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17 pages, 3972 KiB

Open AccessArticle

Investigation of α-Glucosidase Inhibitory Metabolites from Tetracera scandens Leaves by GC–MS Metabolite Profiling and Docking Studies

by Ahmed Nokhala, Mohammad Jamshed Siddiqui, Qamar Uddin Ahmed, Muhammad Safwan Ahamad Bustamam and Zainul Amiruddin Zakaria

Biomolecules 2020, 10(2), 287; https://doi.org/10.3390/biom10020287 - 12 Feb 2020

Cited by 24 | Viewed by 3356

Abstract

Stone leaf (Tetracera scandens) is a Southeast Asian medicinal plant that has been traditionally used for the management of diabetes mellitus. The underlying mechanisms of the antidiabetic activity have not been fully explored yet. Hence, this study aimed to evaluate the [...] Read more.

Stone leaf (Tetracera scandens) is a Southeast Asian medicinal plant that has been traditionally used for the management of diabetes mellitus. The underlying mechanisms of the antidiabetic activity have not been fully explored yet. Hence, this study aimed to evaluate the α-glucosidase inhibitory potential of the hydromethanolic extracts of T. scandens leaves and to characterize the metabolites responsible for such activity through gas chromatography–mass spectrometry (GC–MS) metabolomics. Crude hydromethanolic extracts of different strengths were prepared and in vitro assayed for α-glucosidase inhibition. GC–MS analysis was further carried out and the mass spectral data were correlated to the corresponding α-glucosidase inhibitory IC₅₀ values via an orthogonal partial least squares (OPLS) model. The 100%, 80%, 60% and 40% methanol extracts displayed potent α-glucosidase inhibitory potentials. Moreover, the established model identified 16 metabolites to be responsible for the α-glucosidase inhibitory activity of T. scandens. The putative α-glucosidase inhibitory metabolites showed moderate to high affinities (binding energies of −5.9 to −9.8 kcal/mol) upon docking into the active site of Saccharomyces cerevisiae isomaltase. To sum up, an OPLS model was developed as a rapid method to characterize the α-glucosidase inhibitory metabolites existing in the hydromethanolic extracts of T. scandens leaves based on GC–MS metabolite profiling. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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16 pages, 2245 KiB

Open AccessFeature PaperArticle

The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

by Sean C. Godar, Roberto Cadeddu, Gabriele Floris, Laura J. Mosher, Zhen Mi, David P. Jarmolowicz, Simona Scheggi, Alicia A. Walf, Carolyn J. Koonce, Cheryl A. Frye, Nancy A. Muma and Marco Bortolato

Biomolecules 2019, 9(11), 749; https://doi.org/10.3390/biom9110749 - 19 Nov 2019

Cited by 13 | Viewed by 5782

Abstract

Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; [...] Read more.

Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports. Here, we tested the effects of FIN in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus–pituitary–adrenal (HPA) axis. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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8 pages, 240 KiB

Open AccessArticle

Association of RS708272 (CETP Gene Variant) with Lipid Profile Parameters and the Risk of Myocardial Infarction in the White Population of Western Siberia

by Sergey Semaev, Elena Shakhtshneider, Pavel Orlov, Dinara Ivanoshchuk, Sophia Malyutina, Valery Gafarov, Yuliya Ragino and Mikhail Voevoda

Biomolecules 2019, 9(11), 739; https://doi.org/10.3390/biom9110739 - 14 Nov 2019

Cited by 8 | Viewed by 2785

Abstract

The TaqI B (rs708272) single-nucleotide variant, i.e., the +279 G/A substitution in intron 1 of the CETP gene, is actively investigated as a risk factor of lipid metabolism disorders. The aim of this study was to analyze the association of rs708272 with lipid [...] Read more.

The TaqI B (rs708272) single-nucleotide variant, i.e., the +279 G/A substitution in intron 1 of the CETP gene, is actively investigated as a risk factor of lipid metabolism disorders. The aim of this study was to analyze the association of rs708272 with lipid parameters and the risk of myocardial infarction in the population of Western Siberia (Russia). The study population was selected from a sample surveyed within the framework of the Health, Alcohol and Psychosocial Factors In Eastern Europe (HAPIEE) study (9360 participants, >90% white, aged 45–69 years, males: 50%). In total, 3132 randomly selected patients were included. Plasma lipid levels were determined by standard enzymatic assays. Rs708272 was analyzed by RT-PCR via TaqMan single-nucleotide polymorphism (SNP) Genotyping Assays (Thermo Fisher Scientific, USA). The frequencies of rs708272 genotypes AA (homozygote), AG (heterozygote), and GG were 0.21, 0.49, and 0.30, respectively, in this population. Allele A frequency was 0.46. We found an association of allele G with low levels of high-density lipoprotein cholesterol and a high index of atherogenicity in this population (p < 0.001 and p < 0.001, respectively). Allele G was significantly associated with the risk of myocardial infarction among the male participants (odds ratio 1.96, 95% confidence interval 1.208–3.178, p = 0.008) and in the study population (odds ratio 1.465, 95% confidence interval 1.028–2.087, p = 0.036). Thus, rs708272 is associated with myocardial infarction in the white population of Western Siberia (Russia). Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

14 pages, 1722 KiB

Open AccessArticle

ACSL1 Regulates TNFα-Induced GM-CSF Production by Breast Cancer MDA-MB-231 Cells

by Reeby Thomas, Fatema Al-Rashed, Nadeem Akhter, Fahd Al-Mulla and Rasheed Ahmad

Biomolecules 2019, 9(10), 555; https://doi.org/10.3390/biom9100555 - 01 Oct 2019

Cited by 27 | Viewed by 5698

Abstract

Overexpression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in different types of cancer is associated with tumor growth and progression. Tumor necrosis factor-α (TNFα) is involved in the induction of GM-CSF in different cells; however, the underlying molecular mechanism in this production of GM-CSF has [...] Read more.

Overexpression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in different types of cancer is associated with tumor growth and progression. Tumor necrosis factor-α (TNFα) is involved in the induction of GM-CSF in different cells; however, the underlying molecular mechanism in this production of GM-CSF has not been fully revealed. Recently, it was noted that TNFα mediates inflammatory responses through long-chain acyl-CoA synthetase 1 (ACSL1). Therefore, we investigated the role of ACSL1 in the TNFα mediated production of GM-CSF. Our results showed that MDA-MB-231 cells displayed increased GM-CSF mRNA expression and secretion after incubation with TNFα. Blocking of ACSL1 activity in the cells with triacsin C markedly suppressed the secretion of GM-CSF. However, inhibition of β-oxidation and ceramide biosynthesis were not required for GM-CSF production. By small interfering RNA mediated knockdown, we further demonstrated that TNFα induced GM-CSF production was significantly diminished in ACSL1 deficient cells. TNFα mediated GM-CSF expression was significantly reduced by inhibition of p38 MAPK, ERK1/2 and NF-κB signaling pathways. TNFα induced phosphorylation of p38, ERK1/2, and NF-κB was observed during the secretion of GM-CSF. On the other hand, inhibition of ACSL1 activity attenuates TNFα mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB in the cells. Importantly, our findings suggest that ACSL1 plays an important role in the regulation of GM-CSF induced by TNFα in MDA-MB-231 cells. Therefore, ACSL1 may be considered as a potential novel therapeutic target for tumor growth. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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Review

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29 pages, 1486 KiB

Open AccessReview

Dietary Fatty Acids and Microbiota-Brain Communication in Neuropsychiatric Diseases

by Maria Cristina Marrone and Roberto Coccurello

Biomolecules 2020, 10(1), 12; https://doi.org/10.3390/biom10010012 - 19 Dec 2019

Cited by 24 | Viewed by 7219

Abstract

The gut-brain axis is a multimodal communication system along which immune, metabolic, autonomic, endocrine and enteric nervous signals can shape host physiology and determine liability, development and progression of a vast number of human diseases. Here, we broadly discussed the current knowledge about [...] Read more.

The gut-brain axis is a multimodal communication system along which immune, metabolic, autonomic, endocrine and enteric nervous signals can shape host physiology and determine liability, development and progression of a vast number of human diseases. Here, we broadly discussed the current knowledge about the either beneficial or deleterious impact of dietary fatty acids on microbiota-brain communication (MBC), and the multiple mechanisms by which different types of lipids can modify gut microbial ecosystem and contribute to the pathophysiology of major neuropsychiatric diseases (NPDs), such as schizophrenia (SCZ), depression and autism spectrum disorders (ASD). Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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21 pages, 2341 KiB

Open AccessReview

Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health

by Vidhu Gill, Vijay Kumar, Kritanjali Singh, Ashok Kumar and Jong-Joo Kim

Biomolecules 2019, 9(12), 888; https://doi.org/10.3390/biom9120888 - 17 Dec 2019

Cited by 112 | Viewed by 16859

Abstract

The Maillard reaction is a simple but ubiquitous reaction that occurs both in vivo and ex vivo during the cooking or processing of foods under high-temperature conditions, such as baking, frying, or grilling. Glycation of proteins is a post-translational modification that forms temporary [...] Read more.

The Maillard reaction is a simple but ubiquitous reaction that occurs both in vivo and ex vivo during the cooking or processing of foods under high-temperature conditions, such as baking, frying, or grilling. Glycation of proteins is a post-translational modification that forms temporary adducts, which, on further crosslinking and rearrangement, form permanent residues known as advanced glycation end products (AGEs). Cooking at high temperature results in various food products having high levels of AGEs. This review underlines the basis of AGE formation and their corresponding deleterious effects on the body. Glycated Maillard products have a direct association with the pathophysiology of some metabolic diseases, such as diabetes mellitus type 2 (DM2), acute renal failure (ARF), Alzheimer’s disease, dental health, allergies, and polycystic ovary syndrome (PCOS). The most glycated and structurally abundant protein is collagen, which acts as a marker for diabetes and aging, where decreased levels indicate reduced skin elasticity. In diabetes, high levels of AGEs are associated with carotid thickening, ischemic heart disease, uremic cardiomyopathy, and kidney failure. AGEs also mimic hormones or regulate/modify their receptor mechanisms at the DNA level. In women, a high AGE diet directly correlates with high levels of androgens, anti-Müllerian hormone, insulin, and androstenedione, promoting ovarian dysfunction and/or infertility. Vitamin D3 is well-associated with the pathogenesis of PCOS and modulates steroidogenesis. It also exhibits a protective mechanism against the harmful effects of AGEs. This review elucidates and summarizes the processing of infant formula milk and the associated health hazards. Formulated according to the nutritional requirements of the newborn as a substitute for mother’s milk, formula milk is a rich source of primary adducts, such as carboxy-methyl lysine, which render an infant prone to inflammation, dementia, food allergies, and other diseases. We therefore recommend that understanding this post-translational modification is the key to unlocking the mechanisms and physiology of various metabolic syndromes. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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11 pages, 566 KiB

Open AccessReview

N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

by Natalia Battista, Monica Bari and Tiziana Bisogno

Biomolecules 2019, 9(12), 822; https://doi.org/10.3390/biom9120822 - 03 Dec 2019

Cited by 37 | Viewed by 5333

Abstract

The lipid signal is becoming increasingly crowded as increasingly fatty acid amide derivatives are being identified and considered relevant therapeutic targets. The identification of N-arachidonoyl-ethanolamine as endogenous ligand of cannabinoid type-1 and type-2 receptors as well as the development of different–omics technologies [...] Read more.

The lipid signal is becoming increasingly crowded as increasingly fatty acid amide derivatives are being identified and considered relevant therapeutic targets. The identification of N-arachidonoyl-ethanolamine as endogenous ligand of cannabinoid type-1 and type-2 receptors as well as the development of different–omics technologies have the merit to have led to the discovery of a huge number of naturally occurring N-acyl-amines. Among those mediators, N-acyl amino acids, chemically related to the endocannabinoids and belonging to the complex lipid signaling system now known as endocannabinoidome, have been rapidly growing for their therapeutic potential. Here, we review the current knowledge of the mechanisms for the biosynthesis and inactivation of the N-acyl amino acids, as well as the various molecular targets for some of the N-acyl amino acids described so far. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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19 pages, 1437 KiB

Open AccessReview

Genes Potentially Associated with Familial Hypercholesterolemia

by Svetlana Mikhailova, Dinara Ivanoshchuk, Olga Timoshchenko and Elena Shakhtshneider

Biomolecules 2019, 9(12), 807; https://doi.org/10.3390/biom9120807 - 29 Nov 2019

Cited by 14 | Viewed by 4009

Abstract

This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin [...] Read more.

This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin type 9 or low-density lipoprotein receptor adaptor protein 1), but also lipids, including sphingolipids, fatty acids, and sterols. The genetic cause of familial hypercholesterolemia is unknown in 20%–40% of the cases. The genes STAP1 (signal transducing adaptor family member 1), CYP7A1 (cytochrome P450 family 7 subfamily A member 1), LIPA (lipase A, lysosomal acid type), ABCG5 (ATP binding cassette subfamily G member 5), ABCG8 (ATP binding cassette subfamily G member 8), and PNPLA5 (patatin like phospholipase domain containing 5), which can cause aberrations of lipid metabolism, are being evaluated as new targets for the diagnosis and personalized management of familial hypercholesterolemia. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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14 pages, 1151 KiB

Open AccessEditor’s ChoiceReview

Gangliosides: The Double-Edge Sword of Neuro-Ectodermal Derived Tumors

by Sumeyye Cavdarli, Sophie Groux-Degroote and Philippe Delannoy

Biomolecules 2019, 9(8), 311; https://doi.org/10.3390/biom9080311 - 27 Jul 2019

Cited by 48 | Viewed by 6705

Abstract

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are mostly localized at the plasma membrane in lipid raft domains and implicated in many cellular signaling pathways mostly by interacting with tyrosine kinase receptors. Gangliosides are divided into four series according to [...] Read more.

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are mostly localized at the plasma membrane in lipid raft domains and implicated in many cellular signaling pathways mostly by interacting with tyrosine kinase receptors. Gangliosides are divided into four series according to the number of sialic acid residues, which can be also modified by O-acetylation. Both ganglioside expression and sialic acid modifications can be modified in pathological conditions such as cancer, which can induce either pro-cancerous or anti-cancerous effects. In this review, we summarize the specific functions of gangliosides in neuro-ectodermal derived tumors, and their roles in reprogramming the lipidomic profile of cell membrane occurring with the induction of epithelial-mesenchymal transition. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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