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Bioactive Lipids in Inflammation, Diabetes and Cancer
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Bioactive Lipids in Inflammation, Diabetes and Cancer

A topical collection in Biomolecules (ISSN 2218-273X). This collection belongs to the section "Biological Factors".

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Editors

Prof. Dr. George Kokotos

E-Mail Website
Collection Editor
Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece
Interests: design, synthesis and study of enzyme inhibitors; inhibitors of phospholipase A2; inhibitors of autotaxin; synthesis and study of bioactive lipids; synthesis of small molecules exhibiting anti-inflammatory and cytotoxic activity; organocatalysis; biotransformations in organic synthesis
Special Issues, Collections and Topics in MDPI journals
Prof. Sasanka Ramanadham

E-Mail Website
Collection Editor
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Interests: pancreatic islet function; beta-cell death; lipid signaling; lipidomics; phospholipases A2; type 1 diabetes; autoimmunity; alternative splicing; bone formation

Topical Collection Information

Dear Colleagues,

Lipids are essential components of the cell membrane shown to play many roles in mediating and controlling a wide array of cellular activities including membrane structure and organization, metabolic and gene regulation, protein structure and function, and signaling pathways. Various lipid molecules have been intimately linked to inflammatory and immune responses, cell proliferation and apoptosis and clearly shown to be major contributors to many pathologies, including diabetes, cancer, cardiovascular disease, and neurodegenerative disorders. Lipid metabolizing enzymes and lipid receptors are excellent targets for the development of enzyme inhibitors and receptor modulators as novel therapeutic agents. The aim of this collection is to compile review articles and original research articles covering the recent advances in the biochemistry, chemistry, pharmacology, analysis, functional assessment, and clinical translational impact of bioactive lipids relating to their involvement in inflammation, diabetes and cancer.

Prof. Dr. George Kokotos
Prof. Sasanka Ramanadham
Collection Editors

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Keywords

  • bioactive lipids
  • lipidomics–lipid analysis
  • lipid metabolizing enzymes
  • enzyme inhibitors
  • lipid signaling
  • lipid receptors
  • fatty acids
  • eicosanoids
  • sphingolipids
  • specialized pro-resolving mediators
  • therapeutic molecules

Published Papers (16 papers)

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2024

Jump to: 2023, 2022, 2021, 2020

25 pages, 2345 KiB  
Article
Asymmetric Synthesis of Saturated and Unsaturated Hydroxy Fatty Acids (HFAs) and Study of Their Antiproliferative Activity
by Olga G. Mountanea, Christiana Mantzourani, Dimitrios Gkikas, Panagiotis K. Politis and George Kokotos
Biomolecules 2024, 14(1), 110; https://doi.org/10.3390/biom14010110 - 15 Jan 2024
Viewed by 1428
Abstract
Hydroxy fatty acids (HFAs) constitute a class of lipids, distinguished by the presence of a hydroxyl on a long aliphatic chain. This study aims to expand our insights into HFA bioactivities, while also introducing new methods for asymmetrically synthesizing unsaturated and saturated HFAs. [...] Read more.
Hydroxy fatty acids (HFAs) constitute a class of lipids, distinguished by the presence of a hydroxyl on a long aliphatic chain. This study aims to expand our insights into HFA bioactivities, while also introducing new methods for asymmetrically synthesizing unsaturated and saturated HFAs. Simultaneously, a procedure previously established by us was adapted to generate new HFA regioisomers. An organocatalytic step was employed for the synthesis of chiral terminal epoxides, which either by alkynylation or by Grignard reagents resulted in unsaturated or saturated chiral secondary alcohols and, ultimately, HFAs. 7-(S)-Hydroxyoleic acid (7SHOA), 7-(S)-hydroxypalmitoleic acid (7SHPOA) and 7-(R)- and (S)-hydroxymargaric acids (7HMAs) were synthesized for the first time and, together with regioisomers of (R)- and (S)-hydroxypalmitic acids (HPAs) and hydroxystearic acids (HSAs), whose biological activity has not been tested so far, were studied for their antiproliferative activities. The unsaturation of the long chain, as well as an odd-numbered (C17) fatty acid chain, led to reduced activity, while the new 6-(S)-HPA regioisomer was identified as exhibiting potent antiproliferative activity in A549 cells. 6SHPA induced acetylation of histone 3 in A549 cells, without affecting acetylated α-tubulin levels, suggesting the selective inhibition of histone deacetylase (HDAC) class I enzymes, and was found to inhibit signal transducer and activator of transcription 3 (STAT3) expression. Full article
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2023

Jump to: 2024, 2022, 2021, 2020

12 pages, 927 KiB  
Review
The Roles of sPLA2s in Skin Homeostasis and Disease
by Kei Yamamoto, Haruka Hakoi, Saki Nomura and Makoto Murakami
Biomolecules 2023, 13(4), 668; https://doi.org/10.3390/biom13040668 - 12 Apr 2023
Cited by 2 | Viewed by 2225
Abstract
Among the phospholipase A2 (PLA2) family, the secreted PLA2 (sPLA2) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full [...] Read more.
Among the phospholipase A2 (PLA2) family, the secreted PLA2 (sPLA2) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full set of sPLA2s, in combination with comprehensive lipidomics, have revealed the diverse pathophysiological roles of sPLA2s in various biological events. Individual sPLA2s exert specific functions within tissue microenvironments, likely through the hydrolysis of extracellular phospholipids. Lipids are an essential biological component for skin homeostasis, and disturbance of lipid metabolism by deletion or overexpression of lipid-metabolizing enzymes or lipid-sensing receptors often leads to skin abnormalities that are easily visible on the outside. Over the past decades, our studies using knockout and transgenic mice for various sPLA2s have uncovered several new aspects of these enzymes as modulators of skin homeostasis and disease. This article summarizes the roles of several sPLA2s in skin pathophysiology, providing additional insight into the research fields of sPLA2s, lipids, and skin biology. Full article
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18 pages, 3741 KiB  
Review
The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism
by Sayaka Harada, Yoshitaka Taketomi, Toshiki Aiba, Mai Kawaguchi, Tetsuya Hirabayashi, Baasanjav Uranbileg, Makoto Kurano, Yutaka Yatomi and Makoto Murakami
Biomolecules 2023, 13(3), 471; https://doi.org/10.3390/biom13030471 - 3 Mar 2023
Cited by 7 | Viewed by 3189
Abstract
The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, [...] Read more.
The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7-null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S-adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism. Full article
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2022

Jump to: 2024, 2023, 2021, 2020

23 pages, 5398 KiB  
Article
N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2
by Maria A. Theodoropoulou, Anastasia Psarra, Martin Erhardt, Aikaterini Nikolaou, Anna-Dimitra D. Gerogiannopoulou, Dimitra Hadjipavlou-Litina, Daiki Hayashi, Edward A. Dennis, Andrea Huwiler and George Kokotos
Biomolecules 2022, 12(2), 267; https://doi.org/10.3390/biom12020267 - 7 Feb 2022
Cited by 2 | Viewed by 2242
Abstract
The quest for novel agents to regulate the generation of prostaglandin E2 (PGE2) is of high importance because this eicosanoid is a key player in inflammatory diseases. We synthesized a series of N-acylated and N-alkylated 2-aminobenzothiazoles and related [...] Read more.
The quest for novel agents to regulate the generation of prostaglandin E2 (PGE2) is of high importance because this eicosanoid is a key player in inflammatory diseases. We synthesized a series of N-acylated and N-alkylated 2-aminobenzothiazoles and related heterocycles (benzoxazoles and benzimidazoles) and evaluated their ability to suppress the cytokine-stimulated generation of PGE2 in rat mesangial cells. 2-Aminobenzothiazoles, either acylated by the 3-(naphthalen-2-yl)propanoyl moiety (GK510) or N-alkylated by a chain carrying a naphthalene (GK543) or a phenyl moiety (GK562) at a distance of three carbon atoms, stand out in inhibiting PGE2 generation, with EC50 values ranging from 118 nM to 177 nM. Both GK510 and GK543 exhibit in vivo anti-inflammatory activity greater than that of indomethacin. Thus, N-acylated or N-alkylated 2-aminobenzothiazoles are novel leads for the regulation of PGE2 formation. Full article
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2021

Jump to: 2024, 2023, 2022, 2020

11 pages, 760 KiB  
Review
Lipoprotein Lipase and Its Delivery of Fatty Acids to the Heart
by Rui Shang and Brian Rodrigues
Biomolecules 2021, 11(7), 1016; https://doi.org/10.3390/biom11071016 - 12 Jul 2021
Cited by 19 | Viewed by 9185
Abstract
Ninety percent of plasma fatty acids (FAs) are contained within lipoprotein-triglyceride, and lipoprotein lipase (LPL) is robustly expressed in the heart. Hence, LPL-mediated lipolysis of lipoproteins is suggested to be a key source of FAs for cardiac use. Lipoprotein clearance by LPL occurs [...] Read more.
Ninety percent of plasma fatty acids (FAs) are contained within lipoprotein-triglyceride, and lipoprotein lipase (LPL) is robustly expressed in the heart. Hence, LPL-mediated lipolysis of lipoproteins is suggested to be a key source of FAs for cardiac use. Lipoprotein clearance by LPL occurs at the apical surface of the endothelial cell lining of the coronary lumen. In the heart, the majority of LPL is produced in cardiomyocytes and subsequently is translocated to the apical luminal surface. Here, vascular LPL hydrolyzes lipoprotein-triglyceride to provide the heart with FAs for ATP generation. This article presents an overview of cardiac LPL, explains how the enzyme works, describes key molecules that regulate its activity and outlines how changes in LPL are brought about by physiological and pathological states such as fasting and diabetes, respectively. Full article
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17 pages, 2796 KiB  
Article
A Metalloproteinase Induces an Inflammatory Response in Preadipocytes with the Activation of COX Signalling Pathways and Participation of Endogenous Phospholipases A2
by Priscila Motta Janovits, Elbio Leiguez, Viviane Portas and Catarina Teixeira
Biomolecules 2021, 11(7), 921; https://doi.org/10.3390/biom11070921 - 22 Jun 2021
Cited by 3 | Viewed by 2669
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes that have been associated with the pathogenesis of inflammatory diseases and obesity. Adipose tissue in turn is an active endocrine organ capable of secreting a range of proinflammatory mediators with autocrine and paracrine properties, which contribute to [...] Read more.
Matrix metalloproteinases (MMPs) are proteolytic enzymes that have been associated with the pathogenesis of inflammatory diseases and obesity. Adipose tissue in turn is an active endocrine organ capable of secreting a range of proinflammatory mediators with autocrine and paracrine properties, which contribute to the inflammation of adipose tissue and adjacent tissues. However, the potential inflammatory effects of MMPs in adipose tissue cells are still unknown. This study investigates the effects of BmooMPα-I, a single-domain snake venom metalloproteinase (SVMP), in activating an inflammatory response by 3T3-L1 preadipocytes in culture, focusing on prostaglandins (PGs), cytokines, and adipocytokines biosynthesis and mechanisms involved in prostaglandin E2 (PGE2) release. The results show that BmooMPα-I induced the release of PGE2, prostaglandin I2 (PGI2), monocyte chemoattractant protein-1 (MCP-1), and adiponectin by preadipocytes. BmooMPα-I-induced PGE2 biosynthesis was dependent on group-IIA-secreted phospholipase A2 (sPLA2-IIA), cytosolic phospholipase A2-α (cPLA2-α), and cyclooxygenase (COX)-1 and -2 pathways. Moreover, BmooMPα-I upregulated COX-2 protein expression but not microsomal prostaglandin E synthase-1 (mPGES-1) expression. In addition, we demonstrate that the enzymatic activity of BmooMPα-I is essential for the activation of prostanoid synthesis pathways in preadipocytes. These data highlight preadipocytes as important targets for metalloproteinases and provide new insights into the contribution of these enzymes to the inflammation of adipose tissue and tissues adjacent to it. Full article
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20 pages, 4523 KiB  
Article
Beneficial Modulation of Lipid Mediator Biosynthesis in Innate Immune Cells by Antirheumatic Tripterygium wilfordii Glycosides
by Kehong Zhang, Simona Pace, Paul M. Jordan, Lukas K. Peltner, Alexander Weber, Dagmar Fischer, Robert K. Hofstetter, Xinchun Chen and Oliver Werz
Biomolecules 2021, 11(5), 746; https://doi.org/10.3390/biom11050746 - 17 May 2021
Cited by 12 | Viewed by 3408
Abstract
Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation [...] Read more.
Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation and immune responses and are strongly linked to RA. The mechanism by which TWG affects LM networks in RA treatment remains elusive. Employing LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed striking modulation of LM pathways by TWG in human monocyte-derived macrophage (MDM) phenotypes. In inflammatory M1-MDM, TWG (30 µg/mL) potently suppressed agonist-induced formation of 5-LOX products which was confirmed in human PMNL and traced back to direct inhibition of 5-LOX (IC50 = 2.9 µg/mL). TWG also efficiently blocked thromboxane formation in M1-MDM without inhibiting other prostanoids and COX enzymes. Importantly, in anti-inflammatory M2-MDM, TWG (30 µg/mL) induced pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation. During MDM polarization, TWG (1 µg/mL) decreased the capacity to generate pro-inflammatory 5-LOX and COX products, cytokines and markers for M1 phenotypes. Together, suppression of pro-inflammatory LM but SPM induction may contribute to the antirheumatic properties of TWG. Full article
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18 pages, 1997 KiB  
Review
Regulation of Tissue Inflammation by 12-Lipoxygenases
by Abhishek Kulkarni, Jerry L. Nadler, Raghavendra G. Mirmira and Isabel Casimiro
Biomolecules 2021, 11(5), 717; https://doi.org/10.3390/biom11050717 - 11 May 2021
Cited by 53 | Viewed by 6963
Abstract
Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant [...] Read more.
Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells—a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role. Full article
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9 pages, 582 KiB  
Review
Apolipoprotein Mimetic Peptides: An Emerging Therapy against Diabetic Inflammation and Dyslipidemia
by Paul Wolkowicz, C. Roger White and G. M. Anantharamaiah
Biomolecules 2021, 11(5), 627; https://doi.org/10.3390/biom11050627 - 23 Apr 2021
Cited by 12 | Viewed by 3454
Abstract
Obesity has achieved epidemic status in the United States, resulting in an increase in type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease. Numerous studies have shown that inflammation plays a key role in the development of insulin resistance and diabetic complications. HDL cholesterol [...] Read more.
Obesity has achieved epidemic status in the United States, resulting in an increase in type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease. Numerous studies have shown that inflammation plays a key role in the development of insulin resistance and diabetic complications. HDL cholesterol levels are inversely associated with coronary heart disease in humans. The beneficial effect of HDL is due, in part, to apolipoproteins A-I and E, which possess anti-inflammatory properties. The functional quality of HDL, however, may be reduced in the context of diabetes. Thus, raising levels of functional HDL is an important target for reducing inflammation and diabetic complications. Apo A-I possesses eight alpha-helical sequences, most of which form class A amphipathic helical structures. Peptides belonging to this class inhibit atherogenesis in several mouse models. Additional peptides based on structural components of apoE have been shown to mediate a rapid clearance of atherogenic lipoproteins in dyslipidemic mice. In this review, we discuss the efficacy of apolipoprotein mimetic peptides in improving lipoprotein function, reducing inflammation, and reversing insulin resistance and cardiometabolic disease processes in diabetic animals. Full article
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19 pages, 1651 KiB  
Review
The Impact of the Ca2+-Independent Phospholipase A2β (iPLA2β) on Immune Cells
by Tayleur D. White, Abdulaziz Almutairi, Ying Gai Tusing, Xiaoyong Lei and Sasanka Ramanadham
Biomolecules 2021, 11(4), 577; https://doi.org/10.3390/biom11040577 - 15 Apr 2021
Cited by 2 | Viewed by 3352
Abstract
The Ca2+-independent phospholipase A2β (iPLA2β) is a member of the PLA2 family that has been proposed to have roles in multiple biological processes including membrane remodeling, cell proliferation, bone formation, male fertility, cell death, and signaling. [...] Read more.
The Ca2+-independent phospholipase A2β (iPLA2β) is a member of the PLA2 family that has been proposed to have roles in multiple biological processes including membrane remodeling, cell proliferation, bone formation, male fertility, cell death, and signaling. Such involvement has led to the identification of iPLA2β activation in several diseases such as cancer, cardiovascular abnormalities, glaucoma, periodontitis, neurological disorders, diabetes, and other metabolic disorders. More recently, there has been heightened interest in the role that iPLA2β plays in promoting inflammation. Recognizing the potential contribution of iPLA2β in the development of autoimmune diseases, we review this issue in the context of an iPLA2β link with macrophages and T-cells. Full article
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16 pages, 2990 KiB  
Article
Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation
by Ching-Feng Chiu, Ming-I Hsu, Hsiu-Yen Yeh, Ji Min Park, Yu-Shiuan Shen, Te-Hsuan Tung, Jun-Jie Huang, Hung-Tsung Wu and Shih-Yi Huang
Biomolecules 2021, 11(3), 370; https://doi.org/10.3390/biom11030370 - 2 Mar 2021
Cited by 11 | Viewed by 3620
Abstract
Background: The oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was reported to be the signature genetic event in most cases of pancreatic ductal adenocarcinoma (PDAC). Hepassocin (HPS/FGL1) is involved in regulating lipid metabolism and the progression of several cancer [...] Read more.
Background: The oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was reported to be the signature genetic event in most cases of pancreatic ductal adenocarcinoma (PDAC). Hepassocin (HPS/FGL1) is involved in regulating lipid metabolism and the progression of several cancer types; however, the underlying mechanism of HPS/FGL1 in the KRAS mutant PDAC cells undergoing eicosapentaenoic acid (EPA) treatment remains unclear. Methods: We measured HPS/FGL1 protein expressions in a human pancreatic ductal epithelial (HPNE) normal pancreas cell line, a KRAS-wild-type PDAC cell line (BxPC-3), and KRAS-mutant PDAC cell lines (PANC-1, MIA PaCa-2, and SUIT-2) by Western blot methods. HEK293T cells were transiently transfected with corresponding KRAS-expressing plasmids to examine the level of HPS expression with KRAS activation. We knocked-down HPS/FGL1 using lentiviral vectors in SUIT-2 cells and measured the cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenicity assays. Furthermore, a lipidomic analysis was performed to profile changes in lipid metabolism after HPS/FGL1 knockdown. Results: We found that the HPS/FGL1 level was significantly upregulated in KRAS-mutated PDAC cells and was involved in KRAS/phosphorylated (p)-signal transduction and activator of transcription 3 (STAT3) signaling, and the knockdown of HPS/FGL1 in SUIT-2 cells decreased cell proliferation through increasing G2/M cell cycle arrest and cyclin B1 expression. In addition, the knockdown of HPS/FGL1 in SUIT-2 cells significantly increased omega-3 polyunsaturated fatty acids (PUFAs) and EPA production but not docosahexaenoic acid (DHA). Moreover, EPA treatment in SUIT-2 cells reduced the expression of de novo lipogenic protein, acetyl coenzyme A carboxylase (ACC)-1, and decreased p-STAT3 and HPS/FGL1 expressions, resulting in the suppression of cell viability. Conclusions: Results of this study indicate that HPS is highly expressed by KRAS-mutated PDAC cells, and HPS/FGL1 plays a crucial role in altering lipid metabolism and increasing cell growth in pancreatic cancer. EPA supplements could potentially inhibit or reduce ACC-1-involved lipogenesis and HPS/FGL1-mediated cell survival in KRAS-mutated pancreatic cancer cells. Full article
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19 pages, 4283 KiB  
Article
α-Ketoheterocycles Able to Inhibit the Generation of Prostaglandin E2 (PGE2) in Rat Mesangial Cells
by Anastasia Psarra, Maria A. Theodoropoulou, Martin Erhardt, Marina Mertiri, Christiana Mantzourani, Sofia Vasilakaki, Victoria Magrioti, Andrea Huwiler and George Kokotos
Biomolecules 2021, 11(2), 275; https://doi.org/10.3390/biom11020275 - 13 Feb 2021
Cited by 1 | Viewed by 4020
Abstract
Prostaglandin E2 (PGE2) is a key mediator of inflammation, and consequently huge efforts have been devoted to the development of novel agents able to regulate its formation. In this work, we present the synthesis of various α-ketoheterocycles and a study [...] Read more.
Prostaglandin E2 (PGE2) is a key mediator of inflammation, and consequently huge efforts have been devoted to the development of novel agents able to regulate its formation. In this work, we present the synthesis of various α-ketoheterocycles and a study of their ability to inhibit the formation of PGE2 at a cellular level. A series of α-ketobenzothiazoles, α-ketobenzoxazoles, α-ketobenzimidazoles, and α-keto-1,2,4-oxadiazoles were synthesized and chemically characterized. Evaluation of their ability to suppress the generation of PGE2 in interleukin-1β plus forskolin-stimulated mesangial cells led to the identification of one α-ketobenzothiazole (GK181) and one α-ketobenzoxazole (GK491), which are able to suppress the PGE2 generation at a nanomolar level. Full article
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2020

Jump to: 2024, 2023, 2022, 2021

20 pages, 992 KiB  
Review
The Influence of Physical Activity on the Bioactive Lipids Metabolism in Obesity-Induced Muscle Insulin Resistance
by Monika Imierska, Adam Kurianiuk and Agnieszka Błachnio-Zabielska
Biomolecules 2020, 10(12), 1665; https://doi.org/10.3390/biom10121665 - 12 Dec 2020
Cited by 18 | Viewed by 5013
Abstract
High-fat diet consumption and lack of physical activity are important risk factors for metabolic disorders such as insulin resistance and cardiovascular diseases. Insulin resistance is a state of a weakened response of tissues such as skeletal muscle, adipose tissue, and liver to insulin, [...] Read more.
High-fat diet consumption and lack of physical activity are important risk factors for metabolic disorders such as insulin resistance and cardiovascular diseases. Insulin resistance is a state of a weakened response of tissues such as skeletal muscle, adipose tissue, and liver to insulin, which causes an increase in blood glucose levels. This condition is the result of inhibition of the intracellular insulin signaling pathway. Skeletal muscle is an important insulin-sensitive tissue that accounts for about 80% of insulin-dependent glucose uptake. Although the exact mechanism by which insulin resistance is induced has not been thoroughly understood, it is known that insulin resistance is most commonly associated with obesity. Therefore, it is believed that lipids may play an important role in inducing insulin resistance. Among lipids, researchers’ attention is mainly focused on biologically active lipids: diacylglycerols (DAG) and ceramides. These lipids are able to regulate the activity of intracellular enzymes, including those involved in insulin signaling. Available data indicate that physical activity affects lipid metabolism and has a positive effect on insulin sensitivity in skeletal muscles. In this review, we have presented the current state of knowledge about the impact of physical activity on insulin resistance and metabolism of biologically active lipids. Full article
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18 pages, 1788 KiB  
Article
Hypothermic Effect of Acute Citral Treatment during LPS-induced Systemic Inflammation in Obese Mice: Reduction of Serum TNF-α and Leptin Levels
by Maycon T. Emílio-Silva, Vinicius P. Rodrigues, Gabriela Bueno, Rie Ohara, Marina G. Martins, José A. C. Horta-Júnior, Luiz G. S. Branco, Lúcia R. M. Rocha and Clélia A. Hiruma-Lima
Biomolecules 2020, 10(10), 1454; https://doi.org/10.3390/biom10101454 - 17 Oct 2020
Cited by 14 | Viewed by 4348
Abstract
Citral is a mixture of monoterpenes present in the essential oil of several plants, such as Cymbopogon citratus and Zingiber officinale, possessing anti-inflammatory, anti-ulcerogenic, and antipyretic actions. We investigated the action of citral on body temperature (Tb) and inflammatory signaling in eutrophic [...] Read more.
Citral is a mixture of monoterpenes present in the essential oil of several plants, such as Cymbopogon citratus and Zingiber officinale, possessing anti-inflammatory, anti-ulcerogenic, and antipyretic actions. We investigated the action of citral on body temperature (Tb) and inflammatory signaling in eutrophic and obese mice during Systemic Inflammation (SI) induced by Lipopolysaccharide (LPS). Thus, we assessed the effect of citral (25, 100, and 300 mg/kg) and ibuprofen in LPS-induced SI in Swiss male mice fed a standard diet (SD) or high-fat diet (HFD) for 12 weeks. Following SI induction, we measured Tb and collected the serum, hypothalamus, and gastric mucosa for biochemical measurements. Acute treatment with citral decreased the Tb of both SD and HFD-fed animals. Citral (300 mg/kg) treatment caused a significantly lower Tb variation in HFD-fed animals than in those fed the SD. Citral reduced peripheral levels of tumor necrosis factor (TNF)-α in SD and HFD mice and decreased serum leptin concentration in HFD mice 90 min after the LPS challenge. Furthermore, citral also reduced interleukin (IL)-6 levels in the hypothalamus of obese mice. In summary, citral effectively reduced Tb during SI by reducing inflammatory mediators with a distinct action profile in HFD mice when compared with SD. Full article
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14 pages, 1156 KiB  
Review
Analytical Methods for the Determination of Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) in Biological Samples, Plants and Foods
by Maroula G. Kokotou
Biomolecules 2020, 10(8), 1092; https://doi.org/10.3390/biom10081092 - 22 Jul 2020
Cited by 16 | Viewed by 4886
Abstract
Fatty acid esters of hydroxy fatty acids (FAHFAs) constitute a class of recently identified novel lipids exhibiting anti-diabetic and anti-inflammatory effects. Due to their high biological significance, a tremendous effort has been devoted to the development of analytical methods for the detection and [...] Read more.
Fatty acid esters of hydroxy fatty acids (FAHFAs) constitute a class of recently identified novel lipids exhibiting anti-diabetic and anti-inflammatory effects. Due to their high biological significance, a tremendous effort has been devoted to the development of analytical methods for the detection and quantitation of FAHFAs during the last five years. The analysis of FAHFAs is very challenging due to the great number of possible regio-isomers arising from the great number of possible combinations of FAs with HFAs, and the low abundancies of FAHFAs in biological samples. The aim of this review article is to summarize all the cutting-edge analytical methodologies for the determination of FAHFAs in biological samples, plant tissues and food matrices, with emphasis on extraction and analysis steps. All the analytical methodologies rely on the use of liquid chromatography–mass spectrometry (LC-MS), providing high sensitivity due to the MS detection. Powerful and robust analytical methodologies may highly contribute in studying FAHFAs levels under various biomedical conditions, and facilitate our understanding of the role of these lipid species in physiological and pathological conditions. Full article
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22 pages, 6117 KiB  
Article
Caudatin Isolated from Cynanchum auriculatum Inhibits Breast Cancer Stem Cell Formation via a GR/YAP Signaling
by Xing Zhen, Hack Sun Choi, Ji-Hyang Kim, Su-Lim Kim, Ren Liu, Yu-Chan Ko, Bong-Sik Yun and Dong-Sun Lee
Biomolecules 2020, 10(6), 925; https://doi.org/10.3390/biom10060925 - 18 Jun 2020
Cited by 13 | Viewed by 4735
Abstract
In the complex tumor microenvironment, cancer stem cells (CSCs), a rare population of cells, are responsible for malignant tumor initiation, metastasis, drug resistance and recurrence. Controlling breast CSCs (BCSCs) using natural compounds is a novel potential therapeutic strategy for clinical cancer treatment. In [...] Read more.
In the complex tumor microenvironment, cancer stem cells (CSCs), a rare population of cells, are responsible for malignant tumor initiation, metastasis, drug resistance and recurrence. Controlling breast CSCs (BCSCs) using natural compounds is a novel potential therapeutic strategy for clinical cancer treatment. In this study, a mammosphere assay-guided isolation protocol including silica gel, a C18 column, gel filtration, and high-pressure liquid chromatography was used to isolate an inhibitory compound from Cynanchum auriculatum extracts. The isolated inhibitory compound was identified as caudatin. Caudatin inhibited breast cancer cell proliferation, mammosphere formation and tumor growth. Caudatin decreased the CD44+/CD24− and aldehyde dehydrogenase+ cell proportions and the levels of c-Myc, Oct4, Sox2, and CD44. Caudatin induced ubiquitin (Ub)-dependent glucocorticoid receptor (GR) degradation and blocked subsequent Yes-associated protein (YAP) nuclear accumulation and target gene transcription signals in BCSCs. These results show that the GR/YAP signaling pathway regulates BCSC formation and that caudatin may be a potential chemopreventive agent that targets breast cancer cells and CSCs. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Essential fatty acids and their metabolites in inflammation, fisbetes mellitus and cancer- based on our previous snd current work in these three areas.
Authors: Undurti N. Das; et al.
Affiliation: UND Life Sciences, 2221 NW 5th St, Battle Ground, WA 98604, USA

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