key enzymes for the oxidation of the fatty acids that are structural components of TG, were the opposite (male > female). Castration of male pigs led to an increase in the mRNA level of GPAT1 and decreases in those of CPT1A and ACADL. Furthermore, testosterone propionate (TP)-treatment of castrated males and intact females restored and changed, respectively, these mRNA levels to those of intact males. Notably, castration and TP-treatment increased and decreased, respectively, serum and hepatic TG levels. These findings suggest that sex differences in the serum and hepatic TG levels in Meishan pigs are closely correlated with differences in testosterone-associated mRNA expression levels of the key enzymes (GPAT1, CPT1A, and ACADL) involved in the TG biosynthesis process, although no causes of sex differences in serum and hepatic TCHO levels could be found.
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Affiliation(s)
- Misaki Kojima
- Meat Animal Biosystem Group, Division of Meat Animal and Poultry Research, Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO)
| | - Masakuni Degawa
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka
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Mokgopa KP, Lobb KA, Tshiwawa T. A Computational Study of Green Tea Extracts and their Derivatives as Potential Inhibitors for Squalene Monooxygenase. Med Chem 2024; 20:721-732. [PMID: 38584555 DOI: 10.2174/0115734064280290240211170037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/09/2024] [Accepted: 01/24/2024] [Indexed: 04/09/2024]
Abstract
BACKGROUND According to the World Health Organisation, cardiovascular complications have been recognized as the leading course of death between 2000 and 2019. Cardiovascular complications are caused by excess LDL cholesterol in the body or arteries that can build up to form a plaque. There are drugs currently in clinical use called statins that target HMGCoA reductase. However, these drugs result in several side effects. This work investigated using computational approaches to lower cholesterol by investigating green tea extracts as an inhibitors for squalene monooxygenase (the second-rate-controlling step in cholesterol synthesis). METHODS Pharmacophore modeling was done to identify possible pharmacophoric sites based on the pIC50 values. The best hypothesis generated by pharmacophore modeling was further validated by atom-based 3D QSAR, where 70% of the data set was treated as the training set. Prior molecular docking ADMET studies were done to investigate the physiochemical properties of these molecules. Glide docking was performed, followed by molecular dynamics to evaluate the protein conformational changes. RESULTS Pharmacophore results suggest that the best molecules to interact with the biological target should have at least one hydrogen acceptor (A5), two hydrogen donors (D9 and D10), and two benzene rings (R14 and R15) for green tea polyphenols and theasinensin A. ADMET result shows that all molecules in this class have low oral adsorption. Molecular docking results showed that some green tea polyphenols have good binding affinities, with most of these structures having a docking score of less than -10 kcal/mol. Molecular dynamics further illustrated that the best-docked ligands perfectly stay within the active site over a 100 ns simulation. CONCLUSION The results obtained from this study suggest that green tea polyphenols have the potential for inhibition of squalene monooxygenase, except for theasinensin A.
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Affiliation(s)
| | - Kevin A Lobb
- Department of Chemistry, Rhodes University, Makhanda, South Africa
- Research Unit in Bioinformatics (RUBi), Rhodes University, Makhanda, 6140, South Africa
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Yang J, Lee R, Henning SM, Xing E, Huang J, Yang S, Garcia MC, Surampudi V, Heber D, Li Z. Concentrated Grape Powder Consumption Modulates Cholesterol Metabolism and Homeostasis in Healthy Subjects. Mol Nutr Food Res 2023; 67:e2300224. [PMID: 37672802 DOI: 10.1002/mnfr.202300224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
SCOPE Four weeks' of concentrated grape powder (GP) consumption reduces circulating cholesterol in healthy free-living subjects consuming a low-fiber/low-polyphenol diet. Here, the study aims to investigate the underlying mechanisms for cholesterol reduction by evaluating biomarkers of cholesterol de novo biosynthesis, intestinal absorption, miRNA involved in transcriptional regulation of cholesterol metabolism, as well as cholesterol oxidation. METHODS AND RESULTS Fasting plasma samples collected from 19 healthy free-living subjects at baseline and week 4 of GP consumption are used in this study. Gas chromatography-mass (GC-MS) analysis of plasma samples shows that lathosterol, a precursor of cholesterol synthesis, is significantly decreased after GP consumption indicating reduced cholesterol de novo biosynthesis. Markers of intestinal absorption, campesterol, and β-sitosterol are not changed. Realtime PCR shows that plasma exosomal miRNA-1 is increased after GP consumption. GC-MS also shows that GP consumption reduces the plasma cholesterol oxidation product 27-hydroxycholesterol (27-HC). CONCLUSIONS This study enhances the understanding of the mechanisms of the cholesterol lowering effects of GP, and provides new insights into the potential health benefits of grape consumption.
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Affiliation(s)
- Jieping Yang
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - Rupo Lee
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - Susanne M Henning
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - Emily Xing
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - Jianjun Huang
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - Scarlet Yang
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - Michael C Garcia
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - Vijaya Surampudi
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - David Heber
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
| | - Zhaoping Li
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 1083390095, USA
- Department of Medicine, VA Greater Los Angeles Health Care System, Los Angeles, CA, 90073, USA
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Jackson KD, Achour B, Lee J, Geffert RM, Beers JL, Latham BD. Novel Approaches to Characterize Individual Drug Metabolism and Advance Precision Medicine. Drug Metab Dispos 2023; 51:1238-1253. [PMID: 37419681 PMCID: PMC10506699 DOI: 10.1124/dmd.122.001066] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 05/30/2023] [Accepted: 06/05/2023] [Indexed: 07/09/2023] Open
Abstract
Interindividual variability in drug metabolism can significantly affect drug concentrations in the body and subsequent drug response. Understanding an individual's drug metabolism capacity is important for predicting drug exposure and developing precision medicine strategies. The goal of precision medicine is to individualize drug treatment for patients to maximize efficacy and minimize drug toxicity. While advances in pharmacogenomics have improved our understanding of how genetic variations in drug-metabolizing enzymes (DMEs) affect drug response, nongenetic factors are also known to influence drug metabolism phenotypes. This minireview discusses approaches beyond pharmacogenetic testing to phenotype DMEs-particularly the cytochrome P450 enzymes-in clinical settings. Several phenotyping approaches have been proposed: traditional approaches include phenotyping with exogenous probe substrates and the use of endogenous biomarkers; newer approaches include evaluating circulating noncoding RNAs and liquid biopsy-derived markers relevant to DME expression and function. The goals of this minireview are to 1) provide a high-level overview of traditional and novel approaches to phenotype individual drug metabolism capacity, 2) describe how these approaches are being applied or can be applied to pharmacokinetic studies, and 3) discuss perspectives on future opportunities to advance precision medicine in diverse populations. SIGNIFICANCE STATEMENT: This minireview provides an overview of recent advances in approaches to characterize individual drug metabolism phenotypes in clinical settings. It highlights the integration of existing pharmacokinetic biomarkers with novel approaches; also discussed are current challenges and existing knowledge gaps. The article concludes with perspectives on the future deployment of a liquid biopsy-informed physiologically based pharmacokinetic strategy for patient characterization and precision dosing.
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Affiliation(s)
- Klarissa D Jackson
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.D.J., J.L., R.M.G., J.L.B., B.D.L.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Brahim Achour
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.D.J., J.L., R.M.G., J.L.B., B.D.L.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Jonghwa Lee
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.D.J., J.L., R.M.G., J.L.B., B.D.L.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Raeanne M Geffert
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.D.J., J.L., R.M.G., J.L.B., B.D.L.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Jessica L Beers
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.D.J., J.L., R.M.G., J.L.B., B.D.L.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Bethany D Latham
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.D.J., J.L., R.M.G., J.L.B., B.D.L.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island (B.A.)
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Wongkhieo S, Tangmesupphaisan W, Siriwaseree J, Aramsirirujiwet Y, Wiriyajitsomboon P, Kaewgrajang T, Pumloifa S, Paemanee A, Kuaprasert B, Choowongkomon K, Chester AH, Swainson NM. In vitro cholesterol lowering activity of Ganoderma australe mycelia based on mass spectrometry, synchrotron Fourier-transform infrared analysis and liver-spheroid bioactivity. Sci Rep 2023; 13:13619. [PMID: 37604902 PMCID: PMC10442327 DOI: 10.1038/s41598-023-40861-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 08/17/2023] [Indexed: 08/23/2023] Open
Abstract
Mycelia were cultivated from a Thai wild mushroom identified as Ganoderma australe based on polymerase chain reaction (PCR) and morphological analyses. The mycelial extracts were examined for their active ingredients using a liquid chromatography-tandem mass spectrometry (LC‒MS/MS) method. This revealed the presence of lovastatin and tentative compounds including p-coumaric, nicotinamide, gamma-aminobutyric acid, choline, nucleosides, amino acids, and saccharides. The extracts had an inhibitory effect on the activity of HMG-CoA reductase in a concentration-dependent manner. At 2.5 mg/mL, the G. australe extracts did not interfere with the viability of HepG2 spheroids, but their biochemical composition was altered as determined by Fourier-transform infrared (FTIR) spectroscopy. The lipid profile of the spheroids treated with the mycelial extract was distinct from that of the control and the 5 µM lovastatin treatment, corresponding with the production of cholesterol by the spheroids. The mycelia of G. australe increased the percentage of high-density lipoprotein (HDL) production to 71.35 ± 2.74%, compared to the control and lovastatin-treated spheroids (33.26 ± 3.15% and 32.13 ± 3.24%, respectively). This study revealed the superior effect of natural compound mixtures to pure lovastatin, and the potential use of Thailand's wild G. australe as a functional food to prevent or alleviate hypercholesterolemia.
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Affiliation(s)
- Sudthirak Wongkhieo
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
| | | | - Jeeraprapa Siriwaseree
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
| | - Yaovapa Aramsirirujiwet
- Department of Microbiology, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
| | | | - Tharnrat Kaewgrajang
- Department of Forest Biology, Faculty of Forestry, Kasetsart University, 50 Ngamwongwan Rd, Lat Yao, Chatuchak, Bangkok, 10900, Thailand
| | - Saifa Pumloifa
- National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, 12120, Thailand
| | - Atchara Paemanee
- National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, 12120, Thailand
| | - Buabarn Kuaprasert
- Research Facility Department, Synchrotron Light Research Institute (Public Organization), 111 University Avenue, Muang District, Nakhon Ratchasima, 30000, Thailand
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
| | - Adrian H Chester
- Heart Science Centre, Magdi Yacoub Institute, Harefield, UK
- National Heart and Lung Institute (NHLI), Imperial College London, London, UK
| | - Napachanok M Swainson
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand.
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Nguyen VH, Wemheuer B, Song W, Bennett H, Webster N, Thomas T. Identification, classification, and functional characterization of novel sponge-associated acidimicrobiial species. Syst Appl Microbiol 2023; 46:126426. [PMID: 37141831 DOI: 10.1016/j.syapm.2023.126426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/11/2023] [Accepted: 04/23/2023] [Indexed: 05/06/2023]
Abstract
Sponges are known to harbour an exceptional diversity of uncultured microorganisms, including members of the phylum Actinobacteriota. While members of the actinobacteriotal class Actinomycetia have been studied intensively due to their potential for secondary metabolite production, the sister class of Acidimicrobiia is often more abundant in sponges. However, the taxonomy, functions, and ecological roles of sponge-associated Acidimicrobiia are largely unknown. Here, we reconstructed and characterized 22 metagenome-assembled genomes (MAGs) of Acidimicrobiia from three sponge species. These MAGs represented six novel species, belonging to five genera, four families, and two orders, which are all uncharacterized (except the order Acidimicrobiales) and for which we propose nomenclature. These six uncultured species have either only been found in sponges and/or corals and have varying degrees of specificity to their host species. Functional gene profiling indicated that these six species shared a similar potential to non-symbiotic Acidimicrobiia with respect to amino acid biosynthesis and utilization of sulfur compounds. However, sponge-associated Acidimicrobiia differed from their non-symbiotic counterparts by relying predominantly on organic rather than inorganic sources of energy, and their predicted capacity to synthesise bioactive compounds or their precursors implicated in host defence. Additionally, the species possess the genetic capacity to degrade aromatic compounds that are frequently found in sponges. The novel Acidimicrobiia may also potentially mediate host development by modulating Hedgehog signalling and by the production of serotonin, which can affect host body contractions and digestion. These results highlight unique genomic and metabolic features of six new acidimicrobiial species that potentially support a sponge-associated lifestyle.
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Affiliation(s)
- Viet Hung Nguyen
- Centre for Marine Science and Innovation, School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Bernd Wemheuer
- Centre for Marine Science and Innovation, School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Weizhi Song
- Centre for Marine Science and Innovation, School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Holly Bennett
- Australian Institute of Marine Science, Townsville, Queensland, Australia
| | - Nicole Webster
- Australian Institute of Marine Science, Townsville, Queensland, Australia; Australian Antarctic Division, Hobart, Tasmania, Australia
| | - Torsten Thomas
- Centre for Marine Science and Innovation, School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia.
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12
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Xie X, Liang X, Wang H, Zhu Q, Wang J, Chang Y, Leclercq E, Xue M, Wang J. Effects of paraprobiotics on bile acid metabolism and liver health in largemouth bass (Micropterus salmoides) fed a cottonseed protein concentrate-based diet. ANIMAL NUTRITION 2023; 13:302-312. [PMID: 37168448 PMCID: PMC10165182 DOI: 10.1016/j.aninu.2023.02.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 02/04/2023] [Accepted: 02/13/2023] [Indexed: 03/09/2023]
Abstract
Cottonseed protein concentrate is a sustainable fishmeal alternative in aquafeed. A 10-week experiment was conducted to investigate the effects of a cottonseed protein concentrate-based diet with and without multi-strain yeast fractions (MsYF) on growth, bile acid metabolism, and health in largemouth bass. Four hundred fish (54.0 ± 0.0 g) were casually distributed into 16 tanks (4 replicates/diet). Fish were fed with 4 iso-nitrogen and iso-energetic diets 3 times daily, including a fishmeal diet (FM), a soy protein concentrate-based diet (SPC; replacing 81% fishmeal protein), a cottonseed protein concentrate-based diet (CPC; replacing 81% fishmeal protein), and a CPC diet supplemented with 800 mg/kg MsYF (CPCY). Results showed that the survival of SPC was the lowest, i.e., 48%, with no apparent diet effect among other treatments; we omitted the SPC in additional analyses. Fish fed cottonseed protein concentrate-based diets showed lower growth than FM (P < 0.05). Fish fed CPC showed the highest nuclear dense hepatic phenotypes ratio (50%), followed by CPCY (33%) and FM (17%). Further, dietary CPC increased hepatic total cholesterol and triglyceride levels with concurrently increased cholesterol synthesis but decreased triglyceride synthesis-associated transcription levels (P < 0.05). Furthermore, dietary CPC increased bile acid synthesis but decreased bile acid transport-associated transcription levels (P < 0.05), and then induced an increment of plasma cholic acid and hepatic chenodeoxycholic acid content and the decrement of genus Romboustia (P < 0.05). Regarding the effect of MsYF, fish fed CPCY reduced hepatic lipid accumulation and total plasma bile acid content (P < 0.05) compared to CPC, suggesting an improvement in liver health. Also, dietary MsYF could reverse the microbiota community structure showing a similar gut microbial composition to FM. In conclusion, 81% of fishmeal protein replaced by cottonseed protein concentrate suppressed growth and liver health, while dietary MsYF might mitigate the negative impact of a high cottonseed protein concentrate level diet on liver functions via gut microbiota regulation.
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13
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Wang S, Neel AI, Adams KL, Sun H, Jones SR, Howlett AC, Chen R. Atorvastatin differentially regulates the interactions of cocaine and amphetamine with dopamine transporters. Neuropharmacology 2023; 225:109387. [PMID: 36567004 PMCID: PMC9872521 DOI: 10.1016/j.neuropharm.2022.109387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 12/12/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
The function of the dopamine transporter (DAT) is regulated by membrane cholesterol content. A direct, acute removal of membrane cholesterol by methyl-β-cyclodextrin (MβCD) has been shown to reduce dopamine (DA) uptake and release mediated by the DAT. This is of particular interest because a few widely prescribed statins that lower peripheral cholesterol levels are blood-brain barrier (BBB) penetrants, and therefore could alter DAT function through brain cholesterol modulation. The goal of this study was to investigate the effects of prolonged atorvastatin treatment (24 h) on DAT function in neuroblastoma 2A cells stably expressing DAT. We found that atorvastatin treatment effectively lowered membrane cholesterol content in a concentration-dependent manner. Moreover, atorvastatin treatment markedly reduced DA uptake and abolished cocaine inhibition of DA uptake, independent of surface DAT levels. These deficits induced by atorvastatin treatment were reversed by cholesterol replenishment. However, atorvastatin treatment did not change amphetamine (AMPH)-induced DA efflux. This is in contrast to a small but significant reduction in DA efflux induced by acute depletion of membrane cholesterol using MβCD. This discrepancy may involve differential changes in membrane lipid composition resulting from chronic and acute cholesterol depletion. Our data suggest that the outward-facing conformation of DAT, which favors the binding of DAT blockers such as cocaine, is more sensitive to atorvastatin-induced cholesterol depletion than the inward-facing conformation, which favors the binding of DAT substrates such as AMPH. Our study on statin-DAT interactions may have clinical implications in our understanding of neurological side effects associated with chronic use of BBB penetrant statins.
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Affiliation(s)
- Shiyu Wang
- Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, 27157, United States
| | - Anna I Neel
- Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, 27157, United States
| | - Kristen L Adams
- Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, 27157, United States
| | - Haiguo Sun
- Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, 27157, United States
| | - Sara R Jones
- Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, 27157, United States
| | - Allyn C Howlett
- Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, 27157, United States
| | - Rong Chen
- Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, 27157, United States.
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14
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Metabolic adaptation to high-starch diet in largemouth bass ( Micropterus salmoides) was associated with the restoration of metabolic functions via inflammation, bile acid synthesis and energy metabolism. Br J Nutr 2023; 129:381-394. [PMID: 35473811 DOI: 10.1017/s0007114522001180] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
A short-term 2-week (2w) and long-term 8-week (8w) feeding trial was conducted to investigate the effects of low-starch (LS) and high-starch (HS) diets on the growth performance, metabolism and liver health of largemouth bass (Micropterus salmoides). Two isonitrogenous and isolipidic diets containing two levels of starch (LS, 9·06 %; HS, 13·56 %) were fed to largemouth bass. The results indicated that HS diet had no significant effects on specific growth rate during 2w, whereas significantly lowered specific growth rate at 8w. HS diet significantly increased hepatic glycolysis and gluconeogenesis at postprandial 24 h in 2w. The hepatosomatic index, plasma alkaline phosphatase, total bile acid (TBA) levels, and hepatic glycogen, TAG, total cholesterol, TBA, and NEFA contents were significantly increased in the HS group at 2w. Moreover, HS diet up-regulated fatty acid and TAG synthesis-related genes and down-regulated TAG hydrolysis and β-oxidation-related genes. Therefore, the glucolipid metabolism disorders resulted in metabolic liver disease induced by HS diet at 2w. However, the up-regulation of bile acid synthesis, inflammation and energy metabolism-related genes in 2w indicated that largemouth bass was still in a state of 'self-repair' response. Interestingly, all the metabolic parameters were returned to homoeostasis, with up-regulation of intestinal glucose uptake and transport-related genes, even hepatic histopathological analysis showed no obvious abnormality in the HS group in 8w. In conclusion, HS feed induced short-term acute metabolic disorder, but long-term metabolic adaptation to HS diet was related to repairing metabolism disorders via improving inflammatory responses, bile acid synthesis and energy metabolism. These results strongly indicated that the largemouth bass owned certain adaptability to HS diet.
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15
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Li RX, Chen LY, Limbu SM, Qian YC, Zhou WH, Chen LQ, Luo Y, Qiao F, Zhang ML, Du ZY. High cholesterol intake remodels cholesterol turnover and energy homeostasis in Nile tilapia ( Oreochromis niloticus). MARINE LIFE SCIENCE & TECHNOLOGY 2023; 5:56-74. [PMID: 37073330 PMCID: PMC10077235 DOI: 10.1007/s42995-022-00158-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 12/08/2022] [Indexed: 05/03/2023]
Abstract
The roles of dietary cholesterol in fish physiology are currently contradictory. The issue reflects the limited studies on the metabolic consequences of cholesterol intake in fish. The present study investigated the metabolic responses to high cholesterol intake in Nile tilapia (Oreochromis niloticus), which were fed with four cholesterol-contained diets (0.8, 1.6, 2.4 and 3.2%) and a control diet for eight weeks. All fish-fed cholesterol diets showed increased body weight, but accumulated cholesterol (the peak level was in the 1.6% cholesterol group). Then, we selected 1.6% cholesterol and control diets for further analysis. The high cholesterol diet impaired liver function and reduced mitochondria number in fish. Furthermore, high cholesterol intake triggered protective adaptation via (1) inhibiting endogenous cholesterol synthesis, (2) elevating the expression of genes related to cholesterol esterification and efflux, and (3) promoting chenodeoxycholic acid synthesis and efflux. Accordingly, high cholesterol intake reshaped the fish gut microbiome by increasing the abundance of Lactobacillus spp. and Mycobacterium spp., both of which are involved in cholesterol and/or bile acids catabolism. Moreover, high cholesterol intake inhibited lipid catabolic activities through mitochondrial β-oxidation, and lysosome-mediated lipophagy, and depressed insulin signaling sensitivity. Protein catabolism was elevated as a compulsory response to maintain energy homeostasis. Therefore, although high cholesterol intake promoted growth, it led to metabolic disorders in fish. For the first time, this study provides evidence for the systemic metabolic response to high cholesterol intake in fish. This knowledge contributes to an understanding of the metabolic syndromes caused by high cholesterol intake or deposition in fish. Supplementary Information The online version contains supplementary material available at 10.1007/s42995-022-00158-7.
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Affiliation(s)
- Rui-Xin Li
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
| | - Ling-Yun Chen
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
| | - Samwel M. Limbu
- Department of Aquaculture Technology, School of Aquatic Sciences and Fisheries Technology, University of Dar es Salaam, P. O. Box 60091, Dar es Salaam, Tanzania
| | - Yu-Cheng Qian
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
| | - Wen-Hao Zhou
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
| | - Li-Qiao Chen
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
| | - Yuan Luo
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
| | - Fang Qiao
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
| | - Mei-Ling Zhang
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
| | - Zhen-Yu Du
- LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241 China
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16
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Verdaguer IB, Crispim M, Hernández A, Katzin AM. The Biomedical Importance of the Missing Pathway for Farnesol and Geranylgeraniol Salvage. Molecules 2022; 27:molecules27248691. [PMID: 36557825 PMCID: PMC9782597 DOI: 10.3390/molecules27248691] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 11/30/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Isoprenoids are the output of the polymerization of five-carbon, branched isoprenic chains derived from isopentenyl pyrophosphate (IPP) and its isomer, dimethylallyl pyrophosphate (DMAPP). Isoprene units are consecutively condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively), necessary for the biosynthesis of several metabolites. Polyprenyl transferases and synthases use polyprenyl pyrophosphates as their natural substrates; however, it is known that free polyprenols, such as farnesol (FOH), and geranylgeraniol (GGOH) can be incorporated into prenylated proteins, ubiquinone, cholesterol, and dolichols. Furthermore, FOH and GGOH have been shown to block the effects of isoprenoid biosynthesis inhibitors such as fosmidomycin, bisphosphonates, or statins in several organisms. This phenomenon is the consequence of a short pathway, which was observed for the first time more than 25 years ago: the polyprenol salvage pathway, which works via the phosphorylation of FOH and GGOH. Biochemical studies in bacteria, animals, and plants suggest that this pathway can be carried out by two enzymes: a polyprenol kinase and a polyprenyl-phosphate kinase. However, to date, only a few genes have been unequivocally identified to encode these enzymes in photosynthetic organisms. Nevertheless, pieces of evidence for the importance of this pathway abound in studies related to infectious diseases, cancer, dyslipidemias, and nutrition, and to the mitigation of the secondary effects of several drugs. Furthermore, nowadays it is known that both FOH and GGOH can be incorporated via dietary sources that produce various biological effects. This review presents, in a simplified but comprehensive manner, the most important data on the FOH and GGOH salvage pathway, stressing its biomedical importance The main objective of this review is to bring to light the need to discover and characterize the kinases associated with the isoprenoid salvage pathway in animals and pathogens.
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Affiliation(s)
- Ignasi Bofill Verdaguer
- Department of Parasitology, Institute of Biomedical Sciences of the University of São Paulo, Av. Lineu Prestes 1374, São Paulo 05508-000, Brazil
| | - Marcell Crispim
- Department of Parasitology, Institute of Biomedical Sciences of the University of São Paulo, Av. Lineu Prestes 1374, São Paulo 05508-000, Brazil
| | - Agustín Hernández
- Integrated Unit for Research in Biodiversity (BIOTROP-CCBS), Center for Biological and Health Sciences, Federal University of São Carlos, São Carlos 13565-905, Brazil
| | - Alejandro Miguel Katzin
- Department of Parasitology, Institute of Biomedical Sciences of the University of São Paulo, Av. Lineu Prestes 1374, São Paulo 05508-000, Brazil
- Correspondence: ; Tel.: +55-11-3091-7330; Fax: +55-11-3091-7417
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17
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Nakagawa S, Hayashi A, Nukada Y, Yamane M. Comparison of toxicological effects and exposure levels between triclosan and its structurally similar chemicals using in vitro tests for read-across case study. Regul Toxicol Pharmacol 2022; 132:105181. [PMID: 35526779 DOI: 10.1016/j.yrtph.2022.105181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 03/02/2022] [Accepted: 04/25/2022] [Indexed: 11/27/2022]
Abstract
Read-across based on structural and biological similarities is expected to be a promising alternative method for assessing systemic toxicity. A concrete strategy for quantitative chemical risk assessment would be to stack read-across case studies and extract key considerations from them. Thus, we developed a read-across case study by comparing the toxicological effects based on adverse outcome pathways and exposure levels of different structurally similar chemicals for a target organ. In this study, we selected the hepatotoxicity of triclosan and its structurally similar chemicals including diclosan and 1-chloro-3-(4-chlorophenoxy)benzene. The results of in vitro toxicogenomics showed that disorders of cholesterol synthesis were commonly detected with both triclosan and diclosan. The decrease in hepatocellular cholesterol levels was similar in the cells treated with triclosan and diclosan. Furthermore, the exposure levels of triclosan and diclosan for the liver were similar. Collectively, these results suggest that triclosan and diclosan show similar toxicological effects and severity of hepatotoxicity. Considering the existing repeated dose toxicity data, our prediction results are reasonable regarding the toxicological effect and its severity. Thus, the present study demonstrated the usability of comparing toxicological effects and exposure levels using read-across for quantitative chemical risk assessment.
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Affiliation(s)
- Shota Nakagawa
- Kao Corporation, Safety Science Research, 2606, Akabane, Ichikai-Machi, Haga-Gun Tochigi, 321-3497, Japan.
| | - Akane Hayashi
- Kao Corporation, Safety Science Research, 2606, Akabane, Ichikai-Machi, Haga-Gun Tochigi, 321-3497, Japan
| | - Yuko Nukada
- Kao Corporation, Safety Science Research, 2606, Akabane, Ichikai-Machi, Haga-Gun Tochigi, 321-3497, Japan
| | - Masayuki Yamane
- Kao Corporation, Safety Science Research, 2606, Akabane, Ichikai-Machi, Haga-Gun Tochigi, 321-3497, Japan
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18
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Dutta A, Sarkar P, Shrivastava S, Chattopadhyay A. Effect of Hypoxia on the Function of the Human Serotonin 1A Receptor. ACS Chem Neurosci 2022; 13:1456-1466. [PMID: 35467841 DOI: 10.1021/acschemneuro.2c00181] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Cellular hypoxia causes numerous pathophysiological conditions associated with the disruption of oxygen homeostasis. Under oxygen-deficient conditions, cells adapt by controlling the cellular functions to facilitate the judicious use of available oxygen, such as cessation of cell growth and proliferation. In higher eukaryotes, the process of cholesterol biosynthesis is intimately coupled to the availability of oxygen, where the synthesis of one molecule of cholesterol requires 11 molecules of O2. Cholesterol is an essential component of higher eukaryotic membranes and is crucial for the physiological functions of several membrane proteins and receptors. The serotonin1A receptor, an important neurotransmitter G protein-coupled receptor associated with cognition and memory, has previously been shown to depend on cholesterol for its signaling and function. In this work, in order to explore the interdependence of oxygen levels, cholesterol biosynthesis, and the function of the serotonin1A receptor, we developed a cellular hypoxia model to explore the function of the human serotonin1A receptor heterologously expressed in Chinese hamster ovary cells. We observed cell cycle arrest at G1/S phase and the accumulation of lanosterol in cell membranes under hypoxic conditions, thereby validating our cellular model. Interestingly, we observed a significant reduction in ligand binding and disruption of downstream cAMP signaling of the serotonin1A receptor under hypoxic conditions. To the best of our knowledge, our results represent the first report linking the function of the serotonin1A receptor with hypoxia. From a broader perspective, these results contribute to our overall understanding of the molecular basis underlying neurological conditions often associated with hypoxia-induced brain dysfunction.
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Affiliation(s)
- Aritri Dutta
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
| | - Parijat Sarkar
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
| | - Sandeep Shrivastava
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
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19
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Laka K, Makgoo L, Mbita Z. Cholesterol-Lowering Phytochemicals: Targeting the Mevalonate Pathway for Anticancer Interventions. Front Genet 2022; 13:841639. [PMID: 35391801 PMCID: PMC8981032 DOI: 10.3389/fgene.2022.841639] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/07/2022] [Indexed: 11/15/2022] Open
Abstract
There are a plethora of cancer causes and the road to fully understanding the carcinogenesis process remains a dream that keeps changing. However, a list of role players that are implicated in the carcinogens process is getting lengthier. Cholesterol is known as bad sterol that is heavily linked with cardiovascular diseases; however, it is also comprehensively associated with carcinogenesis. There is an extensive list of strategies that have been used to lower cholesterol; nevertheless, the need to find better and effective strategies remains vastly important. The role played by cholesterol in the induction of the carcinogenesis process has attracted huge interest in recent years. Phytochemicals can be dubbed as magic tramp cards that humans could exploit for lowering cancer-causing cholesterol. Additionally, the mechanisms that are regulated by phytochemicals can be targeted for anticancer drug development. One of the key role players in cancer development and suppression, Tumour Protein 53 (TP53), is crucial in regulating the biogenesis of cholesterol and is targeted by several phytochemicals. This minireview covers the role of p53 in the mevalonate pathway and how bioactive phytochemicals target the mevalonate pathway and promote p53-dependent anticancer activities.
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Affiliation(s)
| | | | - Zukile Mbita
- Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Sovenga, South Africa
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20
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Shi Q, Chen J, Zou X, Tang X. Intracellular Cholesterol Synthesis and Transport. Front Cell Dev Biol 2022; 10:819281. [PMID: 35386193 PMCID: PMC8978673 DOI: 10.3389/fcell.2022.819281] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 02/01/2022] [Indexed: 12/18/2022] Open
Abstract
Cholesterol homeostasis is related to multiple diseases in humans, including cardiovascular disease, cancer, and neurodegenerative and hepatic diseases. The cholesterol levels in cells are balanced dynamically by uptake, biosynthesis, transport, distribution, esterification, and export. In this review, we focus on de novo cholesterol synthesis, cholesterol synthesis regulation, and intracellular cholesterol trafficking. In addition, the progression of lipid transfer proteins (LTPs) at multiple contact sites between organelles is considered.
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Affiliation(s)
- Qingyang Shi
- Center of Reproductive Medicine and Center of Prenatal Diagnosis, The First Hospital, Jilin University, Changchun, China
| | - Jiahuan Chen
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, China
| | - Xiaodong Zou
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, China
| | - Xiaochun Tang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
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21
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Zhao Y, Hu D, Wang R, Sun X, Ropelewski P, Hubler Z, Lundberg K, Wang Q, Adams DJ, Xu R, Qi X. ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models. Nat Commun 2022; 13:1121. [PMID: 35236834 PMCID: PMC8891325 DOI: 10.1038/s41467-022-28769-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 02/11/2022] [Indexed: 12/12/2022] Open
Abstract
Predisposition to Alzheimer's disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive deficits in AD transgenic mice. These findings reveal a role for ATAD3A oligomerization in AD pathogenesis and suggest ATAD3A as a potential therapeutic target for AD.
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Affiliation(s)
- Yuanyuan Zhao
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Di Hu
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Rihua Wang
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Xiaoyan Sun
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Philip Ropelewski
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Zita Hubler
- Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Kathleen Lundberg
- Proteomics Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Quanqiu Wang
- Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Drew J Adams
- Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Rong Xu
- Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Xin Qi
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
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22
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Heravi G, Yazdanpanah O, Podgorski I, Matherly LH, Liu W. Lipid metabolism reprogramming in renal cell carcinoma. Cancer Metastasis Rev 2022; 41:17-31. [PMID: 34741716 PMCID: PMC10045462 DOI: 10.1007/s10555-021-09996-w] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/21/2021] [Indexed: 12/15/2022]
Abstract
Metabolic reprogramming is recognized as a hallmark of cancer. Lipids are the essential biomolecules required for membrane biosynthesis, energy storage, and cell signaling. Altered lipid metabolism allows tumor cells to survive in the nutrient-deprived environment. However, lipid metabolism remodeling in renal cell carcinoma (RCC) has not received the same attention as in other cancers. RCC, the most common type of kidney cancer, is associated with almost 15,000 death in the USA annually. Being refractory to conventional chemotherapy agents and limited available targeted therapy options has made the treatment of metastatic RCC very challenging. In this article, we review recent findings that support the importance of synthesis and metabolism of cholesterol, free fatty acids (FFAs), and polyunsaturated fatty acids (PUFAs) in the carcinogenesis and biology of RCC. Delineating the detailed mechanisms underlying lipid reprogramming can help to better understand the pathophysiology of RCC and to design novel therapeutic strategies targeting this malignancy.
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Affiliation(s)
- Gioia Heravi
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
| | - Omid Yazdanpanah
- Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA
| | - Izabela Podgorski
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.,Karmanos Cancer Institute, Detroit, MI, USA
| | - Larry H Matherly
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.,Karmanos Cancer Institute, Detroit, MI, USA
| | - Wanqing Liu
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA. .,Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA. .,Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA. .,Karmanos Cancer Institute, Detroit, MI, USA.
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23
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Multi-omics Analysis Revealed Coordinated Responses of Rumen Microbiome and Epithelium to High-Grain-Induced Subacute Rumen Acidosis in Lactating Dairy Cows. mSystems 2022; 7:e0149021. [PMID: 35076273 PMCID: PMC8788321 DOI: 10.1128/msystems.01490-21] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Subacute ruminal acidosis (SARA) is a major metabolic disease in lactating dairy cows caused by the excessive intake of high-concentrate diets. Here, we investigated the synergistic responses of rumen bacteria and epithelium to high-grain (HG)-induced SARA. Eight ruminally cannulated lactating Holstein cows were randomly assigned to 2 groups for a 3-week experiment and fed either a conventional (CON) diet or an HG diet. The results showed that the HG-feeding cows had a thickened rumen epithelial papilla with edge injury and a decreased plasma β-hydroxybutyrate concentration. The 16S rRNA gene sequencing results demonstrated that HG feeding caused changes in rumen bacterial structure and composition, which further altered rumen fermentation and metabolism. Cooccurrence network analysis revealed that the distribution of the diet-sensitive bacteria responded to the treatment (CON or HG) and that all diet-sensitive amplicon sequence variants showed low to medium degrees of cooccurrence. Metabolomics analysis indicated that the endothelial permeability-increasing factor prostaglandin E1 and the polyamine synthesis by-product 5′-methylthioadenosine were enriched under HG feeding. Transcriptome analysis suggested that cholesterol biosynthesis genes were upregulated in the rumen epithelium of HG cows. The gene expression changes, coupled with more substrate being available (total volatile fatty acids), may have caused an enrichment of intracellular cholesterol and its metabolites. All of these variations could coordinately stimulate cell proliferation, increase membrane permeability, and trigger epithelial inflammation, which eventually disrupts rumen homeostasis and negatively affects cow health. IMPORTANCE Dairy cows are economically important livestock animals that supply milk for humans. The cow’s rumen is a complex and symbiotic ecosystem composed of diverse microorganisms, which has evolved to digest high-fiber diets. In modern dairy production, SARA is a common health problem due to overfeeding of high-concentrate diets for an ever-increasing milk yield. Although extensive studies have been conducted on SARA, it remains unclear how HG feeding affects rumen cross talk homeostasis. Here, we identified structural and taxonomic fluctuation for the rumen bacterial community, an enrichment of certain detrimental metabolites in rumen fluid, and a general upregulation of cholesterol biosynthesis genes in the rumen epithelium of HG-feeding cows by multi-omics analysis. Based on these results, we propose a speculation to explain cellular events of coordinated rumen bacterial and epithelial adaptation to HG diets. Our work provides new insights into the exploitation of molecular regulation strategies to treat and prevent SARA.
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24
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Chang M, Kumar A, Kumar S, Huhn S, Timp W, Betenbaugh M, Du Z. Epigenetic Comparison of CHO Hosts and Clones Reveals Divergent Methylation and Transcription Patterns Across Lineages. Biotechnol Bioeng 2022; 119:1062-1076. [PMID: 35028935 DOI: 10.1002/bit.28036] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/08/2021] [Accepted: 12/26/2021] [Indexed: 11/11/2022]
Abstract
In this study, we examined DNA methylation and transcription profiles of recombinant clones derived from two different Chinese hamster ovary hosts. We found striking epigenetic differences between the clones, with global hypomethylation in the host 1 clones that produce bispecific antibody with higher productivity and complex assembly efficiency. Whereas the methylation patterns were found mostly inherited from the host, the host 1 clones exhibited continued demethylation reflected by the hypomethylation of newly emerged differential methylation regions (DMRs) even at the clone development stage. Several interconnected biological functions and pathways including cell adhesion, regulation of ion transport, and cholesterol biosynthesis were significantly altered between the clones at the RNA expression level and contained DMR in the promoter and/or gene-body of the transcripts, suggesting epigenetic regulation. Indeed, expression changes of epigenetic regulators were observed including writers (Dnmt1, Setdb1), readers (Mecp2), and erasers (Tet3, Kdm3a, Kdm1b/5c) involved in CpG methylation, histone methylation and heterochromatin maintenance. In addition, we identified putative transcription factors that may be readers or effectors of the epigenetic regulation in these clones. By combining transcriptomics with DNA methylation data, we identified potential processes and factors that may contribute to the variability in cell physiology between different production hosts. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Meiping Chang
- Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA
| | - Amit Kumar
- Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA
| | - Swetha Kumar
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University
| | - Steven Huhn
- Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA
| | - Winston Timp
- Department of Biomedical Engineering, Johns Hopkins University
| | - Michael Betenbaugh
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University
| | - Zhimei Du
- Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA
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25
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Dong Y, Yuan Y, Ma Y, Luo Y, Zhou W, Deng X, Pu J, Hu B, Liu S. Combined Intestinal Metabolomics and Microbiota Analysis for Acute Endometritis Induced by Lipopolysaccharide in Mice. Front Cell Infect Microbiol 2022; 11:791373. [PMID: 34976866 PMCID: PMC8718680 DOI: 10.3389/fcimb.2021.791373] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/24/2021] [Indexed: 01/03/2023] Open
Abstract
Endometritis is generally caused by bacterial infections, including both acute and chronic infections. In the past few decades, accumulated evidence showed that the occurrence of diseases might be related to gut microbiota. The progression of diseases is previously known to change the composition and diversity of intestinal microbiota. Additionally, it also causes corresponding changes in metabolites, primarily by affecting the physiological processes of microbiota. However, the effects of acute endometritis on intestinal microbiota and its metabolism remain unknown. Thus, the present study aimed to assess the effects of acute endometritis on intestinal microbes and their metabolites. Briefly, endometritis was induced in 30 specific pathogen-free (SPF) BALB/c female mice via intrauterine administration of lipopolysaccharide (LPS) after anesthesia. Following this, 16S rRNA gene sequencing and liquid chromatogram-mass spectrometry (LC-MS) were performed. At the genus level, the relative abundance of Klebsiella, Lachnoclostridium_5, and Citrobacter was found to be greater in the LPS group than in the control group. Importantly, the control group exhibited a higher ratio of Christensenellaceae_R−7_group and Parasutterella. Furthermore, intestinal metabolomics analysis in mice showed that acute endometritis altered the concentration of intestinal metabolites and affected biological oxidation, energy metabolism, and biosynthesis of primary bile acids. The correlation analysis between microbial diversity and metabolome provided a basis for a comprehensive understanding of the composition and function of the microbial community. Altogether, the findings of this study would be helpful in the prevention and treatment of acute endometritis in the future.
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Affiliation(s)
- Yuqing Dong
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China.,College of Forestry, Sichuan Agricultural University, Chengdu, China
| | - Yuan Yuan
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China.,College of Life Science, Sichuan Agricultural University, Yaan, China
| | - Yichuan Ma
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China
| | - Yuanyue Luo
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China
| | - Wenjing Zhou
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China
| | - Xin Deng
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China
| | - Jingyu Pu
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China
| | - Binhong Hu
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China
| | - Songqing Liu
- College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, China
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Chen C, Matye D, Wang Y, Li T. Liver-specific microRNA-185 knockout promotes cholesterol dysregulation in mice. LIVER RESEARCH 2021; 5:232-238. [PMID: 35173984 PMCID: PMC8846416 DOI: 10.1016/j.livres.2020.09.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The liver plays a key role in regulating whole body cholesterol homeostasis. Hepatic cholesterol accumulation causes liver injury in fatty liver disease and hypercholesterolemia increases the risk of cardiovascular disease. MicroRNAs (miRNAs, miRs) have been shown to regulate various pathways in cholesterol metabolism. Recently, miR-185 has been shown to regulate sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR) to modulate cholesterol synthesis and uptake. MATERIALS AND METHODS The role of miR-185 in regulating diet-induced metabolic disorders were studied in liver-specific miRNA-185 knockout (L-miR-185 KO) mice. RESULTS L-miR-185 KO mice developed worsened hepatic steatosis upon high fat high cholesterol Western diet feeding with accumulation of triglyceride and cholesterol in the liver. In addition, L-miR-185 KO mice developed hypercholesterolemia upon Western diet feeding. Gene expression analysis showed that L-miR-185 KO mice did not show increased hepatic mRNA expression of SREBP2 or its targets LDLR and HMG-CoA reductase (HMGCR). Although expression of miR-185 mimic inhibited the mRNA of SREBP2, HMGCR and LDLR in HepG2 cells, miR-185 inhibitor did not increase the mRNA of SREBP2, HMGCR or LDLR in HepG2 cells. CONCLUSIONS In conclusion, we reported that L-miR-185 KO mice were more sensitive to Western diet induced hepatic steatosis and hypercholesterolemia. The molecular mechanisms underlying these metabolic changes remain to be investigated in future studies.
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27
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Ashraf AP, Sunil B, Bamba V, Breidbart E, Brar PC, Chung S, Gupta A, Khokhar A, Kumar S, Lightbourne M, Kamboj MK, Miller RS, Patni N, Raman V, Shah AS, Wilson DP, Kohn B. Case Studies in Pediatric Lipid Disorders and Their Management. J Clin Endocrinol Metab 2021; 106:3605-3620. [PMID: 34363474 PMCID: PMC8787854 DOI: 10.1210/clinem/dgab568] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. AIM In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. CASES We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol <145 mg/dL (3.7 mmol/L). If the triglyceride is ≥400 mg/dL (4.5 mmol/L), prescription omega-3 fatty acids and fibrates are considered. In the case of triglyceride >1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. CONCLUSION Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.
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Affiliation(s)
- Ambika P Ashraf
- Division of Pediatric Endocrinology & Diabetes, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Bhuvana Sunil
- Department of Pediatrics, Division of Pediatric Endocrinology & Diabetes, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Vaneeta Bamba
- Department of Pediatrics, Division of Endocrinology, Children’s Hospital of Philadelphia, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Emily Breidbart
- Department of Pediatrics, Division Pediatric Endocrinology and Diabetes NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Preneet Cheema Brar
- Department of Pediatrics, Division Pediatric Endocrinology and Diabetes, NYU Langone Medical Center, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Stephanie Chung
- Section on Pediatric Diabetes, Obesity, and Metabolism, National Institutes of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20814, USA
| | - Anshu Gupta
- Department of Pediatrics, Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA 23219, USA
| | - Aditi Khokhar
- Department of Pediatrics, Rutgers New Jersey Medical School, NJ 07103, USA
| | - Seema Kumar
- Division of Pediatric Endocrinology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Marissa Lightbourne
- Pediatric and Adult Endocrinology Faculty, NICHD, National Institutes of Health, Bethesda, MD 20814, USA
| | - Manmohan K Kamboj
- Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH 43205, USA
| | - Ryan S Miller
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21093, USA
| | - Nivedita Patni
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Vandana Raman
- Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA
| | - Amy S Shah
- Department of Pediatrics, Adolescent Type 2 Diabetes Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Don P Wilson
- Cardiovascular Health and Risk Prevention, Pediatric Endocrinology and Diabetes, Cook Children’s Medical Center, Fort Worth, TX 76104, USA
| | - Brenda Kohn
- Division Pediatric Endocrinology and DiabetesNYU Langone Medical Center, NYU Grossman School of Medicine, New York, NY 10016, USA
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28
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da Silva JS, Rosa AF, Moncau CT, Vignato BS, Pugine SMP, de Melo MP, Sanchez JMD, Zanetti MA. Effect of different selenium sources and concentrations on glutathione peroxidase activity and cholesterol metabolism of beef cattle. J Anim Sci 2021; 99:6424803. [PMID: 34755854 DOI: 10.1093/jas/skab321] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 11/02/2021] [Indexed: 11/15/2022] Open
Abstract
The objective of this study was to investigate the effects of different Se sources and concentrations on glutathione forms and cholesterol metabolism in beef cattle. Sixty-three Nellore bulls (412 ± 19 kg BW; 24 months old) were randomly assigned to a completely randomized design in a 2×3 + 1 factorial arrangement (63 pens; one animal/pen) with two Se sources (sodium selenite, ING and Se-yeast, ORG), three concentrations (0.3, 0.9 and 2.7 mg supplemental Se/kg DM), and control treatment (without Se supplementation) fed for 90 days. Blood samples were collected on d 0, 28, 56, and 84. Muscle and liver samples were collected at harvest. Hepatic GSSG (P = 0.004), GSH/GSSG ratio (P = 0.030), and GSH-Px (P = 0.004) were affected by Se source x concentration interaction. Oxidized glutathione was higher in the ORG group vs. ING at concentration 2.7 mg supplemental Se/kg DM, but at 0.3 mg supplemental Se/kg DM the ING group was higher than ORG. The liver GSH-Px activity was higher in the ORG group vs. ING at concentration 0.9 and 2.7 mg supplemental Se/kg DM. The GSH/GSSG ratio was the highest in animals fed 0.3 mg supplemental Se/kg DM of ORG. Selenium liver concentration increased linearly with the supplemental Se concentration in the diet (y = 0.0583 + 0.4254x, R 2 = 0.92, P < 0.0001), regardless of source. Total meat cholesterol was greater (P < 0.001) in CON (control) vs. SUP (supplemented, regardless source) group. The muscle GSH-Px activity was higher (P < 0.001) in SUP vs. CON and increased (P < 0.004) with increasing supplemental Se concentrations. There was an increase on VLDL, glucose, and triglycerides in ORG vs. ING (P ≤ 0.035). In general, serum Se was higher (P < 0.001) in SUP vs. CON and increased with increasing supplemental Se concentration. Lastly, the HMGCR concentration was lower (P = 0.002) in SUP (0.39 ng/mL) vs. CON (0.55 ng/mL). Selenium supplementation with different sources and concentrations has the potential to affect cholesterol metabolism by affecting GSH/GSSG ratio, GSH-Px, and the HMGCR.
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Affiliation(s)
- Janaina S da Silva
- Department of Animal Science, College of Animal Science and Food Engineering, University of São Paulo, Pirassununga, São Paulo, Brazil
| | - Alessandra F Rosa
- Department of Animal Science, College of Animal Science and Food Engineering, University of São Paulo, Pirassununga, São Paulo, Brazil
| | - Cristina T Moncau
- Department of Animal Science, College of Animal Science and Food Engineering, University of São Paulo, Pirassununga, São Paulo, Brazil
| | - Bárbara Silva Vignato
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, ESALQ/USP, Piracicaba, Brazil
| | - Silvana Marina P Pugine
- Department of Basic Science, College of Animal Science and Food Engineering, University of São Paulo, Pirassununga, São Paulo, Brazil
| | - Mariza P de Melo
- Department of Basic Science, College of Animal Science and Food Engineering, University of São Paulo, Pirassununga, São Paulo, Brazil
| | - João Marcelo D Sanchez
- University of Florida, Institute of Food and Agricultural Sciences, Range Cattle Research and Education Center, USA
| | - Marcus Antonio Zanetti
- Department of Animal Science, College of Animal Science and Food Engineering, University of São Paulo, Pirassununga, São Paulo, Brazil
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29
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Kulathunga K, Wakimoto A, Hiraishi Y, Yadav MK, Gentleman K, Warabi E, Sakasai T, Miwa Y, Mizuno S, Takahashi S, Hamada M. Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility. Sci Rep 2021; 11:21827. [PMID: 34750345 PMCID: PMC8576022 DOI: 10.1038/s41598-021-00501-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 09/06/2021] [Indexed: 11/26/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyrc-2J/J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.
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Affiliation(s)
- Kaushalya Kulathunga
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.,Department of Physiology, Faculty of Medicine, Sabaragamuwa University of Sri Lanka, Hidellana, P.O. Box 01, Ratnapura, Sri Lanka
| | - Arata Wakimoto
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Yukiko Hiraishi
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Manoj Kumar Yadav
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Kyle Gentleman
- Integrated Master of Science Natural Sciences, University of Southampton, Highfield, Southampton, Hampshire, SO17 1BJ, UK
| | - Eiji Warabi
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Tomoki Sakasai
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Yoshihiro Miwa
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.,Gene Engineering Division, BioResource Research Center, RIKEN, 3-1-1, Koyadai, Tsukuba, Ibaraki, 305-0074, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Satoru Takahashi
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. .,Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. .,International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Michito Hamada
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. .,Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
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30
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Kotas ME, Mroz NM, Koga S, Liang HE, Schroeder AW, Ricardo-Gonzalez RR, Schneider C, Locksley RM. CISH constrains the tuft-ILC2 circuit to set epithelial and immune tone. Mucosal Immunol 2021; 14:1295-1305. [PMID: 34290377 PMCID: PMC8528700 DOI: 10.1038/s41385-021-00430-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/15/2021] [Accepted: 07/04/2021] [Indexed: 02/04/2023]
Abstract
Innate lymphoid cells (ILCs) are tissue-resident effectors poised to activate rapidly in response to local signals such as cytokines. To preserve homeostasis, ILCs must employ multiple pathways, including tonic suppressive mechanisms, to regulate their primed state and prevent inappropriate activation and immunopathology. Such mechanisms remain incompletely characterized. Here we show that cytokine-inducible SH2-containing protein (CISH), a suppressor of cytokine signaling (SOCS) family member, is highly and constitutively expressed in type 2 innate lymphoid cells (ILC2s). Mice that lack CISH either globally or conditionally in ILC2s show increased ILC2 expansion and activation, in association with reduced expression of genes inhibiting cell-cycle progression. Augmented proliferation and activation of CISH-deficient ILC2s increases basal and inflammation-induced numbers of intestinal tuft cells and accelerates clearance of the model helminth, Nippostrongylus brasiliensis, but compromises innate control of Salmonella typhimurium. Thus, CISH constrains ILC2 activity both tonically and after perturbation, and contributes to the regulation of immunity in mucosal tissue.
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Affiliation(s)
- Maya E Kotas
- Division of Pulmonary, Critical Care, Allergy & Sleep Medicine, University of California, San Francisco, CA, USA
| | - Nicholas M Mroz
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Satoshi Koga
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Hong-Erh Liang
- Department of Medicine, University of California, San Francisco, CA, USA
| | | | | | | | - Richard M Locksley
- Department of Medicine, University of California, San Francisco, CA, USA.
- Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.
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31
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Lin T, O'Keefe S, Fernández-Fraguas C. A fast and simple ion-pair high performance liquid chromatography method for analysis of primary bile salts in in vitro digested bean samples. MethodsX 2021; 8:101389. [PMID: 34430285 PMCID: PMC8374444 DOI: 10.1016/j.mex.2021.101389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/14/2021] [Indexed: 11/09/2022] Open
Abstract
Bile salts (BS) play a key role in cholesterol and lipid metabolism as well as in many other key metabolic pathways. High performance liquid chromatography (HPLC) is the most common technique used to analyze BS in diverse type of samples. However, current HPLC analysis methods used to analyze and quantify single BS in in vitro digested samples showed poor separation of a complex mixture of BS. In this article, we improved a standard method originally used for quantifying individual BS in food samples subjected to in vitro digestion. We also adapted a method previously developed for BS examination in human blood samples to the analysis of these molecules in chyme samples obtained during simulated gastrointestinal digestion. Our method was simple and achieved a fast and successful separation and quantification of four primary BS (sodium salts of taurocholic, glycocholic, taurochenodeoxycholic and glycochenodeoxycholic acids).
A method used to analyze bile salts in human blood samples has been adapted to separate and quantify four primary bile salts in in vitro digested bean samples. Addition of an ion-pair reagent led to complete separation of glycine and taurine conjugates of chenodeoxycholic and cholic acids within 10 min, and achieved good peak symmetry. The minimum BS concentration that could be measured was as low as 0.03125mM.
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Affiliation(s)
- Tiantian Lin
- Department of Food Science and Technology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Sean O'Keefe
- Department of Food Science and Technology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Cristina Fernández-Fraguas
- Department of Food Science and Technology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.,Macromolecules Innovation Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
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Hypocholesterolemic Effect of Potent Peptide and Bioactive Fraction from Pigeon Pea By-Products in Wistar Rats. Int J Pept Res Ther 2021. [DOI: 10.1007/s10989-021-10261-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Schade DS, Shey L, Eaton RP. Cholesterol Review: A Metabolically Important Molecule. Endocr Pract 2021; 26:1514-1523. [PMID: 33471744 DOI: 10.4158/ep-2020-0347] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 06/27/2020] [Indexed: 01/28/2023]
Abstract
OBJECTIVE Cholesterol is an important molecule in humans and both its excess and its deficiency cause disease. Most clinicians appreciate its role in stabilizing cellular plasma membranes but are unaware of its myriad other functions. METHODS This review highlights cholesterol's newly recognized important roles in human physiology and pathophysiology. RESULTS The basis for cholesterol's ubiquitous presence in eukaryote organisms is its three part structure involving hydrophilic, hydrophobic, and rigid domains. This structure permits cholesterol to regulate multiple cellular processes ranging from membrane fluidity and permeability to gene transcription. Cholesterol not only serves as a molecule of regulation itself, but also forms the backbone of all steroid hormones and vitamin D analogs. Cholesterol is responsible for growth and development throughout life and may be useful as an anticancer facilitator. Because humans have a limited ability to catabolize cholesterol, it readily accumulates in the body when an excess from the diet or a genetic abnormality occurs. This accumulation results in the foremost cause of death and disease (atherosclerosis) in the Western world. Identification of cholesterol's disease-producing capabilities dates back 5,000 years to the Tyrolean iceman and more recently to ancient mummies from many cultures throughout the world. In contrast, a deficiency of cholesterol in the circulation may result in an inability to distribute vitamins K and E to vital organs with serious consequences. CONCLUSION Understanding the benefits and hazards of cholesterol in the clinical setting will improve the endocrinologist's ability to control diseases associated with this unique molecule. ABBREVIATIONS CVD = cardiovascular disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NPC1L1 = Niemann-Pick C-1-like-1 protein; U.S. = United States; USDA = U.S. Department of Agriculture.
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Affiliation(s)
- David S Schade
- From the (1)University of New Mexico School of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, Albuquerque, New Mexico, and the.
| | - Lynda Shey
- University of New Mexico Hospital, Diabetes Comprehensive Care Center, Albuquerque, New Mexico
| | - R Philip Eaton
- From the (1)University of New Mexico School of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, Albuquerque, New Mexico, and the
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Jiang K, Ma Z, Wang Z, Li H, Wang Y, Tian Y, Li D, Liu X. Evolution, Expression Profile, Regulatory Mechanism, and Functional Verification of EBP-Like Gene in Cholesterol Biosynthetic Process in Chickens (Gallus Gallus). Front Genet 2021; 11:587546. [PMID: 33519893 PMCID: PMC7841431 DOI: 10.3389/fgene.2020.587546] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/14/2020] [Indexed: 12/30/2022] Open
Abstract
The emopamil binding protein (EBP) is an important enzyme participating in the final steps of cholesterol biosynthesis in mammals. A predictive gene EBP-like, which encodes the protein with a high identity to human EBP, was found in chicken genome. No regulatory mechanisms and biological functions of EBP-like have been characterized in chickens. In the present study, the coding sequence of EBP-like was cloned, the phylogenetic trees of EBP/EBP-like were constructed and the genomic synteny of EBP-like was analyzed. The regulatory mechanism of EBP-like were explored with in vivo and in vitro experiments. The biological functions of EBP-like in liver cholesterol biosynthetic were examined by using gain- or loss-of-function strategies. The results showed that chicken EBP-like gene was originated from a common ancestral with Japanese quail EBP gene, and was relatively conservative with EBP gene among different species. The EBP-like gene was highly expressed in liver, its expression level was significantly increased in peak-laying stage, and was upregulated by estrogen. Inhibition of the EBP-like mRNA expression could restrain the expressions of EBP-like downstream genes (SC5D, DHCR24, and DHCR7) in the cholesterol synthetic pathway, therefore downregulate the liver intracellular T-CHO level. In conclusion, as substitute of EBP gene in chickens, EBP-like plays a vital role in the process of chicken liver cholesterol synthesis. This research provides a basis for revealing the molecular regulatory mechanism of cholesterol synthesis in birds, contributes insights into the improvement of the growth and development, laying performance and egg quality in poultry.
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Affiliation(s)
- Keren Jiang
- College of Animal Science, Henan Agricultural University, Zhengzhou, China
| | - Zheng Ma
- College of Animal Science, Henan Agricultural University, Zhengzhou, China
- School of Life Sciences and Engineering, Foshan University, Foshan, China
| | - Zhang Wang
- College of Animal Science, Henan Agricultural University, Zhengzhou, China
| | - Hong Li
- College of Animal Science, Henan Agricultural University, Zhengzhou, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou, China
- International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou, China
| | - Yanbin Wang
- College of Animal Science, Henan Agricultural University, Zhengzhou, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou, China
- International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou, China
| | - Yadong Tian
- College of Animal Science, Henan Agricultural University, Zhengzhou, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou, China
- International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou, China
| | - Donghua Li
- College of Animal Science, Henan Agricultural University, Zhengzhou, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou, China
- International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou, China
| | - Xiaojun Liu
- College of Animal Science, Henan Agricultural University, Zhengzhou, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou, China
- International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou, China
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Regulation of Osteoclast Differentiation and Activity by Lipid Metabolism. Cells 2021; 10:cells10010089. [PMID: 33430327 PMCID: PMC7825801 DOI: 10.3390/cells10010089] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/02/2021] [Accepted: 01/05/2021] [Indexed: 02/07/2023] Open
Abstract
Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and skeletal metabolism, which fulfills the energy demand for bone remodeling. Among various metabolic pathways, the importance of lipid metabolism in bone cells has long been appreciated. More recent studies also establish the link between bone loss and lipid-altering conditions—such as atherosclerotic vascular disease, hyperlipidemia, and obesity—and uncover the detrimental effect of fat accumulation on skeletal homeostasis and increased risk of fracture. Targeting lipid metabolism with statin, a lipid-lowering drug, has been shown to improve bone density and quality in metabolic bone diseases. However, the molecular mechanisms of lipid-mediated regulation in osteoclasts are not completely understood. Thus, a better understanding of lipid metabolism in osteoclasts can be used to harness bone cell activity to treat pathological bone disorders. This review summarizes the recent developments of the contribution of lipid metabolism to the function and phenotype of osteoclasts.
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Cokan KB, Urlep Ž, Lorbek G, Matz-Soja M, Skubic C, Perše M, Jeruc J, Juvan P, Režen T, Rozman D. Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer. Cancers (Basel) 2020; 12:3302. [PMID: 33182326 PMCID: PMC7695248 DOI: 10.3390/cancers12113302] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/29/2020] [Accepted: 11/05/2020] [Indexed: 12/16/2022] Open
Abstract
While the role of cholesterol in liver carcinogenesis remains controversial, hepatocellular carcinoma generally prevails in males. Herein, we uncover pathways of female-prevalent progression to hepatocellular carcinoma due to chronic repression of cholesterogenic lanosterol 14α-demethylase (CYP51) in hepatocytes. Tumors develop in knock-out mice after year one, with 2:1 prevalence in females. Metabolic and transcription factor networks were deduced from the liver transcriptome data, combined by sterol metabolite and blood parameter analyses, and interpreted with relevance to humans. Female knock-outs show increased plasma cholesterol and HDL, dampened lipid-related transcription factors FXR, LXRα:RXRα, and importantly, crosstalk between reduced LXRα and activated TGF-β signalling, indicating a higher susceptibility to HCC in aging females. PI3K/Akt signalling and ECM-receptor interaction are common pathways that are disturbed by sex-specific altered genes. Additionally, transcription factors (SOX9)2 and PPARα were recognized as important for female hepatocarcinogenesis, while overexpressed Cd36, a target of nuclear receptor RORC, is a new male-related regulator of ECM-receptor signalling in hepatocarcinogenesis. In conclusion, we uncover the sex-dependent metabolic reprogramming of cholesterol-related pathways that predispose for hepatocarcinogenesis in aging females. This is important in light of increased incidence of liver cancers in post-menopausal women.
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Affiliation(s)
- Kaja Blagotinšek Cokan
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (K.B.C.); (Ž.U.); (G.L.); (C.S.); (P.J.); (T.R.)
| | - Žiga Urlep
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (K.B.C.); (Ž.U.); (G.L.); (C.S.); (P.J.); (T.R.)
| | - Gregor Lorbek
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (K.B.C.); (Ž.U.); (G.L.); (C.S.); (P.J.); (T.R.)
| | - Madlen Matz-Soja
- Rudol-Schönheimer-Institute of Biochemistry, Divison of General Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany;
| | - Cene Skubic
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (K.B.C.); (Ž.U.); (G.L.); (C.S.); (P.J.); (T.R.)
| | - Martina Perše
- Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
| | - Jera Jeruc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
| | - Peter Juvan
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (K.B.C.); (Ž.U.); (G.L.); (C.S.); (P.J.); (T.R.)
| | - Tadeja Režen
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (K.B.C.); (Ž.U.); (G.L.); (C.S.); (P.J.); (T.R.)
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (K.B.C.); (Ž.U.); (G.L.); (C.S.); (P.J.); (T.R.)
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Yeast as a promising heterologous host for steroid bioproduction. J Ind Microbiol Biotechnol 2020; 47:829-843. [PMID: 32661815 PMCID: PMC7358296 DOI: 10.1007/s10295-020-02291-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/06/2020] [Indexed: 12/18/2022]
Abstract
With the rapid development of synthetic biology and metabolic engineering technologies, yeast has been generally considered as promising hosts for the bioproduction of secondary metabolites. Sterols are essential components of cell membrane, and are the precursors for the biosynthesis of steroid hormones, signaling molecules, and defense molecules in the higher eukaryotes, which are of pharmaceutical and agricultural significance. In this mini-review, we summarize the recent engineering efforts of using yeast to synthesize various steroids, and discuss the structural diversity that the current steroid-producing yeast can achieve, the challenge and the potential of using yeast as the bioproduction platform of various steroids from higher eukaryotes.
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38
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Hao W, Kwek E, He Z, Zhu H, Liu J, Zhao Y, Ma KY, He WS, Chen ZY. Ursolic acid alleviates hypercholesterolemia and modulates the gut microbiota in hamsters. Food Funct 2020; 11:6091-6103. [PMID: 32568327 DOI: 10.1039/d0fo00829j] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ursolic acid (UA) is a triterpenoid acid widely abundant in fruits and vegetables such as apple, blueberry and cranberry. The present study was carried out to investigate the effect of UA supplementation in diet on blood cholesterol, intestinal cholesterol absorption and gut microbiota in hypercholesterolemic hamsters. A total of thirty-two hamsters were randomly assigned to four groups and given a non-cholesterol diet (NCD), a high-cholesterol diet containing 0.1% cholesterol (HCD), an HCD diet containing 0.2% UA (UAL), or an HCD diet containing 0.4% UA (UAH) for 6 weeks. Results showed that UA supplementation reduced plasma cholesterol by 15-16% and inhibited intestinal cholesterol absorption by 2.6-9.2%. The in vitro micellar cholesterol solubility experiment clearly demonstrated that UA could displace 40% cholesterol from micelles. In addition, UA decreased the ratio of Firmicutes to Bacteroidetes, whereas it enhanced the growth of short chain fatty acid (SCFA)-producing bacteria in the intestine. In conclusion, UA possessed a cholesterol-lowering activity and could favorably modulate the gut microbiota.
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Affiliation(s)
- Wangjun Hao
- School of Life Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China.
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Sun L, Ling Y, Jiang J, Wang D, Wang J, Li J, Wang X, Wang H. Differential mechanisms regarding triclosan vs. bisphenol A and fluorene-9-bisphenol induced zebrafish lipid-metabolism disorders by RNA-Seq. CHEMOSPHERE 2020; 251:126318. [PMID: 32143076 DOI: 10.1016/j.chemosphere.2020.126318] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/19/2020] [Accepted: 02/22/2020] [Indexed: 05/23/2023]
Abstract
Exposure of endocrine disrupting chemicals (EDCs) is closely related to induction of obesity, nonalcoholic fatty liver disease (NAFLD) and other lipid-metabolism diseases. Herein, we compared the effects of three EDCs exposure (triclosan, bisphenol A and fluorene-9-bisphenol) on lipid metabolism in zebrfish (Danio rerio). The differential lipid-metabolism disorders were analyzed in depth through RNA-Seq and qRT-PCR, as well as assessment of the relationship between lipid disorder and RNA methylation. Histopathological observation along with varying physiological and biochemical indexes all identified that triclosan and bisphenol A induced liver fat accumulation in acute and chronic exposure. RNA-Seq analysis showed that triclosan exposure disrupted multiple physiological processes including drug metabolism, sucrose metabolism, fat metabolism and bile secretion. The dysregulation of lipid-metabolism related genes indicated that liver steatosis in triclosan and BPA-exposed zebrafish resulted from increased fatty acid synthetase, and uptake and suppression of β-oxidation. Besides, the dysregulation of pro-inflammatory genes and endoplasmic reticulum stress showed that triclosan and bisphenol A exposure not only induced occurrence of NAFLD, but also promoted progression of hepatic inflammation. However, no significant effect on lipid metabolism was observed in fluorene-9-bisphenol-exposed treatment although the larval phenotypic malformation was found compared to the control group. Moreover, EDCs exposure led to decreased global m6A level and abnormal expression of m6A modulators in larvae. Especially, the expression of demethylase FTO (fat mass and obesity-associated protein) was significantly increased in triclosan-exposure treatment. These findings are conductive for us to deeply understand the underlying molecular mechanisms regarding the obesity and NAFLD from EDCs exposure.
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Affiliation(s)
- Limei Sun
- Key Laboratory of Laboratory Medicine of Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yuhang Ling
- Key Laboratory of Laboratory Medicine of Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Jiahui Jiang
- Key Laboratory of Laboratory Medicine of Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Danting Wang
- Key Laboratory of Laboratory Medicine of Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Junxia Wang
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou, 215009, China
| | - Jieyi Li
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou, 215009, China
| | - Xuedong Wang
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou, 215009, China.
| | - Huili Wang
- Key Laboratory of Laboratory Medicine of Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
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Meola TR, Schultz HB, Peressin KF, Prestidge CA. Enhancing the oral bioavailability of simvastatin with silica-lipid hybrid particles: The effect of supersaturation and silica geometry. Eur J Pharm Sci 2020; 150:105357. [PMID: 32446169 DOI: 10.1016/j.ejps.2020.105357] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/16/2020] [Accepted: 04/20/2020] [Indexed: 01/01/2023]
Abstract
Silica-lipid hybrid (SLH) microparticles are a solidified lipid-based drug delivery system under investigation for their aptitude to enhance the oral bioavailability of poorly water-soluble drugs. The cholesterol-lowering agent, simvastatin (SIM), is poorly water-soluble and undergoes extensive first pass metabolism, resulting in a low oral bioavailability of approximately 5%. Hence, the current pre-clinical studies investigated the application of SLH technology to SIM with a supersaturation approach, aiming to enhance bioavailability and drug loading capacity. Additionally, the effect of silica was explored by evaluating the performance of SLH fabricated with silica of different particle geometries. SLH microparticles with supersaturated SIM loading levels ranging from 100% to 400% above the equilibrium solubility were successfully fabricated using either Aerosil® 300 or Syloid® 244 silica. All SLH formulations existed as white free-flowing powders, consisting of spherical porous microparticles for Aerosil® 300, and aggregated irregular microparticles for Syloid® 244. During in vitro dissolution in pH 7.0 media, the SLH formulations performed up to 4.4-fold greater than pure SIM powder. Furthermore, in vivo oral pharmacokinetics in male Sprague-Dawley rats revealed that the SLH formulations enhanced the oral bioavailability of SIM up to 6.1-fold and 2.9-fold, in comparison to pure SIM powder and a commercially available formulation (Simvastatin Sandoz®), respectively. The greatest in vivo performance enhancement was observed for the SLH formulation manufactured with Syloid® 244 silica with a supersaturation level of 200%. SLH technology demonstrated to be a successful formulation strategy to significantly improve the oral bioavailability of SIM in rodents and therefore, has a strong potential to also improve the oral bioavailability of SIM in humans.
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Affiliation(s)
- Tahlia R Meola
- University of South Australia, Clinical and Health Sciences, Adelaide, South Australia 5000, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, University of South Australia, City West Campus, Adelaide, South Australia 5000, Australia
| | - Hayley B Schultz
- University of South Australia, Clinical and Health Sciences, Adelaide, South Australia 5000, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, University of South Australia, City West Campus, Adelaide, South Australia 5000, Australia
| | - Karl F Peressin
- University of South Australia, Clinical and Health Sciences, Adelaide, South Australia 5000, Australia
| | - Clive A Prestidge
- University of South Australia, Clinical and Health Sciences, Adelaide, South Australia 5000, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, University of South Australia, City West Campus, Adelaide, South Australia 5000, Australia.
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Tahir MS, Nguyen LT, Schulz BL, Boe-Hansen GA, Thomas MG, Moore SS, Lau LY, Fortes MRS. Proteomics Recapitulates Ovarian Proteins Relevant to Puberty and Fertility in Brahman Heifers ( Bos indicus L.). Genes (Basel) 2019; 10:E923. [PMID: 31726744 PMCID: PMC6895798 DOI: 10.3390/genes10110923] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 11/06/2019] [Indexed: 12/16/2022] Open
Abstract
High fertility and early puberty in Bos indicus heifers are desirable and genetically correlated traits in beef production. The hypothalamus-pituitary-ovarian (HPO) axis synthesizes steroid hormones, which contribute to the shift from the pre-pubertal state into the post-pubertal state and influence subsequent fertility. Understanding variations in abundance of proteins that govern steroid synthesis and ovarian signaling pathways remains crucial to understanding puberty and fertility. We used whole ovaries of six pre-pubertal and six post-pubertal Brahman heifers to conduct differential abundance analyses of protein profiles between the two physiological states. Extracted proteins were digested into peptides followed by identification and quantification with massspectrometry (MS) by sequential window acquisition of all instances of theoretical fragment ion mass spectrometry (SWATH-MS). MS and statistical analysis identified 566 significantly differentially abundant (DA) proteins (adjusted p < 0.05), which were then analyzed for gene ontology and pathway enrichment. Our data indicated an up-regulation of steroidogenic proteins contributing to progesterone synthesis at luteal phase post-puberty. Proteins related to progesterone signaling, TGF-β, retinoic acid, extracellular matrix, cytoskeleton, and pleiotrophin signaling were DA in this study. The DA proteins probably relate to the formation and function of the corpus luteum, which is only present after ovulation, post-puberty. Some DA proteins might also be related to granulosa cells signaling, which regulates oocyte maturation or arrest in ovaries prior to ovulation. Ten DA proteins were coded by genes previously associated with reproductive traits according to the animal quantitative trait loci (QTL) database. In conclusion, the DA proteins and their pathways were related to ovarian activity in Bos indicus cattle. The genes that code for these proteins may explain some known QTLs and could be targeted in future genetic studies.
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Affiliation(s)
- Muhammad S. Tahir
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane 4072, Queensland, Australia; (M.S.T.); (B.L.S.); (L.Y.L.)
| | - Loan T. Nguyen
- Queensland Alliance for Agriculture and Food Innovation, University of Queensland, Brisbane 4072, Queensland, Australia; (L.T.N.); (S.S.M.)
| | - Benjamin L. Schulz
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane 4072, Queensland, Australia; (M.S.T.); (B.L.S.); (L.Y.L.)
| | - Gry A. Boe-Hansen
- School of Veterinary Sciences, University of Queensland, Brisbane 4343, Queensland, Australia;
| | - Milton G. Thomas
- Department of Animal Science, Colorado State University, Fort Collins, CO 80523, USA;
| | - Stephen S. Moore
- Queensland Alliance for Agriculture and Food Innovation, University of Queensland, Brisbane 4072, Queensland, Australia; (L.T.N.); (S.S.M.)
| | - Li Yieng Lau
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane 4072, Queensland, Australia; (M.S.T.); (B.L.S.); (L.Y.L.)
| | - Marina R. S. Fortes
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane 4072, Queensland, Australia; (M.S.T.); (B.L.S.); (L.Y.L.)
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Zhang Y, Chen P, Liang XF, Han J, Wu XF, Yang YH, Xue M. Metabolic disorder induces fatty liver in Japanese seabass, Lateolabrax japonicas fed a full plant protein diet and regulated by cAMP-JNK/NF-kB-caspase signal pathway. FISH & SHELLFISH IMMUNOLOGY 2019; 90:223-234. [PMID: 31029777 DOI: 10.1016/j.fsi.2019.04.060] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 04/20/2019] [Accepted: 04/24/2019] [Indexed: 06/09/2023]
Abstract
A 10-week growth trial was conducted to investigate the effects of replacing dietary fishmeal with plant proteins on nutrition metabolism, immunity, inflammation and apoptosis responses in liver tissues of Japanese seabass, Lateolabrax japonicas (initial body weight = 10.42 ± 0.01 g). Two isonitrogenous and isoenergetic diets were formulated. A basal diet containing 54% fishmeal (FM), whereas another diet was prepared by totally replacing FM with a plant protein blend (PP) composed with soybean protein concentrate and cottonseed protein concentrate. Although essential amino acids, fatty acids, and available phosphorus had been balanced according to the FM diet profile, the significantly lower growth performance, metabolic disorder, and fatty liver symptom were observed in the PP group. Compared with the FM group, fish in the PP group showed significantly lower plasma free EAA level and PPV. Glucose metabolism disorder was expressed as the uncontrollable fasting glycolysis and pyruvate aerobic oxidation at postprandial 24 h with significantly up-regulated GK, PK and PDH genes expression, which potentially over-produced acetyl-CoA as the substrate for protein and lipid synthesis. Significantly reduced plasma GLU, but increased GC level, along with very significantly reduced liver GLY storage could be observed in the PP group. Plasma TG and hepatic NEFA contents were significantly decreased, but the hepatic TC content was very significantly increased in the PP group, in addition, hepatocyte vacuolation appeared. The significantly up-regulated cholesterol synthesis gene (HMGCR) expression but down-regulated bile acid synthesis gene (CYP7A1) expression could be the main reason for the fatty liver induced by cholesterol accumulation. The reduced plasma IgM content accompanied by the up-regulated mRNA levels of pro-inflammatory cytokines (TNFα and IL1β) and activated apoptosis signals of liver tissues were found in the PP group. The hyperthyroidism (higher plasma T3 and T4) and the accelerated energy metabolism rate decreased the growth performance in the PP group. The activated p65NF-kB may promote the hepatocytes apoptosis via the extrinsic pathway (caspase8/caspase3). Simultaneously, a "self-saving" response could be observed that activated cAMP promoted the lipolysis/β-oxidation process and up-regulated gene expression of anti-inflammatory cytokine IL10 via promoting CREB expression, further inhibited the over-phosphorylation of JNK protein, which might impede the intrinsic apoptosis pathway (caspase9/caspase3). In conclusion, the nutrient and energy metabolic disorder induced fatty liver related to the cholesterol accumulation in Japanese seabass fed full PP diet, which was under the regulation by cAMP-JNK/NF-kB-caspase signaling pathway. The hemostasis phosphorylation of JNK protein protected the liver tissues from more serious damage.
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Affiliation(s)
- Y Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, China
| | - P Chen
- National Aquafeed Safety Assessment Center, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - X F Liang
- National Aquafeed Safety Assessment Center, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - J Han
- Institute of Food and Nutrition Development, Ministry of Agriculture, Beijing, 100081, China
| | - X F Wu
- National Aquafeed Safety Assessment Center, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Y H Yang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, China.
| | - M Xue
- National Aquafeed Safety Assessment Center, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
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Gjestad C, Hole K, Haslemo T, Diczfalusy U, Molden E. Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4 Metabolite 4β-Hydroxycholesterol-an Interaction Study in Healthy Volunteers. AAPS JOURNAL 2019; 21:58. [PMID: 31020430 DOI: 10.1208/s12248-019-0330-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 04/05/2019] [Indexed: 12/20/2022]
Abstract
4β-Hydroxycholesterol (4βOHC) is an endogenous CYP3A4 metabolite. However, it is unclear whether circulating levels of 4βOHC may reflect hepatic CYP3A4 activity or both hepatic and intestinal enzyme activity. The aim of this study was to investigate the effect of grapefruit juice, regarded to be a selective intestinal CYP3A4 inhibitor, on serum 4βOHC levels in healthy volunteers. The participants (n = 22) consumed grapefruit juice twice daily for 3 weeks followed by a 2-week washout period. Blood samples for measurements of 4βOHC and the non-CYP3A4-derived oxysterols 24-hydroxycholesterol (24OHC) and 27-hydroxycholesterol (27OHC), as well as lathosterol and total cholesterol, were drawn on days 0, 7, 21, and 35. Median individual changes (ratios) in cholesterol-corrected 4βOHC levels from baseline to weeks 1, 3, and 5 were 0.94 (P = 0.2), 0.98 (P = 0.3), and 0.97 (P = 0.9), respectively. In comparison, median changes (ratios) in cholesterol-corrected levels of 24OHC at the same points were 1.01 (P = 0.6), 0.98 (P = 0.3), and 0.99 (P = 0.5), and of 27OHC 1.01 (P = 0.8), 0.97 (P = 0.5), and 0.99 (P = 0.2). Surprisingly, serum concentration of cholesterol was significantly reduced by approximately 5% after 1 week (P = 0.03), while median cholesterol-corrected levels of lathosterol increased significantly and persistently by approximately 15% during the whole 5-week period (P < 0.04). In conclusion, the present findings suggest that intestinal CYP3A4 is not relevant for the overall formation of 4βOHC in healthy volunteers. The fact that grapefruit juice altered cholesterol homeostasis should be further investigated.
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Affiliation(s)
- Caroline Gjestad
- Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, N-0319, Oslo, Norway.
| | - Kristine Hole
- Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, N-0319, Oslo, Norway
| | - Tore Haslemo
- Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, N-0319, Oslo, Norway
| | - Ulf Diczfalusy
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Espen Molden
- Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, N-0319, Oslo, Norway.,Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
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Development of a Synthetic 3-ketosteroid Δ 1-dehydrogenase for the Generation of a Novel Catabolic Pathway Enabling Cholesterol Degradation in Human Cells. Sci Rep 2019; 9:5969. [PMID: 30979909 PMCID: PMC6461610 DOI: 10.1038/s41598-019-42046-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 03/22/2019] [Indexed: 01/05/2023] Open
Abstract
Cholesterol is an essential component of membranes, which is acquired by cells via receptor-mediated endocytosis of lipoproteins or via de novo synthesis. In specialized cells, anabolic enzymes metabolize cholesterol, generating steroid hormones or bile acids. However, surplus cholesterol cannot be catabolized due to the lack of enzymes capable of degrading the cholestane ring. The inability to degrade cholesterol becomes evident in the development and progression of cardiovascular disease, where the accumulation of cholesterol/cholesteryl-esters in macrophages can elicit a maladaptive immune response leading to the development and progression of atherosclerosis. The discovery of cholesterol catabolic pathways in Actinomycetes led us to the hypothesis that if enzymes enabling cholesterol catabolism could be genetically engineered and introduced into human cells, the atherosclerotic process may be prevented or reversed. Comparison of bacterial enzymes that degrade cholesterol to obtain carbon and generate energy with the action of human enzymes revealed that humans lack a 3-ketosteroid Δ1-dehydrogenase (Δ1-KstD), which catalyzes the C-1 and C-2 desaturation of ring A. Here we describe the construction, heterologous expression, and actions of a synthetic humanized Δ1-KstD expressed in Hep3B and U-937 cells, providing proof that one of three key enzymes required for cholesterol ring opening can be functionally expressed in human cells.
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Variya BC, Bakrania AK, Chen Y, Han J, Patel SS. Suppression of abdominal fat and anti-hyperlipidemic potential of Emblica officinalis: Upregulation of PPARs and identification of active moiety. Biomed Pharmacother 2018; 108:1274-1281. [PMID: 30372828 DOI: 10.1016/j.biopha.2018.09.158] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 09/25/2018] [Accepted: 09/26/2018] [Indexed: 12/28/2022] Open
Abstract
Since ancient time, Emblica officinalis (E. officinalis) is being used for the management of various ailments. Phytochemical analysis proves that fruit juice of E. officinalis contains high amount gallic acid, which could be responsible for medicinal potentials. Hence in this study, gallic acid and fruit juice of E. officinalis were evaluated for anti-hyperlipidemic potential in various experimental animal models. Experimentally, hyperlipidemia was induced through administration of poloxamer-407, tyloxapol and high-fat-diet supplement in rats. Treatment with gallic acid as well as fruit juice of E. officinalis decreased plasma cholesterol and reduced oil infiltration in liver and aorta. Mechanistically, E. officinalis increased peroxisome proliferator-activated receptors-α (PPARα) expression and increased activity of lipid oxidation through carnitine palmitoyl transferase (CPT) along with decreased activity of hepatic lipogenic enzymes i.e. glucose-6-phosphate dehydrogenase (G6PD), fatty acid synthase (FAS) and malic enzyme (ME). Additionally, E. officinalis increased cholesterol uptake through increased LDL-receptor expressions on hepatocytes and decreased LDL-receptor degradation due to decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Simultaneously, E. officinalis showed ability to restore glucose homeostasis through increased Glut4 and PPARγ protein expression in adipose tissue. These findings exposed central role of gallic acid in E. officinalis arbitrated anti-hyperlipidemic action through upregulation of PPARs, Glut4 and lipogenic enzymes, and decreased expression of PCSK9 and lipogenic enzymes. Findings from this experiment demonstrated that E. officinalis is a potential therapy for management of hyperlipidemia and gallic acid could be a potential lead candidate.
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Affiliation(s)
- Bhavesh C Variya
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
| | - Anita K Bakrania
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
| | - Yuanli Chen
- Collaborative Innovation Center of Biotherapy, School of Medicine, Nankai University, Tianjin 300071, China
| | - Jihong Han
- College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Snehal S Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India.
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Zhai L, Wang X. Syringaresinol‑di‑O‑β‑D‑glucoside, a phenolic compound from Polygonatum sibiricum, exhibits an antidiabetic and antioxidative effect on a streptozotocin‑induced mouse model of diabetes. Mol Med Rep 2018; 18:5511-5519. [PMID: 30365054 PMCID: PMC6236259 DOI: 10.3892/mmr.2018.9580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 03/22/2018] [Indexed: 11/26/2022] Open
Abstract
Syringaresinol-di-O-β-D-glucoside (SOG) is a phenolic compound extracted from Polygonatum sibiricum. The present study aimed to investigate the antidiabetic effect of SOG on streptozocin (STZ)-induced diabetic mice and determine the potential underlying mechanisms. In the present study, fasting blood glucose and organ indexes of mice were analyzed. Body weight, water intake and food intake were also recorded. Furthermore, serum fasting insulin, pancreatic insulin and pancreatic interleukin-6 levels of mice were determined using ELISA kits to investigate the effect of SOG on the levels of insulin. Levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) and free fatty acid (FFA) in the serum of mice, and levels of TC, TG and total protein in the kidney, were also determined to investigate the effects of SOG on lipid and protein metabolism in mice. Furthermore, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) levels, as well as total antioxidant capacity (T-AOC), in the kidneys of mice were determined to investigate the effect of SOG on oxidative stress. Western blotting was also performed to determine the expression of proteins associated with oxidative stress. The results demonstrated that SOG (25, 50 and 75 mg/kg) induced a significant antidiabetic effect in mice. Treatment with SOG promoted insulin secretion and decreased TC, TG, LDL-C, VLDL-C, FFA, MDA, SOD, CAT, AST, ALT and ALP levels in the kidneys of mice, as well as kidney TC and TG levels, but increased the levels of kidney total protein and the T-AOC in kidneys. Furthermore, SOG treatment could significantly downregulate the expressions of nitrotyrosine and transforming growth factor-β1 in diabetic mice. Therefore, the present study indicated that SOG may exert an antidiabetic effect on STZ-induced diabetic mice and that the mechanism of SOG may be associated with its antioxidative activity.
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Affiliation(s)
- Liping Zhai
- Department of Endocrinology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xu Wang
- Department of Endocrinology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
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Zarzour RHA, Alshawsh MA, Asif M, Al-Mansoub MA, Mohamed Z, Ahmad M, Majid AMSA, Asmawi MZ, Kaur G, Al-Dualimi DW, Yam MF. Adipocytokine Regulation and Antiangiogenic Activity Underlie the Molecular Mechanisms of Therapeutic Effects of Phyllanthus niruri against Non-Alcoholic Fatty Liver Disease. Nutrients 2018; 10:E1057. [PMID: 30096951 PMCID: PMC6115813 DOI: 10.3390/nu10081057] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/06/2018] [Accepted: 08/07/2018] [Indexed: 12/23/2022] Open
Abstract
The growth of adipose tissues is considered angiogenesis-dependent during non-alcoholic fatty liver disease (NAFLD). We have recently reported that our standardized 50% methanolic extract (ME) of Phyllanthus niruri (50% ME of P. niruri) has alleviated NAFLD in Sprague⁻Dawley rats. This study aimed to assess the molecular mechanisms of action, and to further evaluate the antiangiogenic effect of this extract. NAFLD was induced by eight weeks of high-fat diet, and treatment was applied for four weeks. Antiangiogenic activity was assessed by aortic ring assay and by in vitro tests. Our findings demonstrated that the therapeutic effects of 50% ME among NAFLD rats, were associated with a significant increase in serum adiponectin, reduction in the serum levels of RBP4, vaspin, progranulin, TNF-α, IL-6, and significant downregulation of the hepatic gene expression of PPARγ, SLC10A2, and Collα1. Concomitantly, 50% ME of P. niruri has exhibited a potent antiangiogenic activity on ring assay, cell migration, vascular endothelial growth factor (VEGF), and tube formation, without any cytotoxic effect. Together, our findings revealed that the protective effects of P. niruri against NAFLD might be attributed to its antiangiogenic effect, as well as to the regulation of adipocytokines and reducing the expression of adipogenic genes.
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Affiliation(s)
- Raghdaa Hamdan Al Zarzour
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
| | - Mohammed A Alshawsh
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Muhammad Asif
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan.
| | - Majed Ahmed Al-Mansoub
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
| | - Zahurin Mohamed
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Mariam Ahmad
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
| | - Amin Malik Shah Abdul Majid
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
| | - Mohd Zaini Asmawi
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
| | - Gurjeet Kaur
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
| | - Dhamraa Waleed Al-Dualimi
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
| | - Mun Fei Yam
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
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Tegge AN, Rodrigues RR, Larkin AL, Vu L, Murali TM, Rajagopalan P. Transcriptomic Analysis of Hepatic Cells in Multicellular Organotypic Liver Models. Sci Rep 2018; 8:11306. [PMID: 30054499 PMCID: PMC6063915 DOI: 10.1038/s41598-018-29455-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 07/11/2018] [Indexed: 02/08/2023] Open
Abstract
Liver homeostasis requires the presence of both parenchymal and non-parenchymal cells (NPCs). However, systems biology studies of the liver have primarily focused on hepatocytes. Using an organotypic three-dimensional (3D) hepatic culture, we report the first transcriptomic study of liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) cultured with hepatocytes. Through computational pathway and interaction network analyses, we demonstrate that hepatocytes, LSECs and KCs have distinct expression profiles and functional characteristics. Our results show that LSECs in the presence of KCs exhibit decreased expression of focal adhesion kinase (FAK) signaling, a pathway linked to LSEC dedifferentiation. We report the novel result that peroxisome proliferator-activated receptor alpha (PPARα) is transcribed in LSECs. The expression of downstream processes corroborates active PPARα signaling in LSECs. We uncover transcriptional evidence in LSECs for a feedback mechanism between PPARα and farnesoid X-activated receptor (FXR) that maintains bile acid homeostasis; previously, this feedback was known occur only in HepG2 cells. We demonstrate that KCs in 3D liver models display expression patterns consistent with an anti-inflammatory phenotype when compared to monocultures. These results highlight the distinct roles of LSECs and KCs in maintaining liver function and emphasize the need for additional mechanistic studies of NPCs in addition to hepatocytes in liver-mimetic microenvironments.
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Affiliation(s)
- Allison N Tegge
- Department of Computer Science, Virginia Tech, Blacksburg, USA
- Department of Statistics, Virginia Tech, Blacksburg, USA
| | - Richard R Rodrigues
- Genetics, Bioinformatics, and Computational Biology Ph.D. Program, Virginia Tech, Blacksburg, USA
| | - Adam L Larkin
- Department of Chemical Engineering, Virginia Tech, Blacksburg, USA
| | - Lucas Vu
- Department of Chemical Engineering, Virginia Tech, Blacksburg, USA
| | - T M Murali
- Department of Computer Science, Virginia Tech, Blacksburg, USA.
- ICTAS Center for Systems Biology of Engineered Tissues, Virginia Tech, Blacksburg, USA.
| | - Padmavathy Rajagopalan
- Department of Chemical Engineering, Virginia Tech, Blacksburg, USA.
- ICTAS Center for Systems Biology of Engineered Tissues, Virginia Tech, Blacksburg, USA.
- Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Virginia Tech, Blacksburg, USA.
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Ayoub HM, McDonald MR, Sullivan JA, Tsao R, Meckling KA. Proteomic Profiles of Adipose and Liver Tissues from an Animal Model of Metabolic Syndrome Fed Purple Vegetables. Nutrients 2018; 10:456. [PMID: 29642414 PMCID: PMC5946241 DOI: 10.3390/nu10040456] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/30/2018] [Accepted: 04/03/2018] [Indexed: 12/12/2022] Open
Abstract
Metabolic Syndrome (MetS) is a complex disorder that predisposes an individual to Cardiovascular Diseases and type 2 Diabetes Mellitus. Proteomics and bioinformatics have proven to be an effective tool to study complex diseases and mechanisms of action of nutrients. We previously showed that substitution of the majority of carbohydrate in a high fat diet by purple potatoes (PP) or purple carrots (PC) improved insulin sensitivity and hypertension in an animal model of MetS (obese Zucker rats) compared to a control sucrose-rich diet. In the current study, we used TMT 10plex mass tag combined with LC-MS/MS technique to study proteomic modulation in the liver (n = 3 samples/diet) and adipose tissue (n = 3 samples/diet) of high fat diet-fed rats with or without substituting sucrose for purple vegetables, followed by functional enrichment analysis, in an attempt to elucidate potential molecular mechanisms responsible for the phenotypic changes seen with purple vegetable feeding. Protein folding, lipid metabolism and cholesterol efflux were identified as the main modulated biological themes in adipose tissue, whereas lipid metabolism, carbohydrate metabolism and oxidative stress were the main modulated themes in liver. We propose that enhanced protein folding, increased cholesterol efflux and higher free fatty acid (FFA) re-esterification are mechanisms by which PP and PC positively modulate MetS pathologies in adipose tissue, whereas, decreased de novo lipogenesis, oxidative stress and FFA uptake, are responsible for the beneficial effects in liver. In conclusion, we provide molecular evidence for the reported metabolic health benefits of purple carrots and potatoes and validate that these vegetables are good choices to replace other simple carbohydrate sources for better metabolic health.
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Affiliation(s)
- Hala M Ayoub
- Department of Human Health and Nutrition Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada.
| | - Mary Ruth McDonald
- Department of Plant Agriculture, University of Guelph, Guelph, ON N1G 2W1, Canada.
| | - James Alan Sullivan
- Department of Plant Agriculture, University of Guelph, Guelph, ON N1G 2W1, Canada.
| | - Rong Tsao
- Guelph Research & Development Centre, Agriculture and Agri-Food Canada, Guelph, ON N1G 5C9, Canada.
| | - Kelly A Meckling
- Department of Human Health and Nutrition Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada.
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van Schie MC, Jainandunsing S, van Lennep JER. Monogenetic disorders of the cholesterol metabolism and premature cardiovascular disease. Eur J Pharmacol 2017; 816:146-153. [DOI: 10.1016/j.ejphar.2017.09.046] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 09/05/2017] [Accepted: 09/28/2017] [Indexed: 12/13/2022]
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