Biomolecules

50 pages, 3269 KiB

Open AccessReview

Anti-Diabetic Therapies and Cancer: From Bench to Bedside

by Dimitris Kounatidis, Natalia G. Vallianou, Irene Karampela, Eleni Rebelos, Marina Kouveletsou, Vasileios Dalopoulos, Petros Koufopoulos, Evanthia Diakoumopoulou, Nikolaos Tentolouris and Maria Dalamaga

Biomolecules 2024, 14(11), 1479; https://doi.org/10.3390/biom14111479 - 20 Nov 2024

Abstract

Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian [...] Read more.

Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway and the induction of autophagy. Beyond metformin, other conventional anti-diabetic treatments, such as insulin, sulfonylureas (SUs), pioglitazone, and dipeptidyl peptidase-4 (DPP-4) inhibitors, have also been examined for their roles in cancer biology, though findings are often inconclusive. More recently, novel medications, like glucagon-like peptide-1 (GLP-1) receptor agonists, dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, have revolutionized DM management by not only improving glycemic control but also delivering substantial cardiovascular and renal benefits. Given their diverse metabolic effects, including anti-obesogenic properties, these novel agents are now under meticulous investigation for their potential influence on tumorigenesis and cancer advancement. This review aims to offer a comprehensive exploration of the evolving landscape of glucose-lowering treatments and their implications in cancer biology. It critically evaluates experimental evidence surrounding the molecular mechanisms by which these medications may modulate oncogenic signaling pathways and reshape the tumor microenvironment (TME). Furthermore, it assesses translational research and clinical trials to gauge the practical relevance of these findings in real-world settings. Finally, it explores the potential of anti-diabetic medications as adjuncts in cancer treatment, particularly in enhancing the efficacy of chemotherapy, minimizing toxicity, and addressing resistance within the framework of immunotherapy. Full article

(This article belongs to the Special Issue Nutrition, Metabolism, and Obesity: Novel Strategies and Molecular Mechanisms—Future Perspectives)

25 pages, 3893 KiB

Open AccessReview

Research Progress of Fibroblasts in Human Diseases

by Xiaodong Li, Nana Li, Yujie Wang, Qixiang Han and Boshi Sun

Biomolecules 2024, 14(11), 1478; https://doi.org/10.3390/biom14111478 - 20 Nov 2024

Abstract

Fibroblasts, which originate from embryonic mesenchymal cells, are the predominant cell type seen in loose connective tissue. As the main components of the internal environment that cells depend on for survival, fibroblasts play an essential role in tissue development, wound healing, and the [...] Read more.

Fibroblasts, which originate from embryonic mesenchymal cells, are the predominant cell type seen in loose connective tissue. As the main components of the internal environment that cells depend on for survival, fibroblasts play an essential role in tissue development, wound healing, and the maintenance of tissue homeostasis. Furthermore, fibroblasts are also involved in several pathological processes, such as fibrosis, cancers, and some inflammatory diseases. In this review, we analyze the latest research progress on fibroblasts, summarize the biological characteristics and physiological functions of fibroblasts, and delve into the role of fibroblasts in disease pathogenesis and explore treatment approaches for fibroblast-related diseases. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
Electron microscopic analysis of human skin fibroblasts. The left picture shows the overall imaging of a fibroblast, and the right picture is the locally magnified imaging of the left one. Abbreviations: N, Nucleus; RER, Rough endoplasmic reticulum; Gol, Golgi apparatus; Mit, Mitochondrion; Tf, Tonofilament; Ly, Lysosome. Full article ">Figure 2
The process of fibrosis and common organs that are related to fibrosis diseases. Idiopathic pulmonary fibrosis (IPF), liver cirrhosis, scleroderma, heart failure, diabetic nephropathy, hypertensive nephropathy, chronic pancreatitis, and inflammatory bowel disease have been found to be associated with fibrosis. Full article ">Figure 3
Anticancer immunotherapy methods targeting CAFs and their related molecules. A. The first immunotherapy method is to target CAFs directly by focusing on CAF markers like FAP, PDGFR, and α-SMA to boost the immune response of the body within the TME. B. The second immunotherapy method is to inhibit key signaling pathways or effector molecules related to the activation and function of CAFs, such as IL-6, TGF-β, C–C chemokine ligand 2 (CCL2)-C–C chemokine receptor (CCR2) signal axis, Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signal pathway, and C-X-C chemokine ligand 12 (CXCL12), thus inhibiting the effect of CAFs in the TME. C. The third immunotherapy method is to limit ECM remodeling by inhibiting ECM proteins derived from CAFs, such as MMPs, TNC, hyaluronan (HA), and focal adhesion kinase (FAK) signaling pathways related to fibrosis activation. Full article ">

20 pages, 2485 KiB

Open AccessArticle

Supplementation of Oocytes by Microinjection with Extra Copies of mtDNA Alters Metabolite Profiles and Interactions with Expressed Genes in a Tissue-Specific Manner

by Eryk Andreas, Alexander Penn, Takashi Okada and Justin C. St. John

Biomolecules 2024, 14(11), 1477; https://doi.org/10.3390/biom14111477 - 20 Nov 2024

Abstract

Mitochondrial DNA (mtDNA) supplementation can rescue poor oocyte quality and overcome embryonic arrest. Here, we investigated a series of sexually mature pigs generated through autologous and heterologous mtDNA supplementation. Brain, liver and heart tissues underwent metabolite profiling using gas chromatography–mass spectrometry and gene [...] Read more.

Mitochondrial DNA (mtDNA) supplementation can rescue poor oocyte quality and overcome embryonic arrest. Here, we investigated a series of sexually mature pigs generated through autologous and heterologous mtDNA supplementation. Brain, liver and heart tissues underwent metabolite profiling using gas chromatography–mass spectrometry and gene expression analysis through RNA-seq. They were then assessed for mRNA–metabolite interactions. The comparison between overall mtDNA supplemented and control pigs revealed that mtDNA supplementation reduced the lipids stearic acid and elaidic acid in heart tissue. However, heterologous mtDNA supplemented-derived pigs exhibited lower levels of abundance of metabolites when compared with autologous-derived pigs. In the brain, these included mannose, mannose 6-phosphate and fructose 6-phosphate. In the liver, maltose and cellobiose, and in the heart, glycine and glutamate were affected. mRNA–metabolite pathway analysis revealed a correlation between malate and CS, ACLY, IDH2 and PKLR in the liver and glutamate and PSAT1, PHGDH, CDO1 and ANPEP in the heart. Our outcomes demonstrate that mtDNA supplementation, especially heterologous supplementation, alters the metabolite and transcriptome profiles of brain, liver, and heart tissues. This is likely due to the extensive resetting of the balance between the nuclear and mitochondrial genomes in the preimplantation embryo, which induces a series of downstream effects. Full article

(This article belongs to the Section Molecular Genetics)

► Show Figures

Figure 1

Figure 1
Schematic diagram of carbohydrate (A) and protein (B) metabolism in offspring brain. Red font indicates differentially relatively abundant compounds for the comparison between heterologous and autologous mtDNA-supplemented pigs. Full article ">Figure 2
Schematic diagram of starch and sucrose (A) and carbohydrate–protein (B) metabolism in offspring liver. Red font indicates differentially relatively abundant compounds for the comparison between heterologous and autologous mtDNA-supplemented pigs. Full article ">Figure 3
Schematic diagram of protein metabolism in offspring heart. Red font indicates differentially relatively abundant compounds for the comparison between heterologous and autologous mtDNA-supplemented pigs. Full article ">Figure 4
RNA–metabolite network analyses for liver (A) and heart (C) derived from heterologous compared to autologous mtDNA-supplemented pigs. Schematic diagram of pyruvate metabolism/citrate cycle (TCA cycle) in liver tissue (B) and glycine, serine and threonine metabolism/glutathione metabolism/cysteine and methionine metabolism in heart tissue (D). In A and C, the blue boxes indicate compounds and blue circles indicate mRNA. In C and D, circles and red font indicate compounds and blocks and green font indicate mRNA. Red and blue arrows indicate upregulated and downregulated gene expression in heterologous compared to autologous mtDNA-supplemented cohorts, respectively. Full article ">

15 pages, 4970 KiB

Open AccessArticle

Metabolites and Metabolic Functional Changes—Potential Markers for Endothelial Cell Senescence

by Jingyuan Ya, Alison Whitby and Ulvi Bayraktutan

Biomolecules 2024, 14(11), 1476; https://doi.org/10.3390/biom14111476 - 20 Nov 2024

Abstract

Accumulation of senescent endothelial cells (ECs) in vasculature represents a key step in the development of vascular aging and ensuing age-related diseases. Given that removal of senescent ECs may prevent disease and improve health and wellbeing, the discovery of novel biomarkers that effectively [...] Read more.

Accumulation of senescent endothelial cells (ECs) in vasculature represents a key step in the development of vascular aging and ensuing age-related diseases. Given that removal of senescent ECs may prevent disease and improve health and wellbeing, the discovery of novel biomarkers that effectively identify senescent cells is of particular importance. As crucial elements for biological pathways and reliable bioindicators of cellular processes, metabolites demand attention in this context. Using senescent human brain microvascular endothelial cells (HBMECs) displaying a secretory phenotype and significant morphological, nuclear, and enzymatic changes compared to their young counterparts, this study has shown that senescent HBMECs lose their endothelial characteristics as evidenced by the disappearance of CD31/PECAM-1 from interendothelial cell junctions. The metabolic profiling of young versus senescent HBMECs also indicates significant differences in glucose, glutamine, and fatty acid metabolism. The analysis of intracellular and secreted metabolites proposes L-proline, L-glutamate, NAD⁺, and taurine/hypotaurine pathway components as potential biomarkers. However, further studies are required to assess the value of these agents as potential biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Biomarkers of Cardiovascular and Cerebrovascular Diseases)

► Show Figures

Figure 1

Figure 1
Senescence promotes morphological and functional changes in human brain microvascular endothelial cells (HBMECs) as evidenced by enlarged, heterogenous morphology (A) and increases in β-gal activity (B, orange arrow) and DNA damage accumulation (C, green arrow). White arrow shows normal nuclear staining with DAPI. Senescent HBMECs develop greater numbers of actin stress fibers (D, blue arrow) and lose their endothelial cell characteristics as evidenced by a decrease in CD31 expression (E, yellow arrow). * p < 0.05 compared to young HBMECs. Full article ">Figure 2
Senescent human brain microvascular endothelial cells (HBMECs) express significantly higher levels of p16 (A) and a lower proliferation rate (B) and a lesser telomere length (C) compared to young HBMECs. * p < 0.05 compared to young HBMECs. Original images of (A) can be found in <a href="#app1-biomolecules-14-01476" class="html-app">Supplementary Materials</a>. Full article ">Figure 3
Senescent human brain microvascular endothelial cells display significantly reduced migratory capacity (A) as evidenced by extended time required to repair the wound inflicted on HBMEC monolayer (B). * p < 0.05 compared to young HBMECs. Full article ">Figure 4
Senescent human brain microvascular endothelial cells (HBMECs) display impaired angiogenic capacity as ascertained by their ability to form fewer, shorter, and irregular tubules on Matrigel compared to their young counterparts. * p < 0.05 compared to young HBMECs. Full article ">Figure 5
Compared to young human brain microvascular endothelial cells (HBMECs), senescent cells release greater quantities of inflammatory cytokines, MCP-1, ICAM-1, IL-6, and IL-8. * p < 0.05 compared to young HBMECs. ns = not significant. Full article ">Figure 6
Untargeted metabolite fingerprinting (cell lysate) and footprinting (spent media) in senescent = <img alt="Biomolecules 14 01476 i001" src="/biomolecules/biomolecules-14-01476/article_deploy/html/images/biomolecules-14-01476-i001.png"/> and young <img alt="Biomolecules 14 01476 i002" src="/biomolecules/biomolecules-14-01476/article_deploy/html/images/biomolecules-14-01476-i002.png"/> HBMEC lysate and culture media samples. OPLS-DA of cell lysate (R2Y = 0.980; Q2 = 0.969) and media (R2Y = 0.995; Q2 = 0.985) shows a good fit of data and the predictive ability of the model without overfitting. Full article ">

16 pages, 946 KiB

Open AccessReview

Insulin-like Growth Factor-Binding Protein-1 (IGFBP-1) as a Biomarker of Cardiovascular Disease

by Moira S. Lewitt and Gary W. Boyd

Biomolecules 2024, 14(11), 1475; https://doi.org/10.3390/biom14111475 - 20 Nov 2024

Abstract

Insulin-like growth factor-binding protein-1 (IGFBP-1) contributes to the regulation of IGFs for metabolism and growth and has IGF-independent actions. IGFBP-1 in the circulation is derived from the liver, where it is inhibited by insulin and stimulated by multiple factors, including proinflammatory cytokines. IGFBP-1 [...] Read more.

Insulin-like growth factor-binding protein-1 (IGFBP-1) contributes to the regulation of IGFs for metabolism and growth and has IGF-independent actions. IGFBP-1 in the circulation is derived from the liver, where it is inhibited by insulin and stimulated by multiple factors, including proinflammatory cytokines. IGFBP-1 levels are influenced by sex and age, which also determine cardiometabolic risk and patterns of disease presentation. While lower circulating IGFBP-1 concentrations are associated with an unfavorable cardiometabolic risk profile, higher IGFBP-1 predicts worse cardiovascular disease outcomes. This review explores these associations and the possible roles of IGFBP-1 in the pathophysiology of atherosclerosis. We recommend the evaluation of dynamic approaches, such as simultaneous measurements of fasting IGFBP-1 and proinsulin level in response to an oral glucose challenge, as well as multi-marker approaches incorporating markers of inflammation. Full article

(This article belongs to the Special Issue Biomarkers of Cardiovascular and Cerebrovascular Diseases)

► Show Figures

Figure 1

9 pages, 442 KiB

Open AccessArticle

Serum Leucine-Rich Alpha-2 Glycoprotein 1 Levels in Patients with Lipodystrophy Syndromes

by Michelle Krienke, Susan Kralisch, Leonie Wagner, Anke Tönjes and Konstanze Miehle

Biomolecules 2024, 14(11), 1474; https://doi.org/10.3390/biom14111474 - 19 Nov 2024

Abstract

Serum concentrations of leucine-rich alpha-2 glycoprotein 1 (LRG1) are elevated in several cardio-metabolic and inflammatory diseases. LRG1 also plays an important role in the development of hepatic steatosis and insulin resistance. In lipodystrophies (LDs), severe cardio-metabolic complications can be observed. The dysregulation of [...] Read more.

Serum concentrations of leucine-rich alpha-2 glycoprotein 1 (LRG1) are elevated in several cardio-metabolic and inflammatory diseases. LRG1 also plays an important role in the development of hepatic steatosis and insulin resistance. In lipodystrophies (LDs), severe cardio-metabolic complications can be observed. The dysregulation of several adipokines plays a significant role in the clinical manifestation of this syndrome. To date, there have been no studies of LRG1 levels in non-HIV-LD patients. We performed a cross-sectional analysis of LRG1 serum levels in 60 patients with non-HIV-associated LD and in 60 age-, sex-, and BMI-matched healthy controls. Furthermore, we investigated the gene expression of Lrg1 in a mouse model of generalised LD. No significant difference was found in the median concentration of LRG1 serum levels between LD patients (18.2 ng/L; interquartile range 8.3 ng/L) and healthy controls (17.8 ng/L; interquartile range 11.0 ng/L). LRG1 serum concentrations correlated positively with CRP serum levels (p < 0.001). Lrg1 mRNA expression was downregulated in the adipose tissue, whereas in the liver, no difference in Lrg1 expression between LD and wild-type mice was detected. In summary, circulating levels of LRG1 are associated with low-grade inflammation but cannot distinguish between patients with LD and controls. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

► Show Figures

Figure 1

18 pages, 4941 KiB

Open AccessArticle

Computational Study of Network and Type-I Functional Divergence in Alcohol Dehydrogenase Enzymes Across Species Using Molecular Dynamics Simulation

by Suhyun Park, Petrina Jebamani, Yeon Gyo Seo and Sangwook Wu

Biomolecules 2024, 14(11), 1473; https://doi.org/10.3390/biom14111473 - 19 Nov 2024

Abstract

Alcohol dehydrogenases (ADHs) are critical enzymes involved in the oxidation of alcohols, contributing to various metabolic pathways across organisms. This study investigates type I functional divergence within three ADH1 families: Saccharomyces cerevisiae (PDB ID: 4W6Z), Gadus morhua (PDB ID: 1CDO), and Homo sapiens [...] Read more.

Alcohol dehydrogenases (ADHs) are critical enzymes involved in the oxidation of alcohols, contributing to various metabolic pathways across organisms. This study investigates type I functional divergence within three ADH1 families: Saccharomyces cerevisiae (PDB ID: 4W6Z), Gadus morhua (PDB ID: 1CDO), and Homo sapiens (PDB ID: 1HDX). Understanding the molecular evolution and mechanisms underlying functional divergence of ADHs is essential for comprehending their adaptive significance. For this purpose, we performed a computational analysis that included structural characterization of ADHs through three-dimensional modeling, site-specific analysis to evaluate selective pressures and evolutionary constraints, and network analysis to elucidate relationships between structural features and functional divergence. Our findings indicate substantial variations in evolutionary and structural adaptations among the ADH families. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

► Show Figures

Figure 1

Figure 1
Alcohol dehydrogenase is an enzyme used together with pyruvate decarboxylase in alcoholic fermentation to convert NADH to NAD+ while converting acetaldehyde to ethanol. (a) The conversion process. (b) 2D and (c) 3D structures of NAD. (d) Structure of human ADH in complex with NAD (PDB id: 1HDX). The zinc ions are shown in the boxes. Full article ">Figure 2
(a) Emergence of gene families after gene duplication and formation of clusters. (b) A scheme of the F0 state (functional constraint). (c) A scheme of the F1 state (functional divergence). Full article ">Figure 3
Phylogenetic tree of alcohol dehydrogenase (ADH) enzymes of (a) ADH1/ADH3, (b) ADH1/ADH2/ADH3/ADH4/ADH5, (c) ADH1/ADH2/ADH3/ADH4/ADH5. The entities in the phylogenic tree crystalized are shown in the red box. Full article ">Figure 4
RMSD values and standard deviations of 100 ns MD simulations, repeated three times for three PDB structures and the alignment of the initial structures and final snapshot (100 ns) structures, respectively. (a) RMSD values and standard deviations of 1CDO. (b) RMSD values and standard deviations of 1HDX. (c) RMSD values and standard deviations of 4W6Z. Full article ">Figure 5
Dynamic cross-correlation map (DCCM) calculations throughout 100 ns molecular dynamics simulation of a protein. The maps provide information about the dynamic correlation between the Cα atoms of amino acids. Correlation between residue fluctuations: blue, negative; red, positive correlation. The color coding from blue to red indicates the degree of correlation, with red representing areas of high correlation which often implies coordinated movement or interaction between those residues. The diagonal line of the DCCM represents the correlation of each residue with itself, which is always perfect (hence the line is red). The points not on the diagonal line represent the correlations between different residues. (a) Dynamic cross-correlation map of 1CDO. (b) Dynamic cross-correlation map of 1HDX. (c) Dynamic cross-correlation map of 4W6Z. Full article ">Figure 6
Principal component analysis throughout the 100 ns molecular dynamics simulation of each protein. The plots of PC2 vs. PC1 show the correlation between the first and second principal components, etc. Each point in the scatter plot represents a different conformation of the protein during the simulation. If two points are close together in the plot, it means that those two conformations are similar in terms of the movements of the residues. The percentage values given in the scatter plots represent the variance explained by each principal component. (a) Principal component analysis of 1CDO. (b) Principal component analysis of 1HDX. (c) Principal component analysis of 4W6Z. Full article ">Figure 7
Positions of residues with high betweenness centrality, closeness centrality, and degree centrality in the 3D structure of (a) 1CDO, (b) 1HDX, and (c) 4W6Z. Full article ">Figure 8
Correlation between Q values and centrality measures betweenness, closeness, and degree in (a) 1CDO, (b) 1HDX, and (c) 4W6Z. The amino acid residues on the diagonal lines (orange color) are shown in the boxes. Full article ">

17 pages, 3880 KiB

Open AccessArticle

The Antifungal Potential of Ozonated Extra-Virgin Olive Oil Against Candida albicans: Mechanisms and Efficacy

by Simone Augello, Valentina Cameli, Arianna Montanari, Stefano Tacconi, Daniela Uccelletti, Luciana Dini and Emily Schifano

Biomolecules 2024, 14(11), 1472; https://doi.org/10.3390/biom14111472 - 19 Nov 2024

Abstract

The growing emergence of resistance mechanisms and side effects associated with antifungal agents highlight the need for alternative therapies. This study aims to investigate the antifungal potential of ozonated extra-virgin olive oil (EOO) against Candida albicans, with the goal of developing eco-friendly [...] Read more.

The growing emergence of resistance mechanisms and side effects associated with antifungal agents highlight the need for alternative therapies. This study aims to investigate the antifungal potential of ozonated extra-virgin olive oil (EOO) against Candida albicans, with the goal of developing eco-friendly and highly effective treatments based on natural products. Antifungal activity was evaluated via cell viability and biofilm formation assays using Crystal Violet and Sytox green staining. The results showed that EOO reduced C. albicans viability in a dose-dependent manner, achieving over 90% cell death at a 3% (v/v) concentration. Transmission Electron Microscopy (TEM) revealed cell wall structural damage, and ROS levels increased by approximately 60% compared to untreated controls within 10 min of treatment. Additionally, the expression of autophagy-related genes atg-7 and atg-13was upregulated by 2- and 3.5-fold, respectively, after 15 min, suggesting a stress-induced cell death response. EOO also significantly inhibited hyphal formation and biofilm development, thus reducing C. albicans pathogenicity while preserving cell biocompatibility. EOO antifungal activity was also observed in the case of Candida glabrata. In conclusion, ozonated olive oil demonstrates potent antifungal activity against C. albicans by reducing cell viability, inhibiting hyphal and biofilm formation, and triggering oxidative stress and autophagy pathways. These findings position EOO as a promising alternative therapy for fungal infections. Full article

(This article belongs to the Special Issue Molecular Profiling and Identification of Molecular Signatures Associated with Natural Products)

► Show Figures

Graphical abstract

15 pages, 4295 KiB

Open AccessArticle

Local Stress in Cylindrically Curved Lipid Membrane: Insights into Local Versus Global Lateral Fluidity Models

by Konstantin V. Pinigin

Biomolecules 2024, 14(11), 1471; https://doi.org/10.3390/biom14111471 - 19 Nov 2024

Abstract

Lipid membranes, which are fundamental to cellular function, undergo various mechanical deformations. Accurate modeling of these processes necessitates a thorough understanding of membrane elasticity. The lateral shear modulus, a critical parameter describing membrane resistance to lateral stresses, remains elusive due to the membrane’s [...] Read more.

Lipid membranes, which are fundamental to cellular function, undergo various mechanical deformations. Accurate modeling of these processes necessitates a thorough understanding of membrane elasticity. The lateral shear modulus, a critical parameter describing membrane resistance to lateral stresses, remains elusive due to the membrane’s fluid nature. Two contrasting hypotheses, local fluidity and global fluidity, have been proposed. While the former suggests a zero local lateral shear modulus anywhere within lipid monolayers, the latter posits that only the integral of this modulus over the monolayer thickness vanishes. These differing models lead to distinct estimations of other elastic moduli and affect the modeling of biological processes, such as membrane fusion/fission and membrane-mediated interactions. Notably, they predict distinct local stress distributions in cylindrically curved membranes. The local fluidity model proposes isotropic local lateral stress, whereas the global fluidity model predicts anisotropy due to anisotropic local lateral stretching of lipid monolayers. Using molecular dynamics simulations, this study directly investigates these models by analyzing local stress in a cylindrically curved membrane. The results conclusively demonstrate the existence of static local lateral shear stress and anisotropy in local lateral stress within the monolayers of the cylindrical membrane, strongly supporting the global fluidity model. These findings have significant implications for the calculation of surface elastic moduli and offer novel insights into the fundamental principles governing lipid membrane elasticity. Full article

(This article belongs to the Special Issue Recent Developments in Biophysical Studies of Cell Membranes: Second Edition)

► Show Figures

Figure 1

16 pages, 1504 KiB

Open AccessArticle

Effect of a Concurrent Training Program with and Without Metformin Treatment on Metabolic Markers and Cardiorespiratory Fitness in Individuals with Insulin Resistance: A Retrospective Analysis

by Jairo Azócar-Gallardo, Alex Ojeda-Aravena, Eduardo Báez-San Martín, Tomás Herrera-Valenzuela, Marcelo Tuesta, Luis González-Rojas, Bibiana Calvo-Rico and José Manuel García-García

Biomolecules 2024, 14(11), 1470; https://doi.org/10.3390/biom14111470 - 19 Nov 2024

Abstract

Background: Type 2 diabetes mellitus is a metabolic disorder characterized by insulin resistance (IR), which is prevalent worldwide and has significant adverse health effects. Metformin is commonly prescribed as a pharmacological treatment. Physical exercise is also recognized as an effective regulator of glycemia, [...] Read more.

Background: Type 2 diabetes mellitus is a metabolic disorder characterized by insulin resistance (IR), which is prevalent worldwide and has significant adverse health effects. Metformin is commonly prescribed as a pharmacological treatment. Physical exercise is also recognized as an effective regulator of glycemia, independent of metformin. However, the effects of inter-day concurrent training (CT)—which includes both endurance and resistance exercises—combined with metformin treatment on metabolic markers and cardiorespiratory fitness in individuals with IR remain controversial. Objective: This study aimed to analyze the effects of a 12-week inter-day CT program on metabolic markers and cardiorespiratory fitness in overweight/obese individuals with IR, both with and without metformin treatment. Additionally, inter-individual responses to CT were examined. Materials and Methods: Data from the 2022–2023 Obesity Center database were retrospectively analyzed. According to the eligibility criteria, 20 overweight/obese individuals diagnosed with IR participated in a 12-week CT program (three weekly sessions: two endurance and one resistance exercise session). Participants were divided into three groups: the exercise group (E-G: n = 7, 32.86 ± 8.32 years, 85.2 ± 19.67 kg), the exercise–metformin group (E-MG: n = 6, 34.83 ± 12.91 years, 88.13 ± 12.66 kg), and the metformin-only control group (M-G: n = 7, 34.43 ± 13.96 years, 94.23 ± 13.93 kg). The M-G did not perform physical exercise during the 12 weeks but continued pharmacological treatment. Body composition, metabolic markers, and cardiorespiratory fitness were assessed before and after the 12-week CT program. Results: A group-by-time interaction was observed for fasting insulin (F_2,17 = 34.059, p < 0.001, η²_p = 0.88), the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (F_2,17 = 35.597, p < 0.001, η²_p = 0.80), and maximal fat oxidation (MFO) (F_2,17 = 4.541, p = 0.026, η²_p = 0.348) following the CT program. The maximal oxygen uptake (VO2_max) showed significant improvements in the E-G (F = 4.888, p = 0.041, ∆+13.3%). Additionally, the percentage of fat mass (%FM) and body mass (BM) were significantly reduced across all groups (F = 125.244, p < 0.001 and F = 91.130, p < 0.001, respectively). The BM decreased by ∆−9.43% in the E-G (five responders, Rs), ∆+9.21% in the EM-G (5 Rs), and ∆+5.15% in the M-G (3 Rs). The %FM was reduced in the E-G by ∆−22.52% (seven Rs). Fasting insulin and the HOMA-IR significantly improved in both the E-G and EM-G, with fasting insulin showing a ∆−82.1% reduction in the E-G (five Rs) and a ∆−85% reduction in the EM-G (six Rs). Similarly, the HOMA-IR improved by ∆+82.6% in the E-G (three Rs) and by ∆+84.6% in the EM-G (six Rs). Conclusions: The 12-week inter-day concurrent training program, whether combined with metformin or not, was similarly effective in improving metabolic markers in patients with insulin resistance as metformin treatment alone. Both exercise groups demonstrated a significant reduction in insulin sensitivity and an increase in maximal fat oxidation. Meanwhile, exclusive pharmacological treatment with metformin markedly decreased cardiorespiratory fitness, and consequently, fat oxidation. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

► Show Figures

Figure 1

15 pages, 1433 KiB

Open AccessArticle

Advances in the Regulation of Periostin for Osteoarthritic Cartilage Repair Applications

by Sunny Y. Shih, Michael P. Grant, Laura M. Epure, Muskan Alad, Sophie Lerouge, Olga L. Huk, Stephane G. Bergeron, David J. Zukor, Géraldine Merle, Hee-Jeong Im, John Antoniou and Fackson Mwale

Biomolecules 2024, 14(11), 1469; https://doi.org/10.3390/biom14111469 - 18 Nov 2024

Abstract

Emerging evidence indicates periostin (POSTN) is upregulated in patients with OA, and studies have shown that it can induce the activation of inflammatory cytokines and catabolic enzymes, making it a potential therapeutic target. Link N (LN) is a peptide fragment derived from the [...] Read more.

Emerging evidence indicates periostin (POSTN) is upregulated in patients with OA, and studies have shown that it can induce the activation of inflammatory cytokines and catabolic enzymes, making it a potential therapeutic target. Link N (LN) is a peptide fragment derived from the link protein and has been demonstrated as an anabolic-like factor and anti-catabolic and anti-inflammatory factors both in vitro and in vivo. This study aims to determine if LN can regulate POSTN expression and function in OA cartilage. Articular cartilage was recovered from donors undergoing total knee replacements to isolate chondrocytes and prepare osteochondral explants. Cells and explants were treated with POSTN and LN (1 and 100 μg) and measured for changes in POSTN expression and various matrix proteins, catabolic and proinflammatory factors, and signaling. To determine the effects of POSTN expression in vivo, a rabbit OA model was used. Immunoprecipitation and in silico modeling were used to determine peptide/POSTN interactions. Western blotting, PCR, and immunohistochemistry demonstrated that LN decreased POSTN expression both in vitro and in vivo. LN was also able to directly inhibit POSTN signaling in OA chondrocytes. In silico docking suggested the direct interaction of LN with POSTN at residues responsible for its oligomerization. Immunoprecipitation experiments confirmed the direct interaction of LN with POSTN and the destabilization of its oligomerization. This study demonstrates the ability of a peptide, LN, to suppress the overexpression and function of POSTN in OA cartilage. Full article

(This article belongs to the Section Biological Factors)

► Show Figures

Figure 1

Figure 1
Increased expression of Postn in human OA cartilage. (A) Immunohistochemical analysis of human OA knee cartilage identified increased cell-associated POSTN in lesional areas when compared to normal cartilage (back arrows). OA knee cartilage, obtained from four donors ranging from 35 to 70 years of age and undergoing total knee arthroplasty, was sectioned and stained for POSTN with Vectastain reagents (Vector Laboratories, Burlingame, CA, USA). (B) Quantitation of periostin positively expressing chondrocytes in superficial and deep cartilage zones. Two-way ANOVA; comparison between normal and OA cartilages; **** p < 0.0001; * p < 0.05; n = 4. Full article ">Figure 2
LN suppresses the upregulation of POSTN in human OA osteochondral explants: (a) Human OA osteochondral explants were treated with LN (100 µg/mL) or PBS (CTL) for 14 days. Changes in expression were determined by POSTN staining (arrows); (b) immunohistochemical analysis of POSTN expression in human OA samples, where the stains were divided into three categories: cells unstained with POSTN, cells with minimal Postn staining, and cells with saturated POSTN staining. Means ± SDs; n = 4 donors; chi-squared test. Full article ">Figure 3
Effect of LN on POSTN expression in primary human osteoarthritis chondrocytes. (A) Freshly isolated human osteoarthritis (OA) chondrocytes were cultured as micro-pellets and treated for 6 days with LN at 1 µg/mL and 100 µg/mL. Quantitative real-time PCR was used to measure POSTN mRNA expression levels, normalized against GAPDH. (B) Representative western blot analysis showing the effects of the LN treatments (at 1 µg/mL and 100 µg/mL) on POSTN protein levels over a 3-day treatment period. GAPDH was used as the loading control. (C) Densitometric analysis of POSTN protein levels from western blots (panel B), normalized to GAPDH. Statistical significance is indicated as * p < 0.05; ** p < 0.01; and **** p < 0.0001 compared to the untreated control group. Full article ">Figure 4
LN suppresses the upregulation of POSTN in a rabbit model of OA. Skeletally mature New Zealand white rabbits underwent unilateral anterior cruciate ligament transection (ACLT) of their left femorotibial joints to induce joint degeneration typical of OA. Beginning at 3 weeks postoperatively, and every three weeks thereafter for 12 weeks, either saline (1 mL) or sLN (100 µg in 1 mL of saline) was injected intraarticularly into the operated knee. Six additional rabbits underwent sham surgery but without ACLT or postoperative injections: (A) POSTN expression, as determined using immunostaining at 12 weeks, was significantly higher in the ACLT rabbits’ knee cartilage when compared with sham knees; (B) the immunohistochemical analysis of the POSTN expression in the rabbit model of OA, where the stains were divided into three categories: cells unstained with POSTN, cells with minimal POSTN staining, and cells with saturated POSTN staining. Statistical significance was assessed using a chi-squared test (p < 0.00001). Full article ">Figure 5
LN decreases POSTN signaling in human OA chondrocytes: (A) western blots demonstrating the inhibition of periostin-induced increases in β-catenin (β-Cat) accumulation by LN; (B) densitometry of blots presented in (A). ANOVA; post hoc Dunnett’s test; *** p < 0.0001; n = 3. Full article ">Figure 6
LN regulates periostin-induced gene expression in human OA chondrocytes. Chondrocyte pellets were treated with Link N (at 1 or 100 µg/mL) or PBS (CTL) for 6 days in the absence or presence of periostin (20 μg/mL). Gene expression was measured using qPCR. Means ± SDs; n = 3 donors; ANOVA; post hoc Dunnett’s multiple comparison test; **** p < 0.0001; *** p < 0.001; ** p < 0.01; * p < 0.05 in comparison with the control. Full article ">Figure 7
LN interacts with POSTN and induces dissociation: (A) The peptide docking of the LN to POSTN (crystal structure: 5yjg) was determined using the CABS–dock web server. The model was created using PyMOL (Schrodinger, LLC). POSTN residues known to be important in its dimerization are shown to interact with LN. (B) The immunoprecipitation (IP) of the LN with POSTN. Biotinylated LN or biotinylated scrambled LN (SC) was attached to Avidin-labelled agarose beads and then incubated with POSTN. Western blotting was performed to identify POSTN–LN interactions. Lane 1: CTL (PBS) with POSTN; lane 2: IP of LN with POSTN; lane 3: SC with POSTN. (C) POSTN incubated with LN dissociates dimer/oligomer formation. Full article ">

15 pages, 1880 KiB

Open AccessArticle

High-Sensitivity C-Reactive Protein Levels in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), Metabolic Alcohol-Associated Liver Disease (MetALD), and Alcoholic Liver Disease (ALD) with Metabolic Dysfunction

by Seong-Uk Baek and Jin-Ha Yoon

Biomolecules 2024, 14(11), 1468; https://doi.org/10.3390/biom14111468 - 18 Nov 2024

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a recently introduced term for steatotic liver disease (SLD). Although the inflammatory process is central to the pathogenesis of SLD, research investigating the differences in systemic inflammation across various SLD subtypes as well as sex differences [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a recently introduced term for steatotic liver disease (SLD). Although the inflammatory process is central to the pathogenesis of SLD, research investigating the differences in systemic inflammation across various SLD subtypes as well as sex differences is limited. This population-based, cross-sectional study investigated the association between SLD subtypes and high-sensitivity C-reactive protein (hs-CRP) levels among Korean adults (N = 20,141; mean age: 50.8 ± 16.7 years). The participants were classified into five groups that included no SLD, MASLD, metabolic alcohol-associated liver disease (MetALD), alcoholic liver disease with metabolic dysfunction (ALD with MD), and other SLDs. The median (Q1, Q3) value of the hs-CRP level was 0.54 mg/L (0.33, 1.04). Among men, compared to levels in the no SLD group, the MASLD, MetALD, and ALD with MD groups were associated with 41.9% (95% confidence interval [CI]: 35.1–49.1%), 46.8% (95% CI: 35.0–59.6%), and 51.8% (95% CI: 30.0–77.2%) increases in hs-CRP levels, respectively. The association between SLD subtypes and hs-CRP levels was stronger among women, and compared to the levels in the no SLD group, the MASLD, MetALD, and ALD with MD groups were associated with 81.5% (95% CI: 73.6–89.8%), 84.3% (95% CI: 58.1–114.8%), and 98.2% (95% CI: 38.0–184.8%) increases in hs-CRP levels, respectively. In conclusion, our findings indicate a varying profile of systemic inflammation across SLD subtypes, with more pronounced increases in hs-CRP levels in women with SLDs. Full article

(This article belongs to the Special Issue Liver Damage and Associated Metabolic Disorders)

► Show Figures

Figure 1

Figure 1
Distribution of characteristics among the study sample (SLD, steatotic liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic alcohol-associated liver disease; ALD with MD, alcoholic liver disease with metabolic dysfunction). Full article ">Figure 2
Distribution of hs-CRP (high-sensitivity C-reactive protein) values according to SLD subtypes (SLD, steatotic liver disease). (A) Median (Q1, Q3) values of hs-CRP in the overall sample, (B) median (Q1, Q3) values of hs-CRP in the male sample, and (C) median (Q1, Q3) values of hs-CRP in the female sample. Wilcoxon rank sum test was employed (* p < 0.05, *** p < 0.001). Abbreviation: MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic alcohol-associated liver disease; ALD with MD, alcoholic liver disease with metabolic dysfunction; NS: non-significant differences. Full article ">Figure 3
Scatter plot of hepatic steatosis index (HSI) and high-sensitivity C-reactive protein (hs-CRP) levels based on sex. Pearson’s correlation coefficients were presented. Full article ">Figure 4
The plot depicting the association between SLD categories and hs-CRP levels among the overall sample (SLD, steatotic liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic alcohol-associated liver disease; ALD with MD, alcoholic liver disease with metabolic dysfunction; hs-CRP; high-sensitivity C-reactive protein). Full article ">Figure 5
The plot depicting the association between SLD categories and hs-CRP levels among the male and female samples (SLD, steatotic liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic alcohol-associated liver disease; ALD with MD, alcoholic liver disease with metabolic dysfunction; hs-CRP; high-sensitivity C-reactive protein). Full article ">

15 pages, 1048 KiB

Open AccessArticle

Exploring the Genetic Relationship Between Type 2 Diabetes and Cardiovascular Disease: A Large-Scale Genetic Association and Polygenic Risk Score Study

by Ziwei Yao, Xiaomai Zhang, Liufei Deng, Jiayu Zhang, Yalu Wen, Deqiang Zheng and Long Liu

Biomolecules 2024, 14(11), 1467; https://doi.org/10.3390/biom14111467 - 18 Nov 2024

Abstract

Type 2 diabetes (T2D) is often comorbid with cardiovascular diseases (CVDs). The direction of causation between T2D and CVD is difficult to determine; however, there may be a common underlying pathway attributable to shared genetic factors. We aimed to determine whether there is [...] Read more.

Type 2 diabetes (T2D) is often comorbid with cardiovascular diseases (CVDs). The direction of causation between T2D and CVD is difficult to determine; however, there may be a common underlying pathway attributable to shared genetic factors. We aimed to determine whether there is a shared genetic susceptibility to T2D and CVD. This study utilizes large-scale datasets from the UK Biobank (UKB) and DIAGRAM consortium to investigate the genetic association between T2D and CVD through phenotypic association analyses, linkage disequilibrium score (LDSC) analysis, and polygenic risk score (PRS) analysis. LDSC analysis demonstrates significant genetic associations between T2D and various CVD subtypes, including angina, heart failure (HF), myocardial infarction (MI), peripheral vascular disease (PVD), and stroke. Although the genetic association between T2D and atrial fibrillation (AF) was not significant, individuals in the high-T2D PRS group had a significantly increased risk of CVD. These findings suggest a common genetic basis and suggest that genetic susceptibility to T2D may be a potential predictor of CVD risk. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

► Show Figures

Figure 1

15 pages, 5537 KiB

Open AccessArticle

Methyl Paraben Affects Porcine Oocyte Maturation Through Mitochondrial Dysfunction

by Huimei Huang, Chuman Huang, Yinghua Li, Xingwei Liang, Namhyung Kim and Yongnan Xu

Biomolecules 2024, 14(11), 1466; https://doi.org/10.3390/biom14111466 - 18 Nov 2024

Abstract

Parabens are widely used in various industries, which are including chemical, pharmaceutical, food, cosmetic, and plastic processing industries. Among these, methyl paraben (MP) serves as an antimicrobial preservative in processed foods, pharmaceuticals, and cosmetics, and it is particularly detected in baby care products. [...] Read more.

Parabens are widely used in various industries, which are including chemical, pharmaceutical, food, cosmetic, and plastic processing industries. Among these, methyl paraben (MP) serves as an antimicrobial preservative in processed foods, pharmaceuticals, and cosmetics, and it is particularly detected in baby care products. Studies indicate that MP functions as an endocrine-disrupting compound with estrogenic properties, negatively affecting mitochondrial bioenergetics and antioxidant activity in testicular germ cells. However, limited information exists regarding studies on the effects of MP in oocytes. The aim of this study was to investigate the specific mechanism and the toxic effects of MP during oocyte maturation cultured in vitro using a porcine oocyte model. The results indicated that MP (50 μM) inhibited oocyte expansion, significantly reducing the expression of expansion-related genes MAPK1 and ERK1, and decreased the first polar body extrusion significantly as well. ATP levels decreased, reactive oxygen species (ROS) levels remained unchanged, and glutathione (GSH) levels decreased significantly, resulting in an elevated ROS/GSH ratio. The expression of antioxidant genes SOD1 and GPX was significantly decreased. Additionally, a significant decrease in levels of mitochondrial production and biosynthesis protein PGC1α+β, whereas levels of antioxidant-related protein Nrf2 and related gene expression were significantly increased. Autophagy protein LC3B and gene expression significantly decreased, and apoptosis assay indicated a significant increase in levels of caspase3 protein and apoptosis-related genes. These results demonstrated the negative effect of MP on oocyte maturation. In conclusion, our findings indicate that MP disrupts redox balance and induces mitochondrial dysfunction during meiosis in porcine oocytes, resulting in the inhibition of meiotic progression. The present study reveals the mechanism underlying the effects of methyl para-hydroxybenzoate on oocyte maturation. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

► Show Figures

Figure 1

16 pages, 745 KiB

Open AccessReview

Cardio-Lipotoxicity of Epicardial Adipose Tissue

by Monica L. Bodenstab, Ron T. Varghese and Gianluca Iacobellis

Biomolecules 2024, 14(11), 1465; https://doi.org/10.3390/biom14111465 - 18 Nov 2024

Abstract

Epicardial adipose tissue is a unique visceral adipose tissue depot that plays a crucial role in myocardial metabolism. Epicardial adipose tissue is a major source of energy and free fatty acids for the adjacent myocardium. However, under pathological conditions, epicardial fat can affect [...] Read more.

Epicardial adipose tissue is a unique visceral adipose tissue depot that plays a crucial role in myocardial metabolism. Epicardial adipose tissue is a major source of energy and free fatty acids for the adjacent myocardium. However, under pathological conditions, epicardial fat can affect the heart through the excessive and abnormal influx of lipids. The cardio-lipotoxicity of the epicardial adipose tissue is complex and involves different pathways, such as increased inflammation, the infiltration of lipid intermediates such as diacylglycerol and ceramides, mitochondrial dysfunction, and oxidative stress, ultimately leading to cardiomyocyte dysfunction and coronary artery ischemia. These changes can contribute to the pathogenesis of various cardio-metabolic diseases including atrial fibrillation, coronary artery disease, heart failure, and obstructive sleep apnea. Hence, the role of the cardio-lipotoxicity of epicardial fat and its clinical implications are discussed in this review. Full article

(This article belongs to the Special Issue The Molecular and Pathophysiological Basis of Ectopic Fat Deposition in Non-Adipose Tissues)

► Show Figures

Figure 1

22 pages, 3741 KiB

Open AccessArticle

Schinus molle Resin Essential Oil as Potent Bioinsecticide Against Tribolium castaneum: Chemical Profile, In Vitro Acetylcholinesterase Inhibition, DFT Calculation and Molecular Docking Analysis

by Wiem Baccari, Ilyes Saidi, Achref Jebnouni, Safa Teka, Sayda Osman, Awatif Mansoor Alrasheeday, Nuzaiha Mohamed, Mabrouka El Oudi and Hichem Ben Jannet

Biomolecules 2024, 14(11), 1464; https://doi.org/10.3390/biom14111464 - 18 Nov 2024

Abstract

Plants offer a bountiful source of natural pest control solutions through their essential oils. This research introduces and analyzes an eco-friendly natural essential oil for red flour beetle control. Therefore, the current study was included to show the chemical profile and the insecticidal [...] Read more.

Plants offer a bountiful source of natural pest control solutions through their essential oils. This research introduces and analyzes an eco-friendly natural essential oil for red flour beetle control. Therefore, the current study was included to show the chemical profile and the insecticidal efficacy of resin essential oil (REO) and its fractions (F_1–3), resulting from chromatographic separation, from the plant Schinus molle against Tribolium castaneum adults. The trunk bark resin essential oil and its fractions’ composition were analyzed by GC-MS. Overall, 33 constituents with 98.3% of the total EO composition were identified. REO and F_1–3 displayed impressive repellent properties at a concentration of 0.12 µL/cm². After 120 min of exposure, repellency ranged from 73.3% to a remarkable 96.7%. They also exhibited noteworthy fumigant properties, with median lethal doses of LD₅₀ = 120.6–160.8 μL/L. The fractions F₁ and F₃ showed the most notable topical toxicity at a concentration of 10%, with LD₅₀ values of 8.6% and 5.6%, respectively. Fractions F₃ and F₂ demonstrated the most effective inhibition of acetylcholinesterase (AChE) activity, providing insight into their insecticidal mechanisms. The in silico molecular docking and DFT studies corroborate the results of in vitro tests performed to identify new insecticide products derived from natural sources. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
GC-MS chromatograms of resin essential oil of Schinus molle (REO) and its fractions (F1–3). * Retention time of identified component. Full article ">Figure 2
Percentage of mortality of Tribolium castaneum adults after 24 h of exposure to various concentrations of the resin essential oil (REO) of Schinus molle tree and its fractions (F1–3) using the fumigation bioassay. The same letter above the bars indicates that there is no statistically significant difference at a p-value less than 0.05. Full article ">Figure 3
Toxicity of Tribolium castaneum treated with the resin essential oil (REO) of Schinus molle tree and its fractions (F1–3) by topical application bioassay. The same letter above the bars indicates that there is no statistically significant difference at a p-value less than 0.05. Full article ">Figure 4
3D representations of the binding modes of Tribolium castaneum acetylcholinesterase enzyme with (E)-β-caryophyllene (2), elemol (10), germacrene B (11), caryophyllene oxide (13), β-eudesmol (22), α-eudesmol (23), elemyl acetate (27), (E,E)-farnesyl acetate (33), and galantamine. Full article ">Figure 5
Optimized structure of the major compounds identified in resin essential oil of Schinus molle and its fractions using the DFT/6-31(G) (d, p) basis set. Full article ">Figure 6
DFT-based HOMO and LUMO Frontier Molecular Orbitals (FMO) of the main compounds identified in the resin essential oil of Schinus molle tree and its fractions (F1–3) using B3LYP/6-31G (d, p) method. Full article ">Figure 7
3D Molecular electrostatic potential (MEP) surfaces of the major compounds identified in resin essential oil of Schinus molle and its fractions (F1–3). The red regions correspond to negative potentials and the blue regions to positive potentials. Full article ">

26 pages, 1702 KiB

Open AccessReview

Gut Microbe-Generated Metabolite Trimethylamine-N-Oxide and Ischemic Stroke

by Zhen Li, Xinyi He, Qi Fang and Xulong Yin

Biomolecules 2024, 14(11), 1463; https://doi.org/10.3390/biom14111463 - 18 Nov 2024

Abstract

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite, the production of which in vivo is mainly regulated by dietary choices, gut microbiota, and the hepatic enzyme flavin monooxygenase (FMO), while its elimination occurs via the kidneys. The TMAO level is positively correlated with the [...] Read more.

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite, the production of which in vivo is mainly regulated by dietary choices, gut microbiota, and the hepatic enzyme flavin monooxygenase (FMO), while its elimination occurs via the kidneys. The TMAO level is positively correlated with the risk of developing cardiovascular diseases. Recent studies have found that TMAO plays an important role in the development of ischemic stroke. In this review, we describe the relationship between TMAO and ischemic stroke risk factors (hypertension, diabetes, atrial fibrillation, atherosclerosis, thrombosis, etc.), disease risk, severity, prognostic outcomes, and recurrence and discuss the possible mechanisms by which they interact. Importantly, TMAO induces atherosclerosis and thrombosis through lipid metabolism, foam cell formation, endothelial dysfunction (via inflammation, oxidative stress, and pyroptosis), enhanced platelet hyper-reactivity, and the upregulation and activation of vascular endothelial tissue factors. Although the pathogenic mechanisms underlying TMAO’s aggravation of disease severity and its effects on post-stroke neurological recovery and recurrence risk remain unclear, they may involve inflammation, astrocyte function, and pro-inflammatory monocytes. In addition, this paper provides a summary and evaluation of relevant preclinical and clinical studies on interventions regarding the gut-microbiota-dependent TMAO level to provide evidence for the prevention and treatment of ischemic stroke through the gut microbe–TMAO pathway. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

Figure 1
The relationship between TMAO and ischemic stroke. TMAO is associated with ischemic stroke risk factors (hypertension, diabetes, dyslipidemia, obesity, atrial fibrillation, atherosclerosis, and thrombosis), disease risk, severity, prognostic outcomes, and recurrence. The pathogenic mechanisms underlying the aggravation of the disease severity by TMAO and its effects on prognostic outcomes and recurrence risk remain unclear but may involve inflammation, astrocyte function, and pro-inflammatory monocytes. TMAO: trimethylamine-N-oxide. Full article ">Figure 2
TMAO plays an important role in ischemic stroke risk. It may be involved in the pathogenesis of diseases such as hypertension, diabetes, dyslipidemia, obesity, atrial fibrillation, atherosclerosis, and thrombosis, ultimately increasing the ischemic stroke risk. Importantly, TMAO induces atherosclerosis and thrombosis through several mechanisms, including lipid metabolism, foam cell formation, endothelial dysfunction (via inflammation, oxidative stress, pyroptosis), enhanced platelet hyper-reactivity, and the upregulation and activation of vascular endothelial tissue factor. AGEs: advanced glycation end products, RCT: the reverse cholesterol transport, TMAO: trimethylamine-N-oxide. Full article ">Figure 3
TMAO and interventions. The therapeutic strategies targeting gut dysbiosis and TMAO include diet, movement, probiotics and prebiotics, antibiotics, FMT, TMA- and TMAO-related targeted therapies, phytochemicals, and traditional Chinese medicine. FMT: fecal microbiota transplantation, TMA: trimethylamine, TMAO: trimethylamine-N-oxide. Full article ">

30 pages, 694 KiB

Open AccessReview

Activins and Inhibins in Cardiovascular Pathophysiology

by Wenyi Tang, Zhilin Gu, Jiuqi Guo, Mingzhi Lin, Hongqian Tao, Dalin Jia and Pengyu Jia

Biomolecules 2024, 14(11), 1462; https://doi.org/10.3390/biom14111462 - 18 Nov 2024

Abstract

Activins and inhibins, members of the transforming growth factor β (TGFβ) superfamily, were initially recognized for their opposing effects on the secretion of follicle-stimulating hormone. Subsequent research has demonstrated their broader biological roles across various tissue types. Primarily, activins and inhibins function through [...] Read more.

Activins and inhibins, members of the transforming growth factor β (TGFβ) superfamily, were initially recognized for their opposing effects on the secretion of follicle-stimulating hormone. Subsequent research has demonstrated their broader biological roles across various tissue types. Primarily, activins and inhibins function through the classical TGFβ SMAD signaling pathway, but studies suggest that they also act through other pathways, with their specific signaling being complex and context-dependent. Recent research has identified significant roles for activins and inhibins in the cardiovascular system. Their actions in other systems and their signaling pathways show strong correlations with the development and progression of cardiovascular diseases, indicating potential broader roles in the cardiovascular system. This review summarizes the progress in research on the biological functions and mechanisms of activins and inhibins and their signaling pathways in cardiovascular diseases, offering new insights for the prevention and treatment of cardiovascular diseases. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

10 pages, 1517 KiB

Open AccessPerspective

Plasmalogens in Innate Immune Cells: From Arachidonate Signaling to Ferroptosis

by Jesús Balsinde and María A. Balboa

Biomolecules 2024, 14(11), 1461; https://doi.org/10.3390/biom14111461 - 18 Nov 2024

Abstract

Polyunsaturated fatty acids such as arachidonic acid are indispensable components of innate immune signaling. Plasmalogens are glycerophospholipids with a vinyl ether bond in the sn-1 position of the glycerol backbone instead of the more common sn-1 ester bond present in “classical” glycerophospholipids. This [...] Read more.

Polyunsaturated fatty acids such as arachidonic acid are indispensable components of innate immune signaling. Plasmalogens are glycerophospholipids with a vinyl ether bond in the sn-1 position of the glycerol backbone instead of the more common sn-1 ester bond present in “classical” glycerophospholipids. This kind of phospholipid is particularly rich in polyunsaturated fatty acids, especially arachidonic acid. In addition to or independently of the role of plasmalogens as major providers of free arachidonic acid for eicosanoid synthesis, plasmalogens also perform a varied number of functions. Membrane plasmalogen levels may determine parameters of the plasma membrane, such as fluidity and the formation of microdomains that are necessary for efficient signal transduction leading to optimal phagocytosis by macrophages. Also, plasmalogens may be instrumental for the execution of ferroptosis. This is a nonapoptotic form of cell death that is associated with oxidative stress. This review discusses recent data suggesting that, beyond their involvement in the cellular metabolism of arachidonic acid, the cells maintain stable pools of plasmalogens rich in polyunsaturated fatty acids for executing specific responses. Full article

(This article belongs to the Section Biomacromolecules: Lipids)

► Show Figures

Figure 1

Figure 1
Structure of membrane glycerophospholipids. Most glycerophospholipids contain a fatty acid esterified at the sn-1 position of the glycerol backbone (1-acyl-2-acyl-). However, some instead feature a fatty acid alcohol at the sn-1 position, creating an ether bond (1-O-alkyl-2-acyl-). A subset of these contains in addition a double bound conjugated with the ether oxygen, called a vinyl ether (1-O-alkenyl-2-acyl-). These are the plasmalogens. GPE, glycerophosphoethanolamine. Full article ">Figure 2
Dual role of AA-containing PC (AA-PC) in lipid signaling. The levels of AA within the PC class of phospholipids are influenced by two opposing reactions, resembling a tug-of-war. On the one hand, cytosolic phospholipase A2α (cPLA2α) acts on AA-PC to release free AA. On the other hand, coenzyme-A-independent transacylase (CoA-IT) transfers AA directly from PC to PE. By channeling AA from PC to PE, CoA-IT may effectively reduce the availability of substrate for cPLA2α, thereby limiting eicosanoid formation in activated macrophages. Full article ">Figure 3
Ferroptosis at a glance. This form of cell death, driven by iron, results from the accumulation of phospholipid peroxides, particularly those derived from PUFA-containing PE. These include (PUFA-OOH)PE, a hydroperoxide of PUFA-containing PE, and (PUFA-OO•)PE, a peroxyl radical of PUFA-containing PE. The significance of the CoA-IT pathway in enriching PE with AA derived from PC is also illustrated. For further details please refer to text. GSH, glutathione; GSSG, oxidized glutathione; LOX, lipoxygenase. Full article ">

Journal Description

Biomolecules

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI