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Biomolecules, Volume 14, Issue 11 (November 2024) – 139 articles

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50 pages, 3272 KiB  
Review
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
Viewed by 169
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
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25 pages, 3893 KiB  
Review
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
Viewed by 362
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)
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20 pages, 2485 KiB  
Article
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
Viewed by 353
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)
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15 pages, 4970 KiB  
Article
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
Viewed by 314
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)
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16 pages, 946 KiB  
Review
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
Viewed by 354
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)
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9 pages, 442 KiB  
Article
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
Viewed by 304
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
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18 pages, 4941 KiB  
Article
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
Viewed by 358
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)
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17 pages, 3880 KiB  
Article
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
Viewed by 421
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
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15 pages, 4295 KiB  
Article
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
Viewed by 330
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
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16 pages, 1504 KiB  
Article
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
Viewed by 388
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 (F2,17 = 34.059, p < 0.001, η2p = 0.88), the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (F2,17 = 35.597, p < 0.001, η2p = 0.80), and maximal fat oxidation (MFO) (F2,17 = 4.541, p = 0.026, η2p = 0.348) following the CT program. The maximal oxygen uptake (VO2max) 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
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15 pages, 1433 KiB  
Article
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
Viewed by 410
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)
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15 pages, 1880 KiB  
Article
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
Viewed by 444
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)
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15 pages, 1048 KiB  
Article
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
Viewed by 507
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)
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15 pages, 5537 KiB  
Article
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
Viewed by 457
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)
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16 pages, 745 KiB  
Review
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
Viewed by 389
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
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22 pages, 3741 KiB  
Article
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
Viewed by 436
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 (F1–3), 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 F1–3 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)
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26 pages, 1702 KiB  
Review
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
Viewed by 465
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)
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30 pages, 694 KiB  
Review
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
Viewed by 400
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)
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10 pages, 1517 KiB  
Perspective
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
Viewed by 433
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)
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21 pages, 3774 KiB  
Review
Aflatoxin Exposure-Caused Male Reproductive Toxicity: Molecular Mechanisms, Detoxification, and Future Directions
by Dongyun Ye, Zhihui Hao, Shusheng Tang, Tony Velkov and Chongshan Dai
Biomolecules 2024, 14(11), 1460; https://doi.org/10.3390/biom14111460 - 17 Nov 2024
Viewed by 701
Abstract
Widespread endocrine disorders and infertility caused by environmental and food pollutants have drawn considerable global attention. Aflatoxins (AFTs), a prominent class of mycotoxins, are recognized as one of the key contributors to environmental and food contamination. Aflatoxin B1 (AFB1) is [...] Read more.
Widespread endocrine disorders and infertility caused by environmental and food pollutants have drawn considerable global attention. Aflatoxins (AFTs), a prominent class of mycotoxins, are recognized as one of the key contributors to environmental and food contamination. Aflatoxin B1 (AFB1) is the most potent and toxic pollutant among them and is known to cause multiple toxic effects, including neuro-, nephro-, hepato-, immune-, and genotoxicity. Recently, concerns have been raised regarding AFB1-induced infertility in both animals and humans. Exposure to AFB1 can disrupt the structure and functionality of reproductive organs, leading to gametogenesis impairment in males, subsequently reducing fertility. The potential molecular mechanisms have been demonstrated to involve oxidative stress, cell cycle arrest, apoptosis, inflammatory responses, and autophagy. Furthermore, several signaling pathways, including nuclear factor erythroid 2-related factor 2; NOD-, LRR-, and pyrin domain-containing protein 3; nuclear factor kappa-B; p53; p21; phosphoinositide 3-kinase/protein kinase B; the mammalian target of rapamycin; adenosine 5′-monophosphate-activated protein kinase; and mitochondrial apoptotic pathways, are implicated in these processes. Various interventions, including the use of small molecules, Chinese herbal extracts, probiotic supplementation, and camel milk, have shown efficacy in ameliorating AFB1-induced male reproductive toxicity, by targeting these signaling pathways. This review provides a comprehensive summary of the harmful impacts of AFB1 exposure on male reproductive organs in mammals, highlighting the potential molecular mechanisms and protective agents. Full article
(This article belongs to the Section Molecular Reproduction)
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14 pages, 5781 KiB  
Perspective
Neuroradiological Findings in Cerebral Amyloid Angiopathy with a Particular Consideration of the Boston Criteria 2.0: An Imaging Review
by Ulf Jensen-Kondering, Katharina Heß, Alexander Neumann and Nils G. Margraf
Biomolecules 2024, 14(11), 1459; https://doi.org/10.3390/biom14111459 - 17 Nov 2024
Viewed by 480
Abstract
In the elderly, cerebral amyloid angiopathy (CAA) is the most common cause for intracranial lobar hemorrhages. CAA is caused by the accumulation of amyloid-β fibrils in cortical and leptomeningeal vessels. In 2022, the Boston Criteria 2.0 became the new diagnostic standard for CAA, [...] Read more.
In the elderly, cerebral amyloid angiopathy (CAA) is the most common cause for intracranial lobar hemorrhages. CAA is caused by the accumulation of amyloid-β fibrils in cortical and leptomeningeal vessels. In 2022, the Boston Criteria 2.0 became the new diagnostic standard for CAA, following the Modified Boston Criteria of 2010. The diagnostic criteria are a composite of clinical, imaging and histopathological findings. In the latest version of the Boston Criteria, neuroradiological imaging findings were even expanded compared to the previous version. Crucially, the correct application of the diagnostic criteria is necessary to avoid over- and underdiagnosis. The aim of this review is to demonstrate the diagnostic criteria for CAA with an emphasis on typical imaging findings which are part of the Boston Criteria 2.0 and other imaging findings suggestive of CAA. Full article
(This article belongs to the Special Issue The Role of Amyloid in Neurological Disorders)
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15 pages, 3020 KiB  
Article
Tumor-Colonizing E. coli Expressing Both Collagenase and Hyaluronidase Enhances Therapeutic Efficacy of Gemcitabine in Pancreatic Cancer Models
by Lara C. Avsharian, Suvithanandhini Loganathan, Nancy D. Ebelt, Azadeh F. Shalamzari, Itzel Rodarte Muñoz and Edwin R. Manuel
Biomolecules 2024, 14(11), 1458; https://doi.org/10.3390/biom14111458 - 17 Nov 2024
Viewed by 631
Abstract
Desmoplasia is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC) that contributes significantly to treatment resistance. Approaches to enhance drug delivery into fibrotic PDAC tumors continue to be an important unmet need. In this study, we have engineered a tumor-colonizing E. coli-based [...] Read more.
Desmoplasia is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC) that contributes significantly to treatment resistance. Approaches to enhance drug delivery into fibrotic PDAC tumors continue to be an important unmet need. In this study, we have engineered a tumor-colonizing E. coli-based agent that expresses both collagenase and hyaluronidase as a strategy to reduce desmoplasia and enhance the intratumoral perfusion of anticancer agents. Overall, we observed that the tandem expression of both these enzymes by tumor-colonizing E. coli resulted in the reduced presence of intratumoral collagen and hyaluronan, which likely contributed to the enhanced chemotherapeutic efficacy observed when used in combination. These results highlight the importance of combination treatments involving the depletion of desmoplastic components in PDAC before or during treatment. Full article
(This article belongs to the Special Issue Immune-Related Biomarkers: 2nd Edition)
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16 pages, 2037 KiB  
Article
Modulation of the Gut–Lung Axis by Water Kefir and Kefiran and Their Impact on Toll-like Receptor 3-Mediated Respiratory Immunity
by Stefania Dentice Maidana, Julio Nicolás Argañaraz Aybar, Leonardo Albarracin, Yoshiya Imamura, Luciano Arellano-Arriagada, Fu Namai, Yoshihito Suda, Keita Nishiyama, Julio Villena and Haruki Kitazawa
Biomolecules 2024, 14(11), 1457; https://doi.org/10.3390/biom14111457 - 17 Nov 2024
Viewed by 581
Abstract
The beneficial effect of milk kefir on respiratory heath has been previously demonstrated; however, water kefir and kefiran in the context of respiratory viral infections have not been investigated. Water kefir and kefiran could be alternatives to milk kefir for their application in [...] Read more.
The beneficial effect of milk kefir on respiratory heath has been previously demonstrated; however, water kefir and kefiran in the context of respiratory viral infections have not been investigated. Water kefir and kefiran could be alternatives to milk kefir for their application in persons with lactose intolerance or milk allergy and could be incorporated into vegan diets. Using mice models, this work demonstrated that the oral administration of water kefir or kefiran can modulate the respiratory Toll-like receptor (TLR3)-mediated innate antiviral immunity and improve the resistance to respiratory syncytial virus (RSV) infection. The treatment of mice with water kefir or kefiran for 6 days improved the production of interferons (IFN-β and IFN-γ) and antiviral factors (Mx2, OAS1, RNAseL, and IFITM3) in the respiratory tract after the activation of the TLR3 signaling pathway, differentially modulated the balance of pro- and anti-inflammatory cytokines, reduced RSV replication, and diminished lung tissue damage. Maintaining a proper balance between anti-inflammatory and pro-inflammatory mediators is vital for ensuring an effective and safe antiviral immune response, and the results of this work show that water kefir and kefiran would help to maintain that balance promoting a controlled inflammatory response that defends against infection while minimizing tissue damage. Full article
(This article belongs to the Section Natural and Bio-derived Molecules)
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18 pages, 4300 KiB  
Article
Angiotensin II Induces Vascular Endothelial Dysfunction by Promoting Lipid Peroxidation-Mediated Ferroptosis via CD36
by Qian Zhou, Ying Zhang, Wei Shi, Lu Lu, Jianglan Wei, Jinhan Wang, Hu Zhang, Yuepu Pu and Lihong Yin
Biomolecules 2024, 14(11), 1456; https://doi.org/10.3390/biom14111456 - 17 Nov 2024
Viewed by 432
Abstract
Angiotensin II (Ang II) is an effective vasoconstriction peptide, a major effector molecule of the renin–angiotensin–aldosterone system (RAAS) and one of the important causes of endothelial dysfunction. Ferroptosis is considered to be involved in the occurrence and development of cardiovascular diseases. This study [...] Read more.
Angiotensin II (Ang II) is an effective vasoconstriction peptide, a major effector molecule of the renin–angiotensin–aldosterone system (RAAS) and one of the important causes of endothelial dysfunction. Ferroptosis is considered to be involved in the occurrence and development of cardiovascular diseases. This study is dedicated to exploring the role and mechanism of Ang II-induced ferroptosis in HUVECs and to finding molecular targets for vascular endothelial injury and dysfunction during the progression of hypertension. In this study, we found that with the increase in exposure concentration, the intracellular ROS content and apoptosis rate increased significantly, the NO release decreased significantly in the medium- and high-concentration groups and the ET-1 content in the high-concentration group increased significantly. The expression of ZO-1 protein was significantly decreased in the high-concentration group. The expression of p-eNOS, VE-cadherin and Occludin protein showed a dose-dependent downward trend, while the ICAM-1 protein showed an upward trend. Ang II caused lipid metabolism disorders in HUVECs, and the PL–PUFAs associated with ferroptosis were significantly increased. In addition, Ang II promoted a significant increase in intracellular free Fe2+ content and MDA and a significant decrease in GSH content. Furthermore, the expression of GPX4, SLC7A11 and SLC3A2 was down-regulated, the expression of ACSL4, LPCAT3 and ALOX15 was up-regulated, and the ratio of p-cPLA2/cPLA2 was increased. After the intervention of ferroptosis inhibitor Fer-1, the injury and dysfunction of HUVECs induced by Ang II were significantly rescued. Immunofluorescence results showed that the expression of CD36 showed a significant increasing trend and was localized in the cytoplasm. Over-expression of CD36 promoted Ang II-induced ferroptosis and endothelial dysfunction. In conclusion, Ang II induces the injury of HUVECs, decreases vascular diastole and endothelial barrier-related molecules, and increases vascular constriction and adhesion-related molecules, which may be related to CD36 and its mediated lipid peroxidation and ferroptosis signals. Full article
(This article belongs to the Section Molecular Biology)
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15 pages, 4388 KiB  
Article
Exosomes from Human Periodontal Ligament Stem Cells Promote Differentiation of Osteoblast-like Cells and Bone Healing in Rat Calvarial Bone
by Mhd Safwan Albougha, Hideki Sugii, Orie Adachi, Bara Mardini, Serina Soeno, Sayuri Hamano, Daigaku Hasegawa, Shinichiro Yoshida, Tomohiro Itoyama, Junko Obata and Hidefumi Maeda
Biomolecules 2024, 14(11), 1455; https://doi.org/10.3390/biom14111455 - 17 Nov 2024
Viewed by 393
Abstract
Deep caries and severe periodontitis cause bone resorption in periodontal tissue, and severe bone resorption leads to tooth loss. Periodontal ligament stem cells (PDLSCs) are important for the healing of defective periodontal tissue. It is increasingly understood that healing of periodontal tissue is [...] Read more.
Deep caries and severe periodontitis cause bone resorption in periodontal tissue, and severe bone resorption leads to tooth loss. Periodontal ligament stem cells (PDLSCs) are important for the healing of defective periodontal tissue. It is increasingly understood that healing of periodontal tissue is mediated through the secretion of trophic factors, particularly exosomes. This study investigated the effects of exosomes from human PDLSCs (HPDLSCs-Exo) on human osteoblast-like cells in vitro and on the healing of rat calvarial bone defects in vivo. HPDLSCs-Exo were isolated and characterized by their particle shape, size (133 ± 6.4 nm), and expression of surface markers (CD9, CD63, and CD81). In vitro results showed that HPDLSCs-Exo promoted the migration, mineralization, and expression of bone-related genes such as alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), osteocalcin (OCN), and osteopontin (OPN) in human osteoblast-like cells. Furthermore, in vivo results showed that more newly formed bone was observed in the HPDLSCs-Exo-treated group than in the non-treated group at the defect sites in rats. These results indicated that HPDLSCs-Exo could promote osteogenesis in vitro and in vivo, and this suggests that HPDLSCs-Exo may be an attractive treatment tool for bone healing in defective periodontal tissue. Full article
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23 pages, 4043 KiB  
Article
Chaga Mushroom Triterpenoids Inhibit Dihydrofolate Reductase and Act Synergistically with Conventional Therapies in Breast Cancer
by Junbiao Wang, Daniela Beghelli, Augusto Amici, Stefania Sut, Stefano Dall’Acqua, Giulio Lupidi, Diego Dal Ben, Onelia Bistoni, Daniele Tomassoni, Barbara Belletti, Sanaa Musa, Jamal Mahajna, Stefania Pucciarelli and Cristina Marchini
Biomolecules 2024, 14(11), 1454; https://doi.org/10.3390/biom14111454 - 17 Nov 2024
Viewed by 351
Abstract
Inonotus obliquus (Chaga) is a medicinal mushroom with several pharmacological properties that is used as a tea in traditional Chinese medicine. In this study, Chaga water extract was digested in vitro to mimic the natural processing and absorption of its biocomponents when it [...] Read more.
Inonotus obliquus (Chaga) is a medicinal mushroom with several pharmacological properties that is used as a tea in traditional Chinese medicine. In this study, Chaga water extract was digested in vitro to mimic the natural processing and absorption of its biocomponents when it is consumed as functional beverage, and its anticancer activities were evaluated in breast cancer (BC) cell lines, representing HER2-positive and triple-negative subtypes. After chemical characterization by liquid chromatography/mass spectrometry (HR-QTOF) analysis, the effect of Chaga biocomponents on cell viability and cell cycle progression was assessed by MTT assay, FACS analysis, and Western blot. Dihydrofolate reductase (DHFR) activity was measured by an enzymatic assay. Four highly bioactive triterpenoids (inotodiol, trametenolic acid, 3-hydroxy-lanosta-8,24-dien-21-al, and betulin) were identified as the main components, able to decrease BC cell viability and block the cell cycle in G0/G1 by inducing the downregulation of cyclin D1, CDK4, cyclin E, and phosphorylated retinoblastoma protein. DHFR was identified as their crucial target. Moreover, bioactive Chaga components exerted a synergistic action with cisplatin and with trastuzumab in SK-BR-3 cells by inhibiting both HER2 and HER1 activation and displayed an immunomodulatory effect. Thus, Inonotus obliquus represents a source of triterpenoids that are effective against aggressive BC subtypes and display properties of targeted drugs. Full article
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9 pages, 2102 KiB  
Communication
Tissue-Specific Effects of Aging on Repeat-Mediated Mutation Hotspots In Vivo
by Alexandra M. D’Amico, Tonia T. Li and Karen M. Vasquez
Biomolecules 2024, 14(11), 1453; https://doi.org/10.3390/biom14111453 - 16 Nov 2024
Viewed by 281
Abstract
Aging constitutes complex and dynamic alterations in molecular and physiological processes and is associated with numerous disorders, in part due to increased genetic instability. The aging population is projected to double by 2050, underscoring the urgent need to better understand the relationships between [...] Read more.
Aging constitutes complex and dynamic alterations in molecular and physiological processes and is associated with numerous disorders, in part due to increased genetic instability. The aging population is projected to double by 2050, underscoring the urgent need to better understand the relationships between aging and age-related disorders. Repetitive DNA elements are intrinsic sources of genetic instability and have been found to co-localize with mutation hotspots in human cancer genomes. In this study, we explored the relationship between aging and DNA repeat-mediated genetic instability in vivo using an H-DNA-forming mirror-repeat sequence from the cancer-associated human c-MYC gene. Utilizing a unique mutation-reporter mouse model, we observed tissue-specific effects of aging on H-DNA-induced genetic instability, with mutation frequencies increasing in spleen tissues and remaining unchanged in testis tissues. Analysis of the mutation spectra revealed large deletion mutations as the primary contributor to increasing H-DNA-induced mutations, supported by increased cleavage activity of H-DNA structures in aged spleen tissues. Our findings demonstrate that aging has distinct tissue-specific effects on repeat-mediated, cancer-associated mutations, providing insights into the complex relationship between aging and cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms in DNA and RNA Damage and Repair)
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25 pages, 1595 KiB  
Review
Targeting the mTOR-Autophagy Axis: Unveiling Therapeutic Potentials in Osteoporosis
by Rongjin Chen, Chenhui Yang, Fei Yang, Ao Yang, Hefang Xiao, Bo Peng, Changshun Chen, Bin Geng and Yayi Xia
Biomolecules 2024, 14(11), 1452; https://doi.org/10.3390/biom14111452 - 15 Nov 2024
Viewed by 587
Abstract
Osteoporosis (OP) is a widespread age-related disorder marked by decreased bone density and increased fracture risk, presenting a significant public health challenge. Central to the development and progression of OP is the dysregulation of the mechanistic target of the rapamycin (mTOR)-signaling pathway, which [...] Read more.
Osteoporosis (OP) is a widespread age-related disorder marked by decreased bone density and increased fracture risk, presenting a significant public health challenge. Central to the development and progression of OP is the dysregulation of the mechanistic target of the rapamycin (mTOR)-signaling pathway, which plays a critical role in cellular processes including autophagy, growth, and proliferation. The mTOR-autophagy axis is emerging as a promising therapeutic target due to its regulatory capacity in bone metabolism and homeostasis. This review aims to (1) elucidate the role of mTOR signaling in bone metabolism and its dysregulation in OP, (2) explore the interplay between mTOR and autophagy in the context of bone cell activity, and (3) assess the therapeutic potential of targeting the mTOR pathway with modulators as innovative strategies for OP treatment. By examining the interactions among autophagy, mTOR, and OP, including insights from various types of OP and the impact on different bone cells, this review underscores the complexity of mTOR’s role in bone health. Despite advances, significant gaps remain in understanding the detailed mechanisms of mTOR’s effects on autophagy and bone cell function, highlighting the need for comprehensive clinical trials to establish the efficacy and safety of mTOR inhibitors in OP management. Future research directions include clarifying mTOR’s molecular interactions with bone metabolism and investigating the combined benefits of mTOR modulation with other therapeutic approaches. Addressing these challenges is crucial for developing more effective treatments and improving outcomes for individuals with OP, thereby unveiling the therapeutic potentials of targeting the mTOR-autophagy axis in this prevalent disease. Full article
(This article belongs to the Section Molecular Biology)
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15 pages, 1853 KiB  
Article
Assessing the Impact of Bedaquiline, Clofazimine, and Linezolid on Mycobacterial Genome Integrity
by Dániel Molnár, Éva Viola Surányi, Nikoletta Gálik, Judit Tóth and Rita Hirmondó
Biomolecules 2024, 14(11), 1451; https://doi.org/10.3390/biom14111451 - 15 Nov 2024
Viewed by 432
Abstract
Tuberculosis (TB) presents significant medical challenges, largely due to the genetic diversity of Mycobacterium tuberculosis, which enhances the resilience and resistance of the pathogen to first-line treatments. In response to the global rise of drug-resistant TB, second-line antitubercular drugs like bedaquiline (BDQ), [...] Read more.
Tuberculosis (TB) presents significant medical challenges, largely due to the genetic diversity of Mycobacterium tuberculosis, which enhances the resilience and resistance of the pathogen to first-line treatments. In response to the global rise of drug-resistant TB, second-line antitubercular drugs like bedaquiline (BDQ), linezolid (LZD), and clofazimine (CFZ) have become critical treatment options. Understanding the molecular changes these drugs induce is essential for optimizing TB therapy. To contribute to this effort, we investigated their impact on genome maintenance and stability using Mycobacterium smegmatis as a model organism. Using mutation accumulation assays and whole-genome sequencing, we found that the second-line antibiotics did not significantly increase mutation rates, unlike the positive control UV treatment. However, upon BDQ treatment, we detected mutations in transporter proteins and transcription factors without any increase in the minimal inhibitory concentration. Additionally, BDQ and CFZ were found to alter DNA repair pathways and reduce cellular dNTP levels, particularly CFZ, which depleted dGTP, impacting DNA synthesis. CFZ also upregulated DNA repair enzymes, enhancing error-free repairs. Despite minimal mutagenic effects, both drugs displayed distinct impacts on cellular mechanisms, suggesting additional modes of action. Full article
(This article belongs to the Section Molecular Genetics)
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16 pages, 10975 KiB  
Article
Copy Number Variants in Cardiac Channelopathies: Still a Missed Part in Routine Arrhythmic Diagnostics
by Maria Gnazzo, Giovanni Parlapiano, Francesca Di Lorenzo, Daniele Perrino, Silvia Genovese, Valentina Lanari, Daniela Righi, Federica Calì, Massimo Stefano Silvetti, Elena Falcone, Alessia Bauleo, Fabrizio Drago, Antonio Novelli and Anwar Baban
Biomolecules 2024, 14(11), 1450; https://doi.org/10.3390/biom14111450 - 15 Nov 2024
Viewed by 348
Abstract
Inherited cardiac channelopathies are major causes of sudden cardiac death (SCD) in young people. Genetic testing is focused on the identification of single-nucleotide variants (SNVs) by Next-Generation Sequencing (NGS). However, genetically elusive cases can carry copy number variants (CNVs), which need specific detection [...] Read more.
Inherited cardiac channelopathies are major causes of sudden cardiac death (SCD) in young people. Genetic testing is focused on the identification of single-nucleotide variants (SNVs) by Next-Generation Sequencing (NGS). However, genetically elusive cases can carry copy number variants (CNVs), which need specific detection tools. We underlie the utility of identifying CNVs by investigating the literature data and internally analyzing cohorts with CNVs in KCNQ1, KCNH2, SCN5A, and RYR2. CNVs were reported in 119 patients from the literature and 21 from our cohort. Young patients with CNVs in KCNQ1 show a Long QT (LQT) phenotype > 480 ms and a higher frequency of syncope. None of them had SCD. All patients with CNV in KCNH2 had a positive phenotype for QT > 480 ms. CNVs in SCN5A were represented by the Brugada pattern, with major cardiac events mainly in males. Conversely, adult females show more supraventricular arrhythmias. RYR2-exon3 deletion showed a broader phenotype, including left ventricular non-compaction (LVNC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Pediatric patients showed atrial arrhythmias and paroxysmal atrial fibrillation. Relatively higher syncope and SCA were observed in young females. The detection of CNVs can be of greater yield in two groups: familial channelopathies and patients with suspected Jervell and Lange-Nielsen syndrome or CPVT. The limited number of reported individuals makes it mandatory for multicentric studies to give future conclusive results. Full article
(This article belongs to the Section Molecular Genetics)
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