Biomolecules

23 pages, 1332 KiB

Open AccessReview

Gut Microbiota Modulation: A Novel Strategy for Rheumatoid Arthritis Therapy

by Vitaly Chasov, Elvina Gilyazova, Irina Ganeeva, Ekaterina Zmievskaya, Damir Davletshin, Aygul Valiullina and Emil Bulatov

Biomolecules 2024, 14(12), 1653; https://doi.org/10.3390/biom14121653 - 23 Dec 2024

Viewed by 933

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint inflammation, progressive tissue damage and significant disability, severely impacting patients’ quality of life. While the exact mechanisms underlying RA remain elusive, growing evidence suggests a strong link between intestinal microbiota dysbiosis [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint inflammation, progressive tissue damage and significant disability, severely impacting patients’ quality of life. While the exact mechanisms underlying RA remain elusive, growing evidence suggests a strong link between intestinal microbiota dysbiosis and the disease’s development and progression. Differences in microbial composition between healthy individuals and RA patients point to the role of gut microbiota in modulating immune responses and promoting inflammation. Therapies targeting microbiota restoration have demonstrated promise in improving treatment efficacy, enhancing patient outcomes and slowing disease progression. However, the complex interplay between gut microbiota and autoimmune pathways in RA requires further investigation to establish causative relationships and mechanisms. Here, we review the current understanding of the gut microbiota’s role in RA pathogenesis and its potential as a therapeutic target. Full article

(This article belongs to the Special Issue Prebiotics and Probiotics in Health and Disease: Looking at the Future)

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13 pages, 918 KiB

Open AccessReview

Charge Movements and Conformational Changes: Biophysical Properties and Physiology of Voltage-Dependent GPCRs

by Andreas Rinne and Moritz Bünemann

Biomolecules 2024, 14(12), 1652; https://doi.org/10.3390/biom14121652 - 23 Dec 2024

Viewed by 841

Abstract

G protein-coupled receptors (GPCRs) regulate multiple cellular functions and represent important drug targets. More than 20 years ago, it was noted that GPCR activation (agonist binding) and signaling (G protein activation) are dependent on the membrane potential (V_M). While it is [...] Read more.

G protein-coupled receptors (GPCRs) regulate multiple cellular functions and represent important drug targets. More than 20 years ago, it was noted that GPCR activation (agonist binding) and signaling (G protein activation) are dependent on the membrane potential (V_M). While it is now proven that many GPCRs display an intrinsic voltage dependence, the molecular mechanisms of how GPCRs sense depolarization of the plasma membrane are less well defined. This review summarizes the current knowledge of voltage-dependent signaling in GPCRs. We describe how voltage dependence was discovered in muscarinic receptors, present an overview of GPCRs that are regulated by voltage, and show how biophysical properties of GPCRs led to the discovery of voltage-sensing mechanisms in those receptors. Furthermore, we summarize physiological functions that have been shown to be regulated by voltage-dependent GPCR signaling of endogenous receptors in excitable tissues, such as the nervous system or the heart. Finally, we discuss challenges that remain in analyzing voltage-dependent signaling of GPCRs in vivo and present an outlook on experimental applications of the interesting concept of GPCR signaling. Full article

(This article belongs to the Special Issue Advances in Cellular Biophysics: Transport and Mechanics)

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18 pages, 6081 KiB

Open AccessArticle

PLGA-Nano-Encapsulated Disulfiram Inhibits Cancer Stem Cells and Targets Non-Small Cell Lung Cancer In Vitro and In Vivo

by Kate Butcher, Zhipeng Wang, Sathishkumar Kurusamy, Zaixing Zhang, Mark R. Morris, Mohammad Najlah, Christopher McConville, Vinodh Kannappan and Weiguang Wang

Biomolecules 2024, 14(12), 1651; https://doi.org/10.3390/biom14121651 - 23 Dec 2024

Viewed by 759

Abstract

Cancer stem cells (CSCs) play a key role in non-small cell lung cancer (NSCLC) chemoresistance and metastasis. In this study, we used two NSCLC cell lines to investigate the regulating effect of hypoxia in the induction and maintenance of CSC traits. Our study [...] Read more.

Cancer stem cells (CSCs) play a key role in non-small cell lung cancer (NSCLC) chemoresistance and metastasis. In this study, we used two NSCLC cell lines to investigate the regulating effect of hypoxia in the induction and maintenance of CSC traits. Our study demonstrated hypoxia-induced stemness and chemoresistance at levels comparable to those in typical CSC sphere culture. Activation of the NF-κB pathway (by transfection of NF-κB-p65) plays a key role in NSCLC CSCs and chemoresistance. Disulfiram (DS), an anti-alcoholism drug, showed a strong in vitro anti-CSC effect. It blocked cancer cell sphere reformation and clonogenicity, synergistically enhanced the cytotoxicity of four anti-NSCLC drugs (doxorubicin, gemcitabine, oxaliplatin and paclitaxel) and reversed hypoxia-induced resistance. The effect of DS on CSCs is copper-dependent. A very short half-life in the bloodstream is the major limitation for the translation of DS into a cancer treatment. Our team previously developed a poly lactic-co-glycolic acid (PLGA) nanoparticle encapsulated DS (DS-PLGA) with a long half-life in the bloodstream. Intra venous injection of DS-PLGA in combination with the oral application of copper gluconate has strong anticancer efficacy in a metastatic NSCLC mouse model. Further study may be able to translate DS-PLGA into cancer applications. Full article

(This article belongs to the Special Issue Bioactive Molecules: Structures, Functions and Potential Uses for Cancer Prevention and Targeted Therapies (2nd Edition))

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16 pages, 13174 KiB

Open AccessArticle

MicroRNA-150 Deletion from Adult Myofibroblasts Augments Maladaptive Cardiac Remodeling Following Chronic Myocardial Infarction

by Satoshi Kawaguchi, Marisa N. Sepúlveda, Jian-peng Teoh, Taiki Hayasaka, Bruno Moukette, Tatsuya Aonuma, Hyun Cheol Roh, Meena S. Madhur and Il-man Kim

Biomolecules 2024, 14(12), 1650; https://doi.org/10.3390/biom14121650 - 22 Dec 2024

Viewed by 782

Abstract

MicroRNA (miR: small noncoding RNA)-150 is evolutionarily conserved and is downregulated in patients with diverse forms of heart failure (HF) and in multiple mouse models of HF. Moreover, miR-150 is markedly correlated with the outcome of patients with HF. We previously reported that [...] Read more.

MicroRNA (miR: small noncoding RNA)-150 is evolutionarily conserved and is downregulated in patients with diverse forms of heart failure (HF) and in multiple mouse models of HF. Moreover, miR-150 is markedly correlated with the outcome of patients with HF. We previously reported that systemic or cardiomyocyte-derived miR-150 in mice elicited myocardial protection through the inhibition of cardiomyocyte death, without affecting neovascularization and T cell infiltration. Our mechanistic studies also showed that the protective roles of miR-150 in ischemic mouse hearts and human cardiac fibroblasts were, in part, attributed to the inhibition of fibroblast activation via the repression of multiple profibrotic genes. However, the extent to which miR-150 expression in adult myofibroblasts (MFs) modulates the response to myocardial infarction (MI) remains unknown. Here, we develop a novel 4-hydroxytamoxifen-inducible MF-specific miR-150 conditional knockout mouse model and demonstrate that the mouse line exhibits worse cardiac dysfunction after MI. Our studies further reveal that miR-150 ablation selectively in adult MFs exacerbates cardiac damage and apoptosis after chronic MI. Lastly, MF-specific miR-150 deletion in adult mice promotes the expression of proinflammatory and profibrotic genes as well as cardiac fibrosis following chronic MI. Our findings indicate a key protective role for MF-derived miR-150 in modulating post-MI responses. Full article

(This article belongs to the Special Issue Heart Diseases: Molecular Mechanisms and New Therapies)

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15 pages, 1125 KiB

Open AccessReview

Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson’s Disease

by Lydia Shen and Ulf Dettmer

Biomolecules 2024, 14(12), 1649; https://doi.org/10.3390/biom14121649 - 22 Dec 2024

Cited by 1 | Viewed by 1014

Abstract

The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy (mitophagy). Mitochondrial dysfunction is critically implicated in Parkinson’s disease (PD), a brain disorder characterized by the progressive [...] Read more.

The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy (mitophagy). Mitochondrial dysfunction is critically implicated in Parkinson’s disease (PD), a brain disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Consequently, impaired mitochondrial quality control may play a key role in PD pathology. This is affirmed by work indicating that genes such as PRKN and PINK1, which participate in multiple mitochondrial processes, harbor PD-associated mutations. Furthermore, mitochondrial complex-I-inhibiting toxins like MPTP and rotenone are known to cause Parkinson-like symptoms. At the heart of PD is alpha-synuclein (αS), a small synaptic protein that misfolds and aggregates to form the disease’s hallmark Lewy bodies. The specific mechanisms through which aggregated αS exerts its neurotoxicity are still unknown; however, given the vital role of both αS and mitochondria to PD, an understanding of how αS influences mitochondrial maintenance may be essential to elucidating PD pathogenesis and discovering future therapeutic targets. Here, the current knowledge of the relationship between αS and mitochondrial quality control pathways in PD is reviewed, highlighting recent findings regarding αS effects on mitochondrial biogenesis, dynamics, and autophagy. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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18 pages, 5290 KiB

Open AccessArticle

Serum T2-High Inflammation Mediators in Eosinophilic COPD

by Andrius Januskevicius, Egle Vasyle, Airidas Rimkunas, Jolita Palacionyte, Virginija Kalinauskaite-Zukauske and Kestutis Malakauskas

Biomolecules 2024, 14(12), 1648; https://doi.org/10.3390/biom14121648 - 21 Dec 2024

Viewed by 742

Abstract

Eosinophils are central inflammatory cells in asthma; however, a portion of patients with chronic obstructive pulmonary disease (COPD) have blood or sputum eosinophilia, a condition termed eosinophilic COPD (eCOPD), which may contribute to the progression of the disease. We hypothesize that eosinophilic inflammation [...] Read more.

Eosinophils are central inflammatory cells in asthma; however, a portion of patients with chronic obstructive pulmonary disease (COPD) have blood or sputum eosinophilia, a condition termed eosinophilic COPD (eCOPD), which may contribute to the progression of the disease. We hypothesize that eosinophilic inflammation in eCOPD patients is related to Type 2 (T2)-high inflammation seen in asthma and that serum mediators might help us to identify T2-high inflammation in patients and choose an appropriate personalized treatment strategy. Thus, we aimed to investigate ten serum levels of T2-high inflammation mediators in eCOPD patients and compare them to severe non-allergic eosinophilic asthma (SNEA) patients. We included 8 subjects with eCOPD, 10 with SNEA, and 11 healthy subjects (HS) as a control group. The concentrations of biomarkers in serum samples were analyzed using an enzyme-linked immunosorbent assay (ELISA). In this study, we found that eCOPD patients were distinguished from SNEA patients by elevated serum levels of sIL-5Rα, MET, TRX1, ICTP, and IL-4, as well as decreased serum levels of eotaxin-1 and sFcεRI. Moreover, MET, ICTP, eotaxin-1, and sFcεRI demonstrated high sensitivity and specificity as potential biomarkers for eCOPD patients. Furthermore, serum levels of IL-5 and IL-25 in combination with sIL-5Rα, MET, and IL-4 demonstrated a high value in identifying T2-high inflammation in eCOPD patients. In conclusion, this study highlights that while T2-high inflammation drives eosinophilic inflammation in both eCOPD and SNEA through similar mechanisms, the distinct expression of its mediators reflects an imbalance between T1 and T2 inflammation pathways in eCOPD patients. A combined analysis of serum mediators may aid in identifying T2-high inflammation in eCOPD patients and in selecting an appropriate personalized treatment strategy. Full article

(This article belongs to the Special Issue The Immune System and Allergies)

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20 pages, 669 KiB

Open AccessReview

Binding Molecules in Tick Saliva for Targeting Host Cytokines, Chemokines, and Beyond

by Chamberttan Souza Desidério, Victor Hugo Palhares Flávio-Reis, Yago Marcos Pessoa-Gonçalves, Rafael Destro Rosa Tiveron, Helioswilton Sales-Campos, Andrei Giacchetto Felice, Siomar de Castro Soares, Rhainer Guillermo-Ferreira, Wellington Francisco Rodrigues and Carlo José Freire Oliveira

Biomolecules 2024, 14(12), 1647; https://doi.org/10.3390/biom14121647 - 21 Dec 2024

Viewed by 801

Abstract

Ticks have coevolved with their hosts over millions of years, developing the ability to evade hemostatic, inflammatory, and immunological responses. Salivary molecules from these vectors bind to cytokines, chemokines, antibodies, complement system proteins, vasodilators, and molecules involved in coagulation and platelet aggregation, among [...] Read more.

Ticks have coevolved with their hosts over millions of years, developing the ability to evade hemostatic, inflammatory, and immunological responses. Salivary molecules from these vectors bind to cytokines, chemokines, antibodies, complement system proteins, vasodilators, and molecules involved in coagulation and platelet aggregation, among others, inhibiting or blocking their activities. Initially studied to understand the complexities of tick–host interactions, these molecules have been more recently recognized for their potential clinical applications. Their ability to bind to soluble molecules and modulate important physiological systems, such as immunity, hemostasis, and coagulation, positions them as promising candidates for future therapeutic development. This review aims to identify the binding molecules present in tick saliva, determine their primary targets, and explore the tick species involved in these processes. By associating the binding molecules, the molecules to which they bind, and the effect caused, the review provides a basis for understanding how these molecules can contribute to possible future advances in clinical applications. Full article

(This article belongs to the Special Issue Cytokine Signaling in Immunity and Immune Cell-Mediated Diseases)

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23 pages, 2645 KiB

Open AccessReview

Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy

by Zhi-Nan Hao, Xiao-Ping Tan, Qing Zhang, Jie Li, Ruohan Xia and Zhaowu Ma

Biomolecules 2024, 14(12), 1646; https://doi.org/10.3390/biom14121646 - 21 Dec 2024

Viewed by 1317

Abstract

Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8⁺ T cell functionality and by [...] Read more.

Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8⁺ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies. Full article

(This article belongs to the Section Molecular Biology)

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28 pages, 8683 KiB

Open AccessArticle

Suppression of MT5-MMP Reveals Early Modulation of Alzheimer’s Pathogenic Events in Primary Neuronal Cultures of 5xFAD Mice

by Dominika Pilat, Jean-Michel Paumier, Laurence Louis, Christine Manrique, Laura García-González, Delphine Stephan, Anne Bernard, Raphaëlle Pardossi-Piquard, Frédéric Checler, Michel Khrestchatisky, Eric Di Pasquale, Kévin Baranger and Santiago Rivera

Biomolecules 2024, 14(12), 1645; https://doi.org/10.3390/biom14121645 - 21 Dec 2024

Viewed by 704

Abstract

We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer’s disease (AD) in 5xFAD (Tg) mice in vivo but also impairs interleukin-1 beta (IL-1β)-mediated neuroinflammation and Aβ production in primary Tg immature neural cell cultures after 11 days [...] Read more.

We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer’s disease (AD) in 5xFAD (Tg) mice in vivo but also impairs interleukin-1 beta (IL-1β)-mediated neuroinflammation and Aβ production in primary Tg immature neural cell cultures after 11 days in vitro. We now investigate the effect of MT5-MMP on incipient pathogenic pathways that are activated in cortical primary cultures at 21–24 days in vitro (DIV), during which time neurons are organized into a functional mature network. Using wild-type (WT), MT5-MMP^−/− (MT5^−/−), 5xFAD (Tg), and 5xFADxMT5-MMP^−/− (TgMT5^−/−) mice, we generated primary neuronal cultures that were exposed to IL-1β and/or different proteolytic system inhibitors. We assessed neuroinflammation, APP metabolism, synaptic integrity, and electrophysiological properties using biochemical, imaging and whole-cell patch-clamp approaches. The absence of MT5-MMP impaired the IL-1β-mediated induction of inflammatory genes in TgMT5^−/− cells compared to Tg cells. Furthermore, the reduced density of dendritic spines in Tg neurons was also prevented in TgMT5^−/− neurons. IL-1β caused a strong decrease in the dendritic spine density of WT neurons, which was prevented in MT5^−/− neurons. However, the latter exhibited fewer spines than the WT under untreated conditions. The spontaneous rhythmic firing frequency of the network was increased in MT5^−/− neurons, but not in TgMT5^−/− neurons, and IL-1β increased this parameter only in Tg neurons. In terms of induced somatic excitability, Tg and TgMT5^−/− neurons exhibited lower excitability than WT and MT5^−/−, while IL-1β impaired excitability only in non-AD backgrounds. The synaptic strength of miniature global synaptic currents was equivalent in all genotypes but increased dramatically in WT and MT5^−/− neurons after IL-1β. MT5-MMP deficiency decreased endogenous and overexpressed C83 and C99 levels but did not affect Aβ levels. C99 appears to be cleared by several pathways, including γ-secretase, the autophagolysosomal system, and also α-secretase, via its conversion to C83. In summary, this study confirms that MT5-MMP is a pivotal factor affecting not only neuroinflammation and APP metabolism but also synaptogenesis and synaptic activity at early stages of the pathology, and reinforces the relevance of targeting MT5-MMP to fight AD. Full article

(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Health and Disease)

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12 pages, 4468 KiB

Open AccessArticle

Characterization of the Interaction of Human γS Crystallin with Metal Ions and Its Effect on Protein Aggregation

by Reinier Cardenas, Arline Fernandez-Silva, Vanesa Ramirez-Bello and Carlos Amero

Biomolecules 2024, 14(12), 1644; https://doi.org/10.3390/biom14121644 - 21 Dec 2024

Viewed by 580

Abstract

Cataracts are diseases characterized by the opacity of the ocular lens and the subsequent deterioration of vision. Metal ions are one of the factors that have been reported to induce crystallin aggregation. For HγS crystallin, several equivalent ratios of Cu(II) promote protein aggregation. [...] Read more.

Cataracts are diseases characterized by the opacity of the ocular lens and the subsequent deterioration of vision. Metal ions are one of the factors that have been reported to induce crystallin aggregation. For HγS crystallin, several equivalent ratios of Cu(II) promote protein aggregation. However, reports on zinc are contradictory. To characterize the process of metal ion binding and subsequent HγS crystallin aggregation, we performed dynamic light scattering, turbidimetry, isothermal titration calorimetry, fluorescence, and nuclear magnetic resonance experiments. The data show that both metal ions have multiple binding sites and promote aggregation. Zinc interacts mainly with the N-terminal domain, inducing small conformational changes, while copper interacts with both domains and induces unfolding, exposing the tryptophan residues to the solvent. Our work provides insight into the mechanisms of metal-induced aggregation at one of the lowest doses that appreciably promote aggregation over time. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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Graphical abstract

32 pages, 2635 KiB

Open AccessReview

The Role of Gut Microbiome in Irritable Bowel Syndrome: Implications for Clinical Therapeutics

by Yucui Zhao, Shixiao Zhu, Yingling Dong, Tian Xie, Zhiqiang Chai, Xiumei Gao, Yongna Dai and Xiaoying Wang

Biomolecules 2024, 14(12), 1643; https://doi.org/10.3390/biom14121643 - 21 Dec 2024

Viewed by 1530

Abstract

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by chronic or recurrent gastrointestinal symptoms without organic changes, and it is also a common disorder of gut–brain interaction (DGBIs).. The symptoms of IBS not only affect the quality of life for [...] Read more.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by chronic or recurrent gastrointestinal symptoms without organic changes, and it is also a common disorder of gut–brain interaction (DGBIs).. The symptoms of IBS not only affect the quality of life for individual patients but also place a significant burden on global healthcare systems. The lack of established and universally applicable biomarkers for IBS, along with the substantial variability in symptoms and progression, presents challenges in developing effective clinical treatments. In recent years, preclinical and clinical studies have linked the pathogenesis of IBS to alterations in the composition and function of the intestinal microbiota. Within the complex microbial community of the gut, intricate metabolic and spatial interactions occur among its members and between microbes and their hosts. Amid the multifaceted pathophysiology of IBS, the role of intestinal microenvironment factors in symptom development has become more apparent. This review aims to delve into the changes in the composition and structure of the gut microbiome in individuals with IBS. It explores how diet-mediated alterations in intestinal microbes and their byproducts play a role in regulating the pathogenesis of IBS by influencing the “brain-gut” axis, intestinal barrier function, immune responses, and more. By doing so, this review seeks to lay a theoretical foundation for advancing the development of clinical therapeutics for IBS. Full article

(This article belongs to the Section Molecular Medicine)

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13 pages, 2192 KiB

Open AccessArticle

Gramicidin A in Asymmetric Lipid Membranes

by Oleg V. Kondrashov and Sergey A. Akimov

Biomolecules 2024, 14(12), 1642; https://doi.org/10.3390/biom14121642 - 20 Dec 2024

Viewed by 757

Abstract

Gramicidin A is a natural antimicrobial peptide produced by Bacillus brevis. Its transmembrane dimer is a cation-selective ion channel. The channel is characterized by the average lifetime of the conducting state and the monomer–dimer equilibrium constant. Dimer formation is accompanied by deformations [...] Read more.

Gramicidin A is a natural antimicrobial peptide produced by Bacillus brevis. Its transmembrane dimer is a cation-selective ion channel. The channel is characterized by the average lifetime of the conducting state and the monomer–dimer equilibrium constant. Dimer formation is accompanied by deformations of the membrane. We theoretically studied how the asymmetry in lipid membrane monolayers influences the formation of the gramicidin A channel. We calculated how the asymmetry in the spontaneous curvature and/or lateral tension of lipid monolayers changes the channel lifetime and shifts the equilibrium constant of the dimerization/dissociation process. For the asymmetry expected to arise in plasma membranes of mammalian cells upon the addition of gramicidin A or its derivatives to the cell exterior, our model predicts a manifold increase in the average lifetime and equilibrium constant. Full article

(This article belongs to the Section Molecular Biophysics)

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14 pages, 2426 KiB

Open AccessArticle

Identifying Hub Genes and miRNAs Associated with Alzheimer’s Disease: A Bioinformatics Pathway to Novel Therapeutic Strategies

by Elisa Gascón, Ana Cristina Calvo, Nora Molina, Pilar Zaragoza and Rosario Osta

Biomolecules 2024, 14(12), 1641; https://doi.org/10.3390/biom14121641 - 20 Dec 2024

Viewed by 835

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects the elderly population. It is characterized by cognitive impairment and dementia due to abnormal levels of amyloid beta peptide (Aβ) and axonal Tau protein in the brain. However, the complex underlying mechanisms affecting [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects the elderly population. It is characterized by cognitive impairment and dementia due to abnormal levels of amyloid beta peptide (Aβ) and axonal Tau protein in the brain. However, the complex underlying mechanisms affecting this disease are not yet known, and there is a lack of standardized biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, AD-affected brain tissue was analyzed using the GSE138260 dataset, identifying 612 differentially expressed genes (DEGs). Functional analysis revealed 388 upregulated DEGs associated with sensory perception and 224 downregulated DEGs linked to the regulation and modulation of synaptic processes. Protein–protein interaction network analysis identified 20 hub genes. Furthermore, miRNA target gene networks revealed 1767 miRNAs linked to hub genes, among which hsa-mir-106a-5p, hsa-mir-17-5p, hsa-mir-26a-5p, hsa-mir-27a-3p and hsa-mir-34a-5p were the most relevant. This study presents novel biomarkers and therapeutic targets for AD by analyzing the information obtained with a comprehensive literature review, providing new potential targets to study their role in AD. Full article

(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)

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17 pages, 6802 KiB

Open AccessArticle

The Effect of Tyre and Road Wear Particles on the Terrestrial Isopod Armadillidium pallasii

by Giorgia Torreggiani, Chiara Manfrin, Anita Giglio, Andrea Dissegna, Cinzia Chiandetti, Paola Giotta, Monia Renzi, Serena Anselmi, Tecla Bentivoglio, Agnieszka Babczyńska, Silvia Battistella, Paolo Edomi and Piero G. Giulianini

Biomolecules 2024, 14(12), 1640; https://doi.org/10.3390/biom14121640 - 20 Dec 2024

Viewed by 707

Abstract

(1) Car tyre microplastic particles (TMPs) significantly contribute to global microplastic pollution, with an estimated annual production of 6 million tonnes. However, the impact of TMPs, particularly tyre and road wear particles (TRWPs), resulting from tyre abrasion on the road on terrestrial organisms, [...] Read more.

(1) Car tyre microplastic particles (TMPs) significantly contribute to global microplastic pollution, with an estimated annual production of 6 million tonnes. However, the impact of TMPs, particularly tyre and road wear particles (TRWPs), resulting from tyre abrasion on the road on terrestrial organisms, is poorly understood. This study investigated the effects of TMPs and TRWPs on the growth, immune response, behaviour, and cognition of the woodlouse Armadillidium pallasii over 30 days; (2) TMPs and TRWPs were mixed together in the first experiment and provided at different concentrations of 1.25%, 2.5%, 5%, and 10% (w/w), and with soil at 5% and 10% (w/w) concentrations in the second experiment. (3) No differences in survival or immune responses were observed in both experiments. However, isopods exposed to TRWPs showed significant weight gain at lower concentrations but no gain at higher levels. Behavioural tests revealed increased vigilance in TRWP-exposed animals. Micro-FTIR analysis showed that the number of TMPs and TRWPs in the isopods correlated with soil concentrations, and particle size decreased during the experiment. (4) The study highlights the physiological and behavioural effects of TRWPs and the role of detritivorous species in the biofragmentation of TMPs and TRWPs, contributing to the biogeochemical plastic cycle. Full article

(This article belongs to the Special Issue Host Molecules and Molecular Mechanisms in Insects and Crustaceans)

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11 pages, 4359 KiB

Open AccessArticle

High Glucose Sensitizes Male and Female Rat Cardiomyocytes to Wnt/β-Catenin Signaling

by Ruonan Gu, Jerry Wang, Julianne Morin, Aizhu Lu and Wenbin Liang

Biomolecules 2024, 14(12), 1639; https://doi.org/10.3390/biom14121639 - 20 Dec 2024

Viewed by 618

Abstract

Wnt/β-catenin signaling has been shown to regulate gene expressions in cardiomyocytes. However, it is not known if this effect is dependent on the sex of cells or the glucose level in the culture medium. In the present study, ventricular myocytes were prepared from [...] Read more.

Wnt/β-catenin signaling has been shown to regulate gene expressions in cardiomyocytes. However, it is not known if this effect is dependent on the sex of cells or the glucose level in the culture medium. In the present study, ventricular myocytes were prepared from male and female neonatal rats and maintained in either a glucose-rich (25 mM) medium or a low-glucose (3 mM), lipid-rich medium. Real-time quantitative PCR was used to measure changes in target genes (Axin2, Scn5a, and Tbx3) after treatment with 1, 3, or 10 µM of CHIR-99021, an activator of Wnt/β-catenin signaling. CHIR induced similar changes in Axin2, Tbx3, and Scn5a transcripts in male and female NRVMs in both media, suggesting the absence of sex difference. However, cells in a high-glucose medium showed greater increases in Axin2 and Tbx3 transcripts than cells in a low-glucose medium. In addition, a low concentration of CHIR (1 µM) reduced the Scn5a transcript in cells in a high-glucose medium but not in a low-glucose medium, suggesting an increased sensitivity to Wnt signaling by high glucose. A non-linear relationship was identified between Axin2 transcript upregulation and Scn5a transcript downregulation in CIHR-treated NRVMs. These data suggest that high glucose sensitizes both male and female cardiomyocytes to Wnt/β-catenin signaling. Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 2717 KiB

Open AccessReview

Enzymatic Regulation of the Gut Microbiota: Mechanisms and Implications for Host Health

by Zipeng Jiang, Liang Mei, Yuqi Li, Yuguang Guo, Bo Yang, Zhiyi Huang and Yangyuan Li

Biomolecules 2024, 14(12), 1638; https://doi.org/10.3390/biom14121638 - 20 Dec 2024

Viewed by 1048

Abstract

The gut microbiota, a complex ecosystem, is vital to host health as it aids digestion, modulates the immune system, influences metabolism, and interacts with the brain-gut axis. Various factors influence the composition of this microbiota. Enzymes, as essential catalysts, actively participate in biochemical [...] Read more.

The gut microbiota, a complex ecosystem, is vital to host health as it aids digestion, modulates the immune system, influences metabolism, and interacts with the brain-gut axis. Various factors influence the composition of this microbiota. Enzymes, as essential catalysts, actively participate in biochemical reactions that have an impact on the gut microbial community, affecting both the microorganisms and the gut environment. Enzymes play an important role in the regulation of the intestinal microbiota, but the interactions between enzymes and microbial communities, as well as the precise mechanisms of enzymes, remain a challenge in scientific research. Enzymes serve both traditional nutritional functions, such as the breakdown of complex substrates into absorbable small molecules, and non-nutritional roles, which encompass antibacterial function, immunomodulation, intestinal health maintenance, and stress reduction, among others. This study categorizes enzymes according to their source and explores the mechanistic principles by which enzymes drive gut microbial activity, including the promotion of microbial proliferation, the direct elimination of harmful microbes, the modulation of bacterial interaction networks, and the reduction in immune stress. A systematic understanding of enzymes in regulating the gut microbiota and the study of their associated molecular mechanisms will facilitate the application of enzymes to precisely regulate the gut microbiota in the future and suggest new therapeutic strategies and dietary recommendations. In conclusion, this review provides a comprehensive overview of the role of enzymes in modulating the gut microbiota. It explores the underlying molecular and cellular mechanisms and discusses the potential applications of enzyme-mediated microbiota regulation for host gut health. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies for Animal Health)

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35 pages, 1935 KiB

Open AccessReview

Vaccination as a Promising Approach in Cardiovascular Risk Mitigation: Are We Ready to Embrace a Vaccine Strategy?

by Georgios Tsioulos, Natalia G. Vallianou, Alexandros Skourtis, Maria Dalamaga, Evangelia Kotsi, Sofia Kargioti, Nikolaos Adamidis, Irene Karampela, Iordanis Mourouzis and Dimitris Kounatidis

Biomolecules 2024, 14(12), 1637; https://doi.org/10.3390/biom14121637 - 20 Dec 2024

Viewed by 910

Abstract

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and [...] Read more.

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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14 pages, 5656 KiB

Open AccessArticle

Celecoxib Combined with Tocilizumab Has Anti-Inflammatory Effects and Promotes the Recovery of Damaged Cartilage via the Nrf2/HO-1 Pathway In Vitro

by Miyako Shimasaki, Shusuke Ueda, Masaru Sakurai, Norio Kawahara, Yoshimichi Ueda and Toru Ichiseki

Biomolecules 2024, 14(12), 1636; https://doi.org/10.3390/biom14121636 - 20 Dec 2024

Viewed by 653

Abstract

Inflammation and oxidative stress are crucial for osteoarthritis (OA) pathogenesis. Despite the potential of pharmacological pretreatment of chondrocytes in preventing OA, its efficacy in preventing the progression of cartilage damage and promoting its recovery has not been examined. In this study, an H [...] Read more.

Inflammation and oxidative stress are crucial for osteoarthritis (OA) pathogenesis. Despite the potential of pharmacological pretreatment of chondrocytes in preventing OA, its efficacy in preventing the progression of cartilage damage and promoting its recovery has not been examined. In this study, an H₂O₂-induced human OA-like chondrocyte cell model was created using H1467 primary human chondrocytes to evaluate the efficacy of interleukin (IL)-6 and cyclooxygenase (COX)-2 inhibitors (tocilizumab and celecoxib, respectively) in the prevention and treatment of cartilage damage. H₂O₂ significantly elevated the IL-6, COX-2, and matrix metalloproteinase (MMP)-13 levels. Although monotherapy decreased the levels, nuclear shrinkage and altered cell morphology, similar to those in the H₂O₂ group, were observed. The expression of these factors was significantly lower in the combination therapy group, and the cell morphology was maintained. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was activated, and levels of the antioxidant protein heme oxygenase-1 (HO-1) were increased, especially in the combination group, indicating an anti-inflammatory effect. The treatment groups, particularly the combination group, demonstrated increased cell viability. Overall, the drug combination exhibited superior efficacy in preventing the progression of cartilage damage and promoted its recovery compared with the monotherapy. Given that the drugs herein are already in clinical use, they are suitable candidates for OA treatment. Full article

(This article belongs to the Section Cellular Biochemistry)

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20 pages, 1801 KiB

Open AccessArticle

Bioactive Molecules from the Exoskeleton of Procambarus clarkii: Reducing Capacity, Radical Scavenger, and Antitumor and Anti-Inflammatory Activities

by Francesco Longo, Francesca Di Gaudio, Alessandro Attanzio, Laura Marretta, Claudio Luparello, Serena Indelicato, David Bongiorno, Giampaolo Barone, Luisa Tesoriere, Ilenia Concetta Giardina, Giulia Abruscato, Manuela Perlotti, Lucie Branwen Hornsby, Vincenzo Arizza, Mirella Vazzana, Federico Marrone, Aiti Vizzini, Chiara Martino, Dario Savoca, Vinicius Queiroz, Antonio Fabbrizio and Manuela Mauro Show full author list Hide full author list

Biomolecules 2024, 14(12), 1635; https://doi.org/10.3390/biom14121635 - 20 Dec 2024

Cited by 1 | Viewed by 825

Abstract

This study evaluates, for the first time, the reducing capacity, radical scavenger activity, and in vitro antitumor and anti-inflammatory effects of chitosan, astaxanthin, and bio-phenols extracted from the exoskeleton of Sicilian Procambarus clarkii, the most widespread species of invasive crayfish in the [...] Read more.

This study evaluates, for the first time, the reducing capacity, radical scavenger activity, and in vitro antitumor and anti-inflammatory effects of chitosan, astaxanthin, and bio-phenols extracted from the exoskeleton of Sicilian Procambarus clarkii, the most widespread species of invasive crayfish in the Mediterranean region. Among the extracted compounds, astaxanthin exhibited the highest antioxidant activity in all assays. Chitosan and polyphenols demonstrated reducing and radical scavenging activity; chitosan showed significant ferric ion reducing capacity in the FRAP test, while bio-phenolic compounds displayed notable radical scavenging activity in the DPPH and ABTS assays. Both astaxanthin and polyphenols showed dose-dependent cytotoxicity on two different cancer cell lines, with IC50 values of 1.45 µg/mL (phenolic extract) and 4.28 µg/mL (astaxanthin extract) for HepG2 cells and 2.45 µg/mL (phenolic extract) and 4.57 µg/mL (astaxanthin extract) for CaCo-2 cells. The bio-phenolic extract also showed potential anti-inflammatory effects in vitro by inhibiting nitric oxide production in inflamed RAW 264.7 macrophages, reducing the treated/control NO ratio to 77% and 74% at concentrations of 1.25 and 1.5 μg/mL, respectively. These results suggest that P. clarkii exoskeletons could be a valuable source of bioactive molecules for biomedical, pharmaceutical, and nutraceutical application while contributing to the sustainable management of this invasive species. Full article

(This article belongs to the Topic Molecular and Cellular Aspects of the Beneficial Effects of Natural Products on Chronic Diseases)

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18 pages, 1488 KiB

Open AccessReview

Research Progress of Liquid Biopsy Based on DNA Methylation in Tumor Diagnosis and Treatment

by Yunxia Bao, Xianzhao Wang, Bingjie Zeng, Yichun Shi, Yiman Huang, Yiwen Huang, Shuang Shang, Liang Shan and Lifang Ma

Biomolecules 2024, 14(12), 1634; https://doi.org/10.3390/biom14121634 - 19 Dec 2024

Viewed by 848

Abstract

Liquid biopsy has been gradually applied to the clinical diagnosis and treatment of tumors because of its non-invasive and real-time reflection of the tumor status, as well as the convenience of sample collection, which allows the detection of primary or metastatic malignant tumors [...] Read more.

Liquid biopsy has been gradually applied to the clinical diagnosis and treatment of tumors because of its non-invasive and real-time reflection of the tumor status, as well as the convenience of sample collection, which allows the detection of primary or metastatic malignant tumors and reflects the heterogeneity of the tumors. DNA methylation, which is a type of epigenetic modification, is essential in the progression of tumors. This review introduces the common DNA methylation analysis methods and discusses their advantages and disadvantages, focusing on the new progress of DNA methylation-based liquid biopsy in tumor diagnosis and treatment. Full article

(This article belongs to the Special Issue Emerging Biomarkers Discovery for Molecular Diagnostics)

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10 pages, 899 KiB

Open AccessArticle

The Influence of Bariatric Surgery on Matrix Metalloproteinase Plasma Levels in Patients with Type 2 Diabetes Mellitus

by João Kleber de Almeida Gentile, Renato Migliore, Jaques Waisberg and Marcelo Augusto Fontenelle Ribeiro Junior

Biomolecules 2024, 14(12), 1633; https://doi.org/10.3390/biom14121633 - 19 Dec 2024

Viewed by 726

Abstract

Background: Bariatric surgery is a safe and effective procedure for treating obesity and metabolic conditions such as type 2 diabetes mellitus (T2DM). Remodeling of the extracellular matrix (ECM) supports adipose tissue expansion and its metabolic activity, where matrix metalloproteinases (MMPs) play a key [...] Read more.

Background: Bariatric surgery is a safe and effective procedure for treating obesity and metabolic conditions such as type 2 diabetes mellitus (T2DM). Remodeling of the extracellular matrix (ECM) supports adipose tissue expansion and its metabolic activity, where matrix metalloproteinases (MMPs) play a key role in ECM regulation. The MMPs, particularly MMP-2 and MMP-9, are elevated in patients with morbid obesity, metabolic syndrome, and T2DM. Objectives: To evaluate the effect of weight loss in bariatric surgery patients using oxidative stress markers and to compare MMP levels in patients undergoing bariatric surgery. Methods: This was a prospective, controlled study including 45 morbidly obese patients with T2DM (BMI > 35 kg/m²) who underwent RYGB (n = 24) or VG (n = 21). Weight loss was assessed through anthropometric measurements (weight, height, BMI). MMP-2 and MMP-9 levels were measured preoperatively and at 3 and 12 months postoperatively. Results: Significant and sustained weight loss was observed after surgery in both groups, with reductions in BMI. MMP-2 and MMP-9 levels decreased significantly after one year of follow-up. Conclusions: Bariatric surgery is an effective long-term intervention for weight loss and associated comorbidities, including T2DM. MMP-2 and MMP-9 proved to be effective markers of extracellular matrix remodeling, with significant reductions following surgery. Full article

(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Health and Disease)

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12 pages, 4744 KiB

Open AccessArticle

Peptide-Mediated Transport Across the Intact Tympanic Membrane Is Intracellular, with the Rate Determined by the Middle Ear Mucosal Epithelium

by Arwa Kurabi, Yuge Xu, Eduardo Chavez, Vivian Khieu and Allen F. Ryan

Biomolecules 2024, 14(12), 1632; https://doi.org/10.3390/biom14121632 - 19 Dec 2024

Viewed by 663

Abstract

The tympanic membrane forms an impenetrable barrier between the ear canal and the air-filled middle ear, protecting it from fluid, pathogens, and foreign material entry. We previously screened a phage display library and discovered peptides that mediate transport across the intact membrane. The [...] Read more.

The tympanic membrane forms an impenetrable barrier between the ear canal and the air-filled middle ear, protecting it from fluid, pathogens, and foreign material entry. We previously screened a phage display library and discovered peptides that mediate transport across the intact membrane. The route by which transport occurs is not certain, but possibilities include paracellular transport through loosened intercellular junctions and transcellular transport through the cells that comprise the various tympanic membrane layers. We used confocal imaging to resolve the phage’s path through the membrane. Phages were observed in puncta within the cytoplasm of tympanic membrane cells, with no evidence of phages within junctions between epithelial cells. This result indicates that transport across the membrane is transcellular and within vesicles, consistent with the transcytosis process. The trans-tympanic peptide phages display a wide range of transport efficiencies for unknown reasons. This could include variation in tympanic membrane binding, entry into the membrane, crossing the membrane, or exiting into the middle ear. To address this, we titered phages recovered from within the membrane for phages with differing transport rates. We found that differences in the transport rate were inversely related to their presence within the tympanic membrane. This suggests that differences in the transport rate primarily reflect the efficiency of an exocytotic exit from the mucosal epithelium rather than entry into, or passage across, the membrane. Full article

(This article belongs to the Section Cellular Biochemistry)

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21 pages, 1179 KiB

Open AccessSystematic Review

Cytokine Gene Variants as Predisposing Factors for the Development and Progression of Coronary Artery Disease: A Systematic Review

by Fang Li, Yingshuo Zhang, Yichao Wang, Xiaoyan Cai and Xiongwei Fan

Biomolecules 2024, 14(12), 1631; https://doi.org/10.3390/biom14121631 - 19 Dec 2024

Viewed by 675

Abstract

Coronary artery disease (CAD) is the most prevalent form of cardiovascular disease. A growing body of research shows that interleukins (ILs), such as IL-8, IL-18 and IL-16, elicit pro-inflammatory responses and may play critical roles in the pathologic process of CAD. Single nucleotide [...] Read more.

Coronary artery disease (CAD) is the most prevalent form of cardiovascular disease. A growing body of research shows that interleukins (ILs), such as IL-8, IL-18 and IL-16, elicit pro-inflammatory responses and may play critical roles in the pathologic process of CAD. Single nucleotide polymorphisms (SNPs), capable of generating functional modifications in IL genes, appear to be associated with CAD risk. This study aims to evaluate the associations of ten previously identified SNPs of the three cytokines with susceptibility to or protection of CAD. A systematic review and meta-analysis were conducted using Pubmed, EMBASE, WOS, CENTRAL, CNKI, CBM, Weipu, WANFANG Data and Google Scholar databases for relevant literature published up to September 2024. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the four genetic models of the investigated SNPs in overall and subgroups analyses. Thirty-eight articles from 16 countries involving 14574 cases and 13001 controls were included. The present meta-analysis revealed no significant association between CAD and IL-8-rs2227306 or five IL-16 SNPs (rs8034928, rs3848180, rs1131445, rs4778889 and rs11556218). However, IL-8-rs4073 was significantly associated with an increased risk of CAD across all genetic models. In contrast, three IL-18 (rs187238, rs1946518 and rs1946519) variants containing minor alleles were associated with decreased risks of CAD under all models. Subgroups analyses by ethnicity indicated that IL-8-rs4073 conferred a significantly higher risk of CAD among Asians, including East, South and West Asians (allelic OR = 1.46, homozygous OR = 1.96, heterozygous OR = 1.47, dominant OR = 1.65), while it showed an inversely significant association with CAD risk in Caucasians (homozygous OR = 0.82, dominant OR = 0.85). Additionally, IL-18-rs187238 and IL-18-rs1946518 were significantly associated with reduced CAD risks in East Asians (for rs187238: allelic OR = 0.72, homozygous OR = 0.33, heterozygous OR = 0.73, dominant OR = 0.71; for rs1946518: allelic OR = 0.62, homozygous OR = 0.38, heterozygous OR = 0.49, dominant OR = 0.45). IL-18-rs187238 also demonstrated protective effects in Middle Eastern populations (allelic OR = 0.76, homozygous OR = 0.63, heterozygous OR = 0.72, dominant OR = 0.71). No significant associations were observed in South Asians or Caucasians for these IL-18 SNPs. Consistent with the overall analysis results, subgroups analyses further highlighted a significant association between IL-8-rs4073 and increased risk of acute coronary syndrome (heterozygous OR = 0.72). IL-18-rs187238 was significantly associated with decreased risks of myocardial infarction (MI) (allelic OR = 0.81, homozygous OR = 0.55, dominant OR = 0.80) and multiple vessel stenosis (allelic OR = 0.54, heterozygous OR = 0.45, dominant OR = 0.45). Similarly, IL-18-rs1946518 was significantly associated with reduced MI risk (allelic OR = 0.75, heterozygous OR = 0.68). These findings support the role of cytokine gene IL-8 and IL-18 variants as predisposing factors for the development and progression of CAD. Full article

(This article belongs to the Special Issue Recent Advances in the Role of Translation Machinery and Translational Control in the Cardiovascular System)

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28 pages, 1200 KiB

Open AccessReview

The Role of Cardiac Troponin and Other Emerging Biomarkers Among Athletes and Beyond: Underlying Mechanisms, Differential Diagnosis, and Guide for Interpretation

by Mihail Celeski, Andrea Segreti, Filippo Crisci, Riccardo Cricco, Mariagrazia Piscione, Giuseppe Di Gioia, Annunziata Nusca, Chiara Fossati, Fabio Pigozzi, Gian Paolo Ussia, Ross John Solaro and Francesco Grigioni

Biomolecules 2024, 14(12), 1630; https://doi.org/10.3390/biom14121630 - 19 Dec 2024

Viewed by 738

Abstract

Cardiovascular (CV) disease remains the leading cause of morbidity and mortality worldwide, highlighting the necessity of understanding its underlying molecular and pathophysiological pathways. Conversely, physical activity (PA) and exercise are key strategies in reducing CV event risks. Detecting latent CV conditions in apparently [...] Read more.

Cardiovascular (CV) disease remains the leading cause of morbidity and mortality worldwide, highlighting the necessity of understanding its underlying molecular and pathophysiological pathways. Conversely, physical activity (PA) and exercise are key strategies in reducing CV event risks. Detecting latent CV conditions in apparently healthy individuals, such as athletes, presents a unique challenge. The early identification and treatment of CV disorders are vital for long-term health and patient survival. Cardiac troponin is currently the most commonly used biomarker for assessing CV changes in both athletes and the general population. However, there remains considerable debate surrounding the mechanisms underlying exercise-induced troponin elevations and its release in non-ischemic contexts. Thus, there is a pressing need to identify and implement more sensitive and specific biomarkers for CV disorders in clinical practice. Indeed, research continues to explore reliable biomarkers for evaluating the health of athletes and the effectiveness of physical exercise. It is essential to analyze current evidence on troponin release in non-ischemic conditions, post-strenuous exercise, and the complex biological pathways that influence its detection. Furthermore, this study summarizes current research on cytokines and exosomes, including their physiological roles and their relevance in various CV conditions, especially in athletes. In addition, this paper gives special attention to underlying mechanisms, potential biomarkers, and future perspectives. Full article

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

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12 pages, 4071 KiB

Open AccessArticle

IL6 and IL6R as Prognostic Biomarkers in Colorectal Cancer

by Kathryn A. F. Pennel, Ahmad Kurniawan, Sara Samir Foad Al-Badran, Leonor Schubert Santana, Jean Quinn, Colin Nixon, Phimmada Hatthakarnkul, Noori Maka, Campbell Roxburgh, Donald McMillan and Joanne Edwards

Biomolecules 2024, 14(12), 1629; https://doi.org/10.3390/biom14121629 - 19 Dec 2024

Viewed by 937

Abstract

Colorectal cancer is the third most diagnosed malignancy worldwide and survival outcomes remain poor. Research is focused on the identification of novel prognostic and predictive biomarkers to improve clinical practice. There is robust evidence in the literature that inflammatory cytokine interleukin-6 (IL6) is [...] Read more.

Colorectal cancer is the third most diagnosed malignancy worldwide and survival outcomes remain poor. Research is focused on the identification of novel prognostic and predictive biomarkers to improve clinical practice. There is robust evidence in the literature that inflammatory cytokine interleukin-6 (IL6) is elevated systemically in CRC patients and that this phenomenon is a predictor of poor survival outcome. However, evidence is more limited for the role of IL6 and its cognate receptor, IL6R, within the tumour epithelium and microenvironment. This study aimed to investigate IL6 and IL6R expression in a large cohort of retrospectively collected patient tumour specimens and determine association with clinical outcomes and characteristics. High expression of IL6R in the tumour epithelium was associated with reduced cancer-specific survival in patients with right-sided colon cancer. In these patients, high IL6R expression was also associated with an increased systemic neutrophil-to-lymphocyte ratio. A high number of copies of IL6 mRNA within the tumour-associated stroma, but not epithelium, was associated with reduced cancer-specific survival. The results from this study have validated IL6R as a marker of poor prognosis in a subgroup of CRC patients and identified the spatially resolved prognostic nature of intra-tumoural IL6 expression. This study has also highlighted the need for investigation of IL6/IL6R-targeted therapies as novel treatment strategies for patients with colon cancer. Full article

(This article belongs to the Special Issue Colorectal and Gastric Cancers: Molecular Mechanisms and Potential Biomarkers)

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24 pages, 5266 KiB

Open AccessReview

Research Progress of Phospholipid Vesicles in Biological Field

by Na Zhang, Jie Song and Yuchun Han

Biomolecules 2024, 14(12), 1628; https://doi.org/10.3390/biom14121628 - 19 Dec 2024

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Abstract

Due to their high biocompatibility, biodegradability, and facile surface functionalization, phospholipid vesicles as carriers have garnered significant attention in the realm of disease diagnosis and treatment. On the one hand, phospholipid vesicles can function as probes for the detection of various diseases by [...] Read more.

Due to their high biocompatibility, biodegradability, and facile surface functionalization, phospholipid vesicles as carriers have garnered significant attention in the realm of disease diagnosis and treatment. On the one hand, phospholipid vesicles can function as probes for the detection of various diseases by encapsulating nanoparticles, thereby enabling the precise localization of pathological changes and the monitoring of disease progression. On the other hand, phospholipid vesicles possess the capability to selectively target and deliver therapeutic agents, including drug molecules, genes and immune modulators, to affected sites, thereby enhancing the sustained release of these agents and improving therapeutic efficacy. Recent advancements in nanotechnology have led to an increased focus on the application of phospholipid vesicles in drug delivery, biological detection, gene therapy, and cell mimics. This review aims to provide a concise overview of the structure, characteristics, and preparation techniques of phospholipid vesicles of varying sizes. Furthermore, we will summarize the latest research developments regarding their use as nanomedicines and gene carriers in disease treatment. Additionally, we will elucidate the potential of phospholipid vesicles in facilitating the internalization, controlled release, and targeted delivery of therapeutic substrates. Through this review, we aspire to enhance the understanding of the evolution of phospholipid vesicles within the biological field, outline prospective research, and address the forthcoming challenges associated with phospholipid vesicles in disease diagnosis and treatment. Full article

(This article belongs to the Section Biomacromolecules: Lipids)

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22 pages, 2166 KiB

Open AccessReview

Treatment Strategies for Painful Pelvic Floor Conditions: A Focus on the Potential Benefits of Cannabidiol

by Roberto Bonanni, Patrizia Ratano, Ida Cariati, Virginia Tancredi and Pierangelo Cifelli

Biomolecules 2024, 14(12), 1627; https://doi.org/10.3390/biom14121627 - 19 Dec 2024

Viewed by 1203

Abstract

Painful conditions of the pelvic floor include a set of disorders of the pelvic region, discreetly prevalent in the female population, in which pain emerges as the predominant symptom. Such disorders have a significant impact on quality of life as they impair couple [...] Read more.

Painful conditions of the pelvic floor include a set of disorders of the pelvic region, discreetly prevalent in the female population, in which pain emerges as the predominant symptom. Such disorders have a significant impact on quality of life as they impair couple relationships and promote states of anxiety and irascibility in affected individuals. Although numerous treatment approaches have been proposed for the management of such disorders, there is a need to identify strategies to promote muscle relaxation, counter pelvic pain, and reduce inflammation. The endocannabinoid system (ECS) represents a complex system spread throughout the body and is involved in the regulation of numerous physiological processes representing a potential therapeutic target for mood and anxiety disorders as well as pain management. Cannabidiol (CBD), acting on the ECS, can promote relief from hyperalgesia and allodynia typical of disorders affecting the pelvic floor and promote muscle relaxation by restoring balance to this delicate anatomical region. However, its use is currently limited due to a lack of evidence supporting its efficacy and harmlessness, and the mechanism of action on the ECS remains partially unexplored to this day. This comprehensive review of the literature examines the impact of pain disorders affecting the pelvic floor and major treatment approaches and brings together the main evidence supporting CBD in the management of such disorders. Full article

(This article belongs to the Special Issue New Advances of Cannabinoid Receptors in Health and Disease: 2nd Edition)

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28 pages, 3624 KiB

Open AccessArticle

In-Depth Phenotyping of PIGW-Related Disease and Its Role in 17q12 Genomic Disorder

by Agnese Feresin, Mathilde Lefebvre, Emilie Sjøstrøm, Caterina Zanus, Elisa Paccagnella, Irene Bruno, Erica Valencic, Anna Morgan, Alberto Tommasini, Christel Thauvin, Allan Bayat, Giorgia Girotto and Luciana Musante

Biomolecules 2024, 14(12), 1626; https://doi.org/10.3390/biom14121626 - 18 Dec 2024

Viewed by 778

Abstract

Glycosylphosphatidylinositol (GPI) biosynthesis defect 11 (GPIBD11), part of the heterogeneous group of congenital disorders of glycosylation, is caused by biallelic pathogenic variants in PIGW. This rare disorder has previously been described in only 12 patients. We report four novel patients: two sib [...] Read more.

Glycosylphosphatidylinositol (GPI) biosynthesis defect 11 (GPIBD11), part of the heterogeneous group of congenital disorders of glycosylation, is caused by biallelic pathogenic variants in PIGW. This rare disorder has previously been described in only 12 patients. We report four novel patients: two sib fetuses with congenital anomalies affecting several organs, including the heart; a living girl with tetralogy of Fallot, global developmental delay, behavioral abnormalities, and atypic electroencephalography (EEG) without epilepsy; a girl with early-onset, treatment-resistant seizures, developmental regression, and recurrent infections, that ultimately passed away prematurely due to pneumonia. We also illustrate evolving facial appearance and biochemical abnormalities. We identify two novel genotypes and the first frameshift variant, supporting a loss-of-function pathogenic mechanism. By merging our cohort with patients documented in the literature, we deeply analyzed the clinical and genetic features of 16 patients with PIGW-related disorder, revealing a severe multisystemic condition deserving complex management and with uncertain long-term prognosis. We consider the role of PIGW within the critical 17q12 region, which is already associated with genomic disorders caused by deletion or duplication and characterized by variable expressivity. Finally, we discuss PIGW dosage effects and a second hit hypothesis in human development and disease. Full article

(This article belongs to the Special Issue New Insight into the Molecular Genetics of Neurodevelopmental Disorders)

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11 pages, 1793 KiB

Open AccessFeature PaperArticle

Installation of an Indole on the BRCA1 Disordered Domain Using Triazine Chemistry

by Liam E. Claton, Chrissy Baker, Hayes Martin, Sergei V. Dzyuba, Khadiza Zaman, Laszlo Prokai, Mikaela D. Stewart and Eric E. Simanek

Biomolecules 2024, 14(12), 1625; https://doi.org/10.3390/biom14121625 - 18 Dec 2024

Viewed by 660

Abstract

The functionalization of protein sidechains with highly water-soluble chlorotriazines (or derivatives thereof) using nucleophilic aromatic substitution reactions has been commonly employed to install various functional groups, including poly(ethylene glycol) tags or fluorogenic labels. Here, a poorly soluble dichlorotriazine with an appended indole is [...] Read more.

The functionalization of protein sidechains with highly water-soluble chlorotriazines (or derivatives thereof) using nucleophilic aromatic substitution reactions has been commonly employed to install various functional groups, including poly(ethylene glycol) tags or fluorogenic labels. Here, a poorly soluble dichlorotriazine with an appended indole is shown to react with a construct containing the disordered domain of BRCA1. Subsequently, this construct can undergo proteolytic cleavage to remove the SUMO-tag: the N-terminal poly(His) tag is still effective for purification. Steady-state fluorescence, circular dichroism spectroscopy, and isothermal titration calorimetry with the binding partner of BRCA1, PALB2, are used to characterize the indole-labeled BRCA1. Neither the reaction conditions nor the indole-tag appreciably alter the structure of the BRCA1. Mass spectrometry confirms that the target is modified once, although the location of modification cannot be determined by tandem mass spectrometry with collision-induced dissociation due to disadvantageous fragmentation patterns. Full article

(This article belongs to the Special Issue Structural Proteomics–Structural Biology Led by Advancements in Mass Spectrometry Techniques)

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17 pages, 3787 KiB

Open AccessArticle

Direct On-Chip Diagnostics of Streptococcus bovis/Streptococcus equinus Complex in Bovine Mastitis Using Bioinformatics-Driven Portable qPCR

by Jaewook Kim, Eiseul Kim, Seung-Min Yang, Si Hong Park and Hae-Yeong Kim

Biomolecules 2024, 14(12), 1624; https://doi.org/10.3390/biom14121624 - 18 Dec 2024

Viewed by 726

Abstract

This study introduces an innovative on-site diagnostic method for rapidly detecting the Streptococcus bovis/Streptococcus equinus complex (SBSEC), crucial for livestock health and food safety. Through a comprehensive genomic analysis of 206 genomes, this study identified genetic markers that improved classification and [...] Read more.

This study introduces an innovative on-site diagnostic method for rapidly detecting the Streptococcus bovis/Streptococcus equinus complex (SBSEC), crucial for livestock health and food safety. Through a comprehensive genomic analysis of 206 genomes, this study identified genetic markers that improved classification and addressed misclassifications, particularly in genomes labeled S. equinus and S. lutetiensis. These markers were integrated into a portable quantitative polymerase chain reaction (qPCR) that can detect SBSEC species with high sensitivity (down to 10¹ or 10⁰ colony-forming units/mL). The portable system featuring a flat chip and compact equipment allows immediate diagnosis within 30 min. The diagnostic method was validated in field conditions directly from cattle udders, farm environments, and dairy products. Among the 100 samples, 51 tested positive for bacteria associated with mastitis. The performance of this portable qPCR was comparable to laboratory methods, offering a reliable alternative to whole-genome sequencing for early detection in clinical, agricultural, and environmental settings. Full article

(This article belongs to the Special Issue The Genomics Era: From Reference Genomes to Pan-Genomic Approach, 2nd Edition)

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