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Biomolecules, Volume 14, Issue 7 (July 2024) – 142 articles

Cover Story (view full-size image): DMD4B-HYDRA simulations of oligomer formation by naturally occurring Aβ1−38, Aβ1−40, Aβ1−42, and Aβ1−43 reveal that they assemble through distinct oligomer formation pathways. Oligomers of different sizes exhibit self-similarity, yet their structure is isoform specific. While Aβ1−38 and Aβ1−40 hexamers adopt dumb-bell shapes, Aβ1−42 hexamers have a compact C-terminally stabilized core with flexible, solvent-exposed N-termini. Aβ1−42 and Aβ1−43, reported to be neurotoxic, form on average larger oligomers than presumably neuroprotective Aβ1−38 and Aβ1−40. Because larger oligomers are expected to possess an increased affinity to form water-permeable pores in a bilayer, these findings suggest that therapeutic strategies targeting oligomer size reduction will mitigate Aβ-mediated toxicity. View this paper
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20 pages, 447 KiB  
Review
How Transcription Factor Clusters Shape the Transcriptional Landscape
by Rahul Munshi
Biomolecules 2024, 14(7), 875; https://doi.org/10.3390/biom14070875 (registering DOI) - 20 Jul 2024
Abstract
In eukaryotic cells, gene transcription typically occurs in discrete periods of promoter activity, interspersed with intervals of inactivity. This pattern deviates from simple stochastic events and warrants a closer examination of the molecular interactions that activate the promoter. Recent studies have identified transcription [...] Read more.
In eukaryotic cells, gene transcription typically occurs in discrete periods of promoter activity, interspersed with intervals of inactivity. This pattern deviates from simple stochastic events and warrants a closer examination of the molecular interactions that activate the promoter. Recent studies have identified transcription factor (TF) clusters as key precursors to transcriptional bursting. Often, these TF clusters form at chromatin segments that are physically distant from the promoter, making changes in chromatin conformation crucial for promoter–TF cluster interactions. In this review, I explore the formation and constituents of TF clusters, examining how the dynamic interplay between chromatin architecture and TF clustering influences transcriptional bursting. Additionally, I discuss techniques for visualizing TF clusters and provide an outlook on understanding the remaining gaps in this field. Full article
19 pages, 965 KiB  
Review
The Role and Therapeutic Potential of Pyroptosis in Colorectal Cancer: A Review
by Qing Fang, Yunhua Xu, Xiangwen Tan, Xiaofeng Wu, Shuxiang Li, Jinyi Yuan, Xiguang Chen, Qiulin Huang, Kai Fu and Shuai Xiao
Biomolecules 2024, 14(7), 874; https://doi.org/10.3390/biom14070874 (registering DOI) - 20 Jul 2024
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The unlimited proliferation of tumor cells is one of the key features resulting in the malignant development and progression of CRC. Consequently, understanding the potential proliferation and growth molecular mechanisms [...] Read more.
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The unlimited proliferation of tumor cells is one of the key features resulting in the malignant development and progression of CRC. Consequently, understanding the potential proliferation and growth molecular mechanisms and developing effective therapeutic strategies have become key in CRC treatment. Pyroptosis is an emerging type of regulated cell death (RCD) that has a significant role in cells proliferation and growth. For the last few years, numerous studies have indicated a close correlation between pyroptosis and the occurrence, progression, and treatment of many malignancies, including CRC. The development of effective therapeutic strategies to inhibit tumor growth and proliferation has become a key area in CRC treatment. Thus, this review mainly summarized the different pyroptosis pathways and mechanisms, the anti-tumor (tumor suppressor) and protective roles of pyroptosis in CRC, and the clinical and prognostic value of pyroptosis in CRC, which may contribute to exploring new therapeutic strategies for CRC. Full article
15 pages, 7280 KiB  
Article
Diminished Immune Response and Elevated Abundance in Gut Microbe Dubosiella in Mouse Models of Chronic Colitis with GBP5 Deficiency
by Yichen Li, Wenxia Wang, Yuxuan Liu, Senru Li, Jingyu Wang and Linlin Hou
Biomolecules 2024, 14(7), 873; https://doi.org/10.3390/biom14070873 (registering DOI) - 20 Jul 2024
Abstract
Guanylate binding protein 5 (GBP5) is an emerging immune component that has been increasingly recognized for its involvement in autoimmune diseases, particularly inflammatory bowel disease (IBD). IBD is a complex disease involving inflammation of the gastrointestinal tract. Here, we explored the functional significance [...] Read more.
Guanylate binding protein 5 (GBP5) is an emerging immune component that has been increasingly recognized for its involvement in autoimmune diseases, particularly inflammatory bowel disease (IBD). IBD is a complex disease involving inflammation of the gastrointestinal tract. Here, we explored the functional significance of GBP5 using Gbp5 knockout mice and wildtype mice exposed to dextran sulfate sodium (DSS) to generate chronic colitis model. We found that Gbp5 deficiency protected mice from DSS-induced chronic colitis. Transcriptome analysis of colon tissues showed reduced immune responses in Gbp5 knockout mice compared to those in corresponding wildtype mice. We further observed that after repeated DSS exposure, the gut microbiota was altered, both in wildtype mice and Gbp5 knockout mice; however, the gut microbiome health index was higher in the Gbp5 knockout mice. Notably, a probiotic murine commensal bacterium, Dubosiella, was predominantly enriched in these knockout mice. Our findings suggest that GBP5 plays an important role in promoting inflammation and dysbiosis in the intestine, the prevention of which might therefore be worth exploring in regards to IBD treatment. Full article
(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Disease)
20 pages, 1357 KiB  
Article
Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration
by Katherine O. Kopp, Yazhou Li, Elliot J. Glotfelty, David Tweedie and Nigel H. Greig
Biomolecules 2024, 14(7), 872; https://doi.org/10.3390/biom14070872 - 19 Jul 2024
Viewed by 86
Abstract
Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors (“multi-agonists”), including the glucose-dependent [...] Read more.
Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors (“multi-agonists”), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment. Full article
(This article belongs to the Special Issue The Role of Microglia in Aging and Neurodegenerative Disease)
16 pages, 936 KiB  
Article
The Ubiquity of the Reaction of the Labile Iron Pool That Attenuates Peroxynitrite-Dependent Oxidation Intracellularly
by Gabriel Simonetti da Silva, Maria Beatriz Braghetto Hernandes and José Carlos Toledo Junior
Biomolecules 2024, 14(7), 871; https://doi.org/10.3390/biom14070871 - 19 Jul 2024
Viewed by 86
Abstract
Although the labile iron pool (LIP) biochemical identity remains a topic of debate, it serves as a universal homeostatically regulated and essential cellular iron source. The LIP plays crucial cellular roles, being the source of iron that is loaded into nascent apo-iron proteins, [...] Read more.
Although the labile iron pool (LIP) biochemical identity remains a topic of debate, it serves as a universal homeostatically regulated and essential cellular iron source. The LIP plays crucial cellular roles, being the source of iron that is loaded into nascent apo-iron proteins, a process akin to protein post-translational modification, and implicated in the programmed cell death mechanism known as ferroptosis. The LIP is also recognized for its reactivity with chelators, nitric oxide, and peroxides. Our recent investigations in a macrophage cell line revealed a reaction of the LIP with the oxidant peroxynitrite. In contrast to the LIP’s pro-oxidant interaction with hydrogen peroxide, this reaction is rapid and attenuates the peroxynitrite oxidative impact. In this study, we demonstrate the existence and antioxidant characteristic of the LIP and peroxynitrite reaction in various cell types. Beyond its potential role as a ubiquitous complementary or substitute protection system against peroxynitrite for cells, the LIP and peroxynitrite reaction may influence cellular iron homeostasis and ferroptosis by changing the LIP redox state and LIP binding properties and reactivity. Full article
(This article belongs to the Section Chemical Biology)
18 pages, 947 KiB  
Article
Leucine-Rich Repeat Kinase-2 Controls the Differentiation and Maturation of Oligodendrocytes in Mice and Zebrafish
by Alice Filippini, Elena Cannone, Valentina Mazziotti, Giulia Carini, Veronica Mutti, Cosetta Ravelli, Massimo Gennarelli, Marco Schiavone and Isabella Russo
Biomolecules 2024, 14(7), 870; https://doi.org/10.3390/biom14070870 - 19 Jul 2024
Viewed by 98
Abstract
Leucine-rich repeat kinase-2 (LRRK2), a gene mutated in familial and sporadic Parkinson’s disease (PD), controls multiple cellular processes important for GLIA physiology. Interestingly, emerging studies report that LRRK2 is highly expressed in oligodendrocyte precursor cells (OPCs) compared to the pathophysiology of [...] Read more.
Leucine-rich repeat kinase-2 (LRRK2), a gene mutated in familial and sporadic Parkinson’s disease (PD), controls multiple cellular processes important for GLIA physiology. Interestingly, emerging studies report that LRRK2 is highly expressed in oligodendrocyte precursor cells (OPCs) compared to the pathophysiology of other brain cells and oligodendrocytes (OLs) in PD. Altogether, these observations suggest crucial function(s) of LRRK2 in OPCs/Ols, which would be interesting to explore. In this study, we investigated the role of LRRK2 in OLs. We showed that LRRK2 knock-out (KO) OPC cultures displayed defects in the transition of OPCs into OLs, suggesting a role of LRRK2 in OL differentiation. Consistently, we found an alteration of myelin basic protein (MBP) striosomes in LRRK2 KO mouse brains and reduced levels of oligodendrocyte transcription factor 2 (Olig2) and Mbp in olig2:EGFP and mbp:RFP transgenic zebrafish embryos injected with lrrk2 morpholino (MO). Moreover, lrrk2 knock-down zebrafish exhibited a lower amount of nerve growth factor (Ngf) compared to control embryos, which represents a potent regulator of oligodendrogenesis and myelination. Overall, our findings indicate that LRRK2 controls OL differentiation, affecting the number of mature OLs. Full article
16 pages, 3601 KiB  
Review
Molybdenum’s Role as an Essential Element in Enzymes Catabolizing Redox Reactions: A Review
by Jakub Piotr Adamus, Anna Ruszczyńska and Aleksandra Wyczałkowska-Tomasik
Biomolecules 2024, 14(7), 869; https://doi.org/10.3390/biom14070869 - 19 Jul 2024
Viewed by 126
Abstract
Molybdenum (Mo) is an essential element for human life, acting as a cofactor in various enzymes crucial for metabolic homeostasis. This review provides a comprehensive insight into the latest advances in research on molybdenum-containing enzymes and their clinical significance. One of these enzymes [...] Read more.
Molybdenum (Mo) is an essential element for human life, acting as a cofactor in various enzymes crucial for metabolic homeostasis. This review provides a comprehensive insight into the latest advances in research on molybdenum-containing enzymes and their clinical significance. One of these enzymes is xanthine oxidase (XO), which plays a pivotal role in purine catabolism, generating reactive oxygen species (ROS) capable of inducing oxidative stress and subsequent organ dysfunction. Elevated XO activity is associated with liver pathologies such as non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Aldehyde oxidases (AOs) are also molybdenum-containing enzymes that, similar to XO, participate in drug metabolism, with notable roles in the oxidation of various substrates. However, beneath its apparent efficacy, AOs’ inhibition may impact drug effectiveness and contribute to liver damage induced by hepatotoxins. Another notable molybdenum-enzyme is sulfite oxidase (SOX), which catalyzes the conversion of sulfite to sulfate, crucial for the degradation of sulfur-containing amino acids. Recent research highlights SOX’s potential as a diagnostic marker for HCC, offering promising sensitivity and specificity in distinguishing cancerous lesions. The newest member of molybdenum-containing enzymes is mitochondrial amidoxime-reducing component (mARC), involved in drug metabolism and detoxification reactions. Emerging evidence suggests its involvement in liver pathologies such as HCC and NAFLD, indicating its potential as a therapeutic target. Overall, understanding the roles of molybdenum-containing enzymes in human physiology and disease pathology is essential for advancing diagnostic and therapeutic strategies for various health conditions, particularly those related to liver dysfunction. Further research into the molecular mechanisms underlying these enzymes’ functions could lead to novel treatments and improved patient outcomes. Full article
(This article belongs to the Section Molecular Medicine)
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18 pages, 12170 KiB  
Article
Characterization of Subcellular Dynamics of Sterol Methyltransferases Clarifies Defective Cell Division in smt2 smt3, a C-24 Ethyl Sterol-Deficient Mutant of Arabidopsis
by Daisaku Ohta, Ayaka Fuwa, Yuka Yamaroku, Kazuki Isobe, Masatoshi Nakamoto, Atsushi Okazawa, Takumi Ogawa, Kazuo Ebine, Takashi Ueda, Pierre Mercier and Hubert Schaller
Biomolecules 2024, 14(7), 868; https://doi.org/10.3390/biom14070868 - 19 Jul 2024
Viewed by 126
Abstract
An Arabidopsis sterol mutant, smt2 smt3, defective in sterolmethyltransferase2 (SMT2), exhibits severe growth abnormalities. The loss of C-24 ethyl sterols, maintaining the biosynthesis of C-24 methyl sterols and brassinosteroids, suggests specific roles of C-24 ethyl sterols. We characterized the subcellular localizations of [...] Read more.
An Arabidopsis sterol mutant, smt2 smt3, defective in sterolmethyltransferase2 (SMT2), exhibits severe growth abnormalities. The loss of C-24 ethyl sterols, maintaining the biosynthesis of C-24 methyl sterols and brassinosteroids, suggests specific roles of C-24 ethyl sterols. We characterized the subcellular localizations of fluorescent protein-fused sterol biosynthetic enzymes, such as SMT2-GFP, and found these enzymes in the endoplasmic reticulum during interphase and identified their movement to the division plane during cytokinesis. The mobilization of endoplasmic reticulum-localized SMT2-GFP was independent of the polarized transport of cytokinetic vesicles to the division plane. In smt2 smt3, SMT2-GFP moved to the abnormal division plane, and unclear cell plate ends were surrounded by hazy structures from SMT2-GFP fluorescent signals and unincorporated cellulose debris. Unusual cortical microtubule organization and impaired cytoskeletal function accompanied the failure to determine the cortical division site and division plane formation. These results indicated that both endoplasmic reticulum membrane remodeling and cytokinetic vesicle transport during cytokinesis were impaired, resulting in the defects of cell wall generation. The cell wall integrity was compromised in the daughter cells, preventing the correct determination of the subsequent cell division site. We discuss the possible roles of C-24 ethyl sterols in the interaction between the cytoskeletal network and the plasma membrane. Full article
(This article belongs to the Special Issue Sterol Biosynthesis and Function in Organisms)
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20 pages, 3742 KiB  
Review
Therapeutic Applications of Rosmarinic Acid in Cancer-Chemotherapy-Associated Resistance and Toxicity
by Cecilia Villegas, Nicole Cortez, Ayorinde Victor Ogundele, Viviana Burgos, Paulo Celso Pardi, Jaime R. Cabrera-Pardo and Cristian Paz
Biomolecules 2024, 14(7), 867; https://doi.org/10.3390/biom14070867 - 19 Jul 2024
Viewed by 113
Abstract
Chemotherapeutic drugs and radiotherapy are fundamental treatments to combat cancer, but, often, the doses in these treatments are restricted by their non-selective toxicities, which affect healthy tissues surrounding tumors. On the other hand, drug resistance is recognized as the main cause of chemotherapeutic [...] Read more.
Chemotherapeutic drugs and radiotherapy are fundamental treatments to combat cancer, but, often, the doses in these treatments are restricted by their non-selective toxicities, which affect healthy tissues surrounding tumors. On the other hand, drug resistance is recognized as the main cause of chemotherapeutic treatment failure. Rosmarinic acid (RA) is a polyphenol of the phenylpropanoid family that is widely distributed in plants and vegetables, including medicinal aromatic herbs, consumption of which has demonstrated beneficial activities as antioxidants and anti-inflammatories and reduced the risks of cancers. Recently, several studies have shown that RA is able to reverse cancer resistance to first-line chemotherapeutics, as well as play a protective role against toxicity induced by chemotherapy and radiotherapy, mainly due to its scavenger capacity. This review compiles information from 56 articles from Google Scholar, PubMed, and ClinicalTrials.gov aimed at addressing the role of RA as a complementary therapy in cancer treatment. Full article
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19 pages, 4887 KiB  
Review
Calreticulin—Enigmatic Discovery
by Gillian C. Okura, Alamelu G. Bharadwaj and David M. Waisman
Biomolecules 2024, 14(7), 866; https://doi.org/10.3390/biom14070866 - 19 Jul 2024
Viewed by 83
Abstract
Calreticulin (CRT) is an intrinsically disordered multifunctional protein that plays essential roles intra-and extra-cellularly. The Michalak laboratory has proposed that CRT was initially identified in 1974 by the MacLennan laboratory as the high-affinity Ca2+-binding protein (HACBP) of the sarcoplasmic reticulin (SR). [...] Read more.
Calreticulin (CRT) is an intrinsically disordered multifunctional protein that plays essential roles intra-and extra-cellularly. The Michalak laboratory has proposed that CRT was initially identified in 1974 by the MacLennan laboratory as the high-affinity Ca2+-binding protein (HACBP) of the sarcoplasmic reticulin (SR). This widely accepted belief has been ingrained in the scientific literature but has never been rigorously tested. In our report, we have undertaken a comprehensive reexamination of this assumption by meticulously examining the majority of published studies that present a proteomic analysis of the SR. These analyses have utilized proteomic analysis of purified SR preparations or purified components of the SR, namely the longitudinal tubules and junctional terminal cisternae. These studies have consistently failed to detect the HACBP or CRT in skeletal muscle SR. We propose that the existence of the HACBP has failed the test of reproducibility and should be retired to the annals of antiquity. Therefore, the scientific dogma that the HACBP and CRT are identical proteins is a non sequitur. Full article
(This article belongs to the Special Issue The Structure and Function of Proteins, Lipids and Nucleic Acids)
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5 pages, 1521 KiB  
Editorial
Application of Calcium Kinetics Characterization in Cardiac Disease Modeling and Drug Discovery
by Richard J. Roberts and Chi Keung Lam
Biomolecules 2024, 14(7), 865; https://doi.org/10.3390/biom14070865 - 19 Jul 2024
Viewed by 165
Abstract
Calcium regulation is essential in virtually any cell due to its critical role as a second messenger in multiple signaling pathways [...] Full article
(This article belongs to the Special Issue Calcium Regulation in the Cardiac Cells)
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7 pages, 2549 KiB  
Brief Report
TRAF1 Deficiency in Macrophages Drives Exacerbated Joint Inflammation in Rheumatoid Arthritis
by Ali Mirzaesmaeili and Ali A. Abdul-Sater
Biomolecules 2024, 14(7), 864; https://doi.org/10.3390/biom14070864 - 19 Jul 2024
Viewed by 145
Abstract
The tumor necrosis factor receptor-associated factor 1 (TRAF1) plays a key role in promoting lymphocyte survival, proliferation, and cytokine production. Recent evidence showed that TRAF1 plays opposing roles in monocytes and macrophages where it controls NF-κB activation and limits pro-inflammatory cytokine production as [...] Read more.
The tumor necrosis factor receptor-associated factor 1 (TRAF1) plays a key role in promoting lymphocyte survival, proliferation, and cytokine production. Recent evidence showed that TRAF1 plays opposing roles in monocytes and macrophages where it controls NF-κB activation and limits pro-inflammatory cytokine production as well as inflammasome-dependent IL-1β secretion. Importantly, TRAF1 polymorphisms have been strongly linked to an increased risk of rheumatoid arthritis (RA). However, whether and how TRAF1 contributes to RA pathogenesis is not fully understood. Moreover, investigating the role of TRAF1 in driving RA pathogenesis is complicated by its multifaceted and opposing roles in various immune cells. In this study, we subjected wildtype (WT) mice to the collagen antibody-induced arthritis (CAIA) model of RA and injected them intra-articularly with WT- or TRAF1-deficient macrophages. We show that mice injected with TRAF1-deficient macrophages exhibited significantly exacerbated joint inflammation, immune cell infiltration, and tissue damage compared to mice injected with WT macrophages. This study may lay the groundwork for novel therapies for RA that target TRAF1 in macrophages. Full article
(This article belongs to the Special Issue Role of TRAF1 in Regulating Inflammation and Cell Survival)
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22 pages, 1014 KiB  
Review
Zinc Deficiency and Zinc Supplementation in Allergic Diseases
by Martina Maywald and Lothar Rink
Biomolecules 2024, 14(7), 863; https://doi.org/10.3390/biom14070863 - 19 Jul 2024
Viewed by 237
Abstract
In recent decades, it has become clear that allergic diseases are on the rise in both Western and developing countries. The exact reason for the increase in prevalence has not been conclusively clarified yet. Multidimensional approaches are suspected in which diet and nutrition [...] Read more.
In recent decades, it has become clear that allergic diseases are on the rise in both Western and developing countries. The exact reason for the increase in prevalence has not been conclusively clarified yet. Multidimensional approaches are suspected in which diet and nutrition seem to play a particularly important role. Allergic diseases are characterized by a hyper-reactive immune system to usually harmless allergens, leading to chronic inflammatory diseases comprising respiratory diseases like asthma and allergic rhinitis (AR), allergic skin diseases like atopic dermatitis (AD), and food allergies. There is evidence that diet can have a positive or negative influence on both the development and severity of allergic diseases. In particular, the intake of the essential trace element zinc plays a very important role in modulating the immune response, which was first demonstrated around 60 years ago. The most prevalent type I allergies are mainly based on altered immunoglobulin (Ig)E and T helper (Th)2 cytokine production, leading to type 2 inflammation. This immune status can also be observed during zinc deficiency and can be positively influenced by zinc supplementation. The underlying immunological mechanisms are very complex and multidimensional. Since zinc supplements vary in dose and bioavailability, and clinical trials often differ in design and structure, different results can be observed. Therefore, different results are not surprising. However, the current literature suggests a link between zinc deficiency and the development of allergies, and shows positive effects of zinc supplementation on modulating the immune system and reducing allergic symptoms, which are discussed in more detail in this review. Full article
(This article belongs to the Special Issue Zinc in Health and Disease Conditions II)
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21 pages, 2364 KiB  
Review
Roles of Lysine Methylation in Glucose and Lipid Metabolism: Functions, Regulatory Mechanisms, and Therapeutic Implications
by Zhen Wang and Huadong Liu
Biomolecules 2024, 14(7), 862; https://doi.org/10.3390/biom14070862 - 19 Jul 2024
Viewed by 218
Abstract
Glucose and lipid metabolism are essential energy sources for the body. Dysregulation in these metabolic pathways is a significant risk factor for numerous acute and chronic diseases, including type 2 diabetes (T2DM), Alzheimer’s disease (AD), obesity, and cancer. Post-translational modifications (PTMs), which regulate [...] Read more.
Glucose and lipid metabolism are essential energy sources for the body. Dysregulation in these metabolic pathways is a significant risk factor for numerous acute and chronic diseases, including type 2 diabetes (T2DM), Alzheimer’s disease (AD), obesity, and cancer. Post-translational modifications (PTMs), which regulate protein structure, localization, function, and activity, play a crucial role in managing cellular glucose and lipid metabolism. Among these PTMs, lysine methylation stands out as a key dynamic modification vital for the epigenetic regulation of gene transcription. Emerging evidence indicates that lysine methylation significantly impacts glucose and lipid metabolism by modifying key enzymes and proteins. This review summarizes the current understanding of lysine methylation’s role and regulatory mechanisms in glucose and lipid metabolism. We highlight the involvement of methyltransferases (KMTs) and demethylases (KDMs) in generating abnormal methylation signals affecting these metabolic pathways. Additionally, we discuss the chemical biology and pharmacology of KMT and KDM inhibitors and targeted protein degraders, emphasizing their clinical implications for diseases such as diabetes, obesity, neurodegenerative disorders, and cancers. This review suggests that targeting lysine methylation in glucose and lipid metabolism could be an ideal therapeutic strategy for treating these diseases. Full article
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39 pages, 2267 KiB  
Review
Recent Advances in Hydrogel-Based 3D Bioprinting and Its Potential Application in the Treatment of Congenital Heart Disease
by Tasneem Salih, Massimo Caputo and Mohamed T. Ghorbel
Biomolecules 2024, 14(7), 861; https://doi.org/10.3390/biom14070861 - 18 Jul 2024
Viewed by 203
Abstract
Congenital heart disease (CHD) is the most common birth defect, requiring invasive surgery often before a child’s first birthday. Current materials used during CHD surgery lack the ability to grow, remodel, and regenerate. To solve those limitations, 3D bioprinting is an emerging tool [...] Read more.
Congenital heart disease (CHD) is the most common birth defect, requiring invasive surgery often before a child’s first birthday. Current materials used during CHD surgery lack the ability to grow, remodel, and regenerate. To solve those limitations, 3D bioprinting is an emerging tool with the capability to create tailored constructs based on patients’ own imaging data with the ability to grow and remodel once implanted in children with CHD. It has the potential to integrate multiple bioinks with several cell types and biomolecules within 3D-bioprinted constructs that exhibit good structural fidelity, stability, and mechanical integrity. This review gives an overview of CHD and recent advancements in 3D bioprinting technologies with potential use in the treatment of CHD. Moreover, the selection of appropriate biomaterials based on their chemical, physical, and biological properties that are further manipulated to suit their application are also discussed. An introduction to bioink formulations composed of various biomaterials with emphasis on multiple cell types and biomolecules is briefly overviewed. Vasculogenesis and angiogenesis of prefabricated 3D-bioprinted structures and novel 4D printing technology are also summarized. Finally, we discuss several restrictions and our perspective on future directions in 3D bioprinting technologies in the treatment of CHD. Full article
(This article belongs to the Special Issue Biomolecules and Biomaterials for Tissue Engineering)
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22 pages, 1582 KiB  
Article
Cimicifugoside H-2 as an Inhibitor of IKK1/Alpha: A Molecular Docking and Dynamic Simulation Study
by Shahd Aboul Hosn, Christina El Ahmadieh, Sergio Thoumi, Aia Sinno and Charbel Al Khoury
Biomolecules 2024, 14(7), 860; https://doi.org/10.3390/biom14070860 - 17 Jul 2024
Viewed by 200
Abstract
One of the most challenging issues scientists face is finding a suitable non-invasive treatment for cancer, as it is widespread around the world. The efficacy of phytochemicals that target oncogenic pathways appears to be quite promising and has gained attention over the past [...] Read more.
One of the most challenging issues scientists face is finding a suitable non-invasive treatment for cancer, as it is widespread around the world. The efficacy of phytochemicals that target oncogenic pathways appears to be quite promising and has gained attention over the past few years. We investigated the effect of docking phytochemicals isolated from the rhizomes of the Cimicifuga foetida plant on different domains of the IκB kinase alpha (IKK1/alpha) protein. The Cimicifugoside H-2 phytochemical registered a high docking score on the activation loop of IKK1/alpha amongst the other phytochemicals compared to the positive control. The interaction of the protein with Cimicifugoside H-2 was mostly stabilized by hydrogen bonds and hydrophobic interactions. A dynamic simulation was then performed with the Cimicifugoside H-2 phytochemical on the activation loop of IKK1/alpha, revealing that Cimicifugoside H-2 is a possible inhibitor of this protein. The pharmacokinetic properties of the drug were also examined to assess the safety of administering the drug. Therefore, in this in silico study, we discovered that the Cimicifugoside H-2 phytochemical inhibits the actively mutated conformation of IKK1/alpha, potentially suppressing the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway. Full article
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29 pages, 3133 KiB  
Review
Comprehensive Review on Bimolecular Fluorescence Complementation and Its Application in Deciphering Protein–Protein Interactions in Cell Signaling Pathways
by Houming Ren, Qingshan Ou, Qian Pu, Yuqi Lou, Xiaolin Yang, Yujiao Han and Shiping Liu
Biomolecules 2024, 14(7), 859; https://doi.org/10.3390/biom14070859 - 17 Jul 2024
Viewed by 197
Abstract
Signaling pathways are responsible for transmitting information between cells and regulating cell growth, differentiation, and death. Proteins in cells form complexes by interacting with each other through specific structural domains, playing a crucial role in various biological functions and cell signaling pathways. Protein–protein [...] Read more.
Signaling pathways are responsible for transmitting information between cells and regulating cell growth, differentiation, and death. Proteins in cells form complexes by interacting with each other through specific structural domains, playing a crucial role in various biological functions and cell signaling pathways. Protein–protein interactions (PPIs) within cell signaling pathways are essential for signal transmission and regulation. The spatiotemporal features of PPIs in signaling pathways are crucial for comprehending the regulatory mechanisms of signal transduction. Bimolecular fluorescence complementation (BiFC) is one kind of imaging tool for the direct visualization of PPIs in living cells and has been widely utilized to uncover novel PPIs in various organisms. BiFC demonstrates significant potential for application in various areas of biological research, drug development, disease diagnosis and treatment, and other related fields. This review systematically summarizes and analyzes the technical advancement of BiFC and its utilization in elucidating PPIs within established cell signaling pathways, including TOR, PI3K/Akt, Wnt/β-catenin, NF-κB, and MAPK. Additionally, it explores the application of this technology in revealing PPIs within the plant hormone signaling pathways of ethylene, auxin, Gibberellin, and abscisic acid. Using BiFC in conjunction with CRISPR-Cas9, live-cell imaging, and ultra-high-resolution microscopy will enhance our comprehension of PPIs in cell signaling pathways. Full article
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28 pages, 7866 KiB  
Review
Recent Advances in Hydrogel Technology in Delivering Mesenchymal Stem Cell for Osteoarthritis Therapy
by Xiangjiang Wang, Wentao He, Hao Huang, Jiali Han, Ruren Wang, Hongyi Li, Ying Long, Guiqing Wang and Xianjing Han
Biomolecules 2024, 14(7), 858; https://doi.org/10.3390/biom14070858 - 17 Jul 2024
Viewed by 263
Abstract
Osteoarthritis (OA), a chronic joint disease affecting over 500 million individuals globally, is characterized by the destruction of articular cartilage and joint inflammation. Conventional treatments are insufficient for repairing damaged joint tissue, necessitating novel therapeutic approaches. Mesenchymal stem cells (MSCs), with their potential [...] Read more.
Osteoarthritis (OA), a chronic joint disease affecting over 500 million individuals globally, is characterized by the destruction of articular cartilage and joint inflammation. Conventional treatments are insufficient for repairing damaged joint tissue, necessitating novel therapeutic approaches. Mesenchymal stem cells (MSCs), with their potential for differentiation and self-renewal, hold great promise as a treatment for OA. However, challenges such as MSC viability and apoptosis in the ischemic joint environment hinder their therapeutic effectiveness. Hydrogels with biocompatibility and degradability offer a three-dimensional scaffold that support cell viability and differentiation, making them ideal for MSC delivery in OA treatment. This review discusses the pathological features of OA, the properties of MSCs, the challenges associated with MSC therapy, and methods for hydrogel preparation and functionalization. Furthermore, it highlights the advantages of hydrogel-based MSC delivery systems while providing insights into future research directions and the clinical potential of this approach. Full article
(This article belongs to the Special Issue Recent Developments in Mesenchymal Stem Cells)
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11 pages, 743 KiB  
Perspective
Towards a Treatment for Leukodystrophy Using Cell-Based Interception and Precision Medicine
by Benoit Coulombe, Alexandra Chapleau, Julia Macintosh, Thomas M. Durcan, Christian Poitras, Yena A. Moursli, Denis Faubert, Maxime Pinard and Geneviève Bernard
Biomolecules 2024, 14(7), 857; https://doi.org/10.3390/biom14070857 - 17 Jul 2024
Viewed by 233
Abstract
Cell-based interception and precision medicine is a novel approach aimed at improving healthcare through the early detection and treatment of diseased cells. Here, we describe our recent progress towards developing cell-based interception and precision medicine to detect, understand, and advance the development of [...] Read more.
Cell-based interception and precision medicine is a novel approach aimed at improving healthcare through the early detection and treatment of diseased cells. Here, we describe our recent progress towards developing cell-based interception and precision medicine to detect, understand, and advance the development of novel therapeutic approaches through a single-cell omics and drug screening platform, as part of a multi-laboratory collaborative effort, for a group of neurodegenerative disorders named leukodystrophies. Our strategy aims at the identification of diseased cells as early as possible to intercept progression of the disease prior to severe clinical impairment and irreversible tissue damage. Full article
(This article belongs to the Section Molecular Biology)
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9 pages, 588 KiB  
Communication
Ischemic Neuroprotection by Insulin with Down-Regulation of Divalent Metal Transporter 1 (DMT1) Expression and Ferrous Iron-Dependent Cell Death
by Francesca Fenaroli, Alessandra Valerio and Rosaria Ingrassia
Biomolecules 2024, 14(7), 856; https://doi.org/10.3390/biom14070856 - 15 Jul 2024
Viewed by 375
Abstract
Background: The regulation of divalent metal transporter-1 (DMT1) by insulin has been previously described in Langerhans cells and significant neuroprotection was found by insulin and insulin-like growth factor 1 treatment during experimental cerebral ischemia in acute ischemic stroke patients and in a rat [...] Read more.
Background: The regulation of divalent metal transporter-1 (DMT1) by insulin has been previously described in Langerhans cells and significant neuroprotection was found by insulin and insulin-like growth factor 1 treatment during experimental cerebral ischemia in acute ischemic stroke patients and in a rat 6-OHDA model of Parkinson’s disease, where DMT1 involvement is described. According to the regulation of DMT1, previously described as a target gene of NF-kB in the early phase of post-ischemic neurodegeneration, both in vitro and in vivo, and because insulin controls the NFkB signaling with protection from ischemic cell death in rat cardiomyocytes, we evaluated the role of insulin in relation to DMT1 expression and function during ischemic neurodegeneration. Methods: Insulin neuroprotection is evaluated in differentiated human neuroblastoma cells, SK-N-SH, and in primary mouse cortical neurons exposed to oxygen glucose deprivation (OGD) for 8 h or 3 h, respectively, with or without 300 nM insulin. The insulin neuroprotection during OGD was evaluated in both cellular models in terms of cell death, and in SK-N-SH for DMT1 protein expression and acute ferrous iron treatment, performed in acidic conditions, known to promote the maximum DMT1 uptake as a proton co-transporter; and the transactivation of 1B/DMT1 mouse promoter, already known to be responsive to NF-kB, was analyzed in primary mouse cortical neurons. Results: Insulin neuroprotection during OGD was concomitant to the down-regulation of both DMT1 protein expression and 1B/DMT1 mouse promoter transactivation. We also showed the insulin-dependent protection from cell death after acute ferrous iron treatment. In conclusion, although preliminary, this evaluation highlights the peculiar role of DMT1 as a possible pharmacological target, involved in neuroprotection by insulin during in vitro neuronal ischemia and acute ferrous iron uptake. Full article
(This article belongs to the Special Issue The Role of Metals Ions in Neurodegenerative Diseases)
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19 pages, 2747 KiB  
Article
Pathological Defects in a Drosophila Model of Alzheimer’s Disease and Beneficial Effects of the Natural Product Lisosan G
by Silvia Bongiorni, Elisabetta Catalani, Ivan Arisi, Francesca Lazzarini, Simona Del Quondam, Kashi Brunetti, Davide Cervia and Giorgio Prantera
Biomolecules 2024, 14(7), 855; https://doi.org/10.3390/biom14070855 - 15 Jul 2024
Viewed by 322
Abstract
Alzheimer’s disease (AD) brains are histologically marked by the presence of intracellular and extracellular amyloid deposits, which characterize the onset of the disease pathogenesis. Increasing evidence suggests that certain nutrients exert a direct or indirect effect on amyloid β (Aβ)-peptide production and accumulation [...] Read more.
Alzheimer’s disease (AD) brains are histologically marked by the presence of intracellular and extracellular amyloid deposits, which characterize the onset of the disease pathogenesis. Increasing evidence suggests that certain nutrients exert a direct or indirect effect on amyloid β (Aβ)-peptide production and accumulation and, consequently, on AD pathogenesis. We exploited the fruit fly Drosophila melanogaster model of AD to evaluate in vivo the beneficial properties of Lisosan G, a fermented powder obtained from organic whole grains, on the intracellular Aβ-42 peptide accumulation and related pathological phenotypes of AD. Our data showed that the Lisosan G-enriched diet attenuates the production of neurotoxic Aβ peptides in fly brains and reduces neuronal apoptosis. Notably, Lisosan G exerted anti-oxidant effects, lowering brain levels of reactive oxygen species and enhancing mitochondrial activity. These aspects paralleled the increase in autophagy turnover and the inhibition of nucleolar stress. Our results give support to the use of the Drosophila model not only to investigate the molecular genetic bases of neurodegenerative disease but also to rapidly and reliably test the efficiency of potential therapeutic agents and diet regimens. Full article
(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)
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29 pages, 1451 KiB  
Review
Recent Advances in Gene Therapy for Hemophilia: Projecting the Perspectives
by Nikita Chernyi, Darina Gavrilova, Mane Saruhanyan, Ezekiel S. Oloruntimehin, Alexander Karabelsky, Evgeny Bezsonov and Alexander Malogolovkin
Biomolecules 2024, 14(7), 854; https://doi.org/10.3390/biom14070854 - 15 Jul 2024
Viewed by 350
Abstract
One of the well-known X-linked genetic disorders is hemophilia, which could be hemophilia A as a result of a mutation in the F8 (factor VIII) gene or hemophilia B as a result of a mutation in the F9 (factor IX) gene, leading to [...] Read more.
One of the well-known X-linked genetic disorders is hemophilia, which could be hemophilia A as a result of a mutation in the F8 (factor VIII) gene or hemophilia B as a result of a mutation in the F9 (factor IX) gene, leading to insufficient levels of the proteins essential for blood coagulation cascade. In patients with severe hemophilia, factor VIII or factor IX activities in the blood plasma are considerably low, estimated to be less than 1%. This is responsible for spontaneous or post-traumatic bleeding episodes, or both, leading to disease complications and death. Current treatment of hemophilia relies on the prevention of bleeding, which consists of expensive lifelong replacement infusion therapy of blood plasma clotting factors, their recombinant versions, or therapy with recombinant monoclonal antibodies. Recently emerged gene therapy approaches may be a potential game changer that could reshape the therapeutic outcomes of hemophilia A or B using a one-off vector in vivo delivery and aim to achieve long-term endogenous expression of factor VIII or IX. This review examines both traditional approaches to the treatment of hemophilia and modern methods, primarily focusing on gene therapy, to update knowledge in this area. Recent technological advances and gene therapeutics in the pipeline are critically reviewed and summarized. We consider gene therapy to be the most promising method as it may overcome the problems associated with more traditional treatments, such as the need for constant and expensive infusions and the presence of an immune response to the antibody drugs used to treat hemophilia. Full article
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16 pages, 1899 KiB  
Review
Calcium and Non-Penetrating Traumatic Brain Injury: A Proposal for the Implementation of an Early Therapeutic Treatment for Initial Head Insults
by Danton H. O’Day
Biomolecules 2024, 14(7), 853; https://doi.org/10.3390/biom14070853 - 15 Jul 2024
Viewed by 317
Abstract
Finding an effective treatment for traumatic brain injury is challenging for multiple reasons. There are innumerable different causes and resulting levels of damage for both penetrating and non-penetrating traumatic brain injury each of which shows diverse pathophysiological progressions. More concerning is that disease [...] Read more.
Finding an effective treatment for traumatic brain injury is challenging for multiple reasons. There are innumerable different causes and resulting levels of damage for both penetrating and non-penetrating traumatic brain injury each of which shows diverse pathophysiological progressions. More concerning is that disease progression can take decades before neurological symptoms become obvious. Currently, the primary treatment for non-penetrating mild traumatic brain injury, also called concussion, is bed rest despite the fact the majority of emergency room visits for traumatic brain injury are due to this mild form. Furthermore, one-third of mild traumatic brain injury cases progress to long-term serious symptoms. This argues for the earliest therapeutic intervention for all mild traumatic brain injury cases which is the focus of this review. Calcium levels are greatly increased in damaged brain regions as a result of the initial impact due to tissue damage as well as disrupted ion channels. The dysregulated calcium level feedback is a diversity of ways to further augment calcium neurotoxicity. This suggests that targeting calcium levels and function would be a strong therapeutic approach. An effective calcium-based traumatic brain injury therapy could best be developed through therapeutic programs organized in professional team sports where mild traumatic brain injury events are common, large numbers of subjects are involved and professional personnel are available to oversee treatment and documentation. This review concludes with a proposal with that focus. Full article
(This article belongs to the Special Issue Recent Advances in Neurological Diseases)
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22 pages, 5924 KiB  
Article
The Immunological Profile of Adipose Mesenchymal Stromal/Stem Cells after Cell Expansion and Inflammatory Priming
by Karolien Buyl, Makram Merimi, Robim M. Rodrigues, Saida Rahmani, Mohammad Fayyad-Kazan, Fatima Bouhtit, Noureddine Boukhatem, Tamara Vanhaecke, Hassan Fahmi, Joery De Kock and Mehdi Najar
Biomolecules 2024, 14(7), 852; https://doi.org/10.3390/biom14070852 - 15 Jul 2024
Viewed by 390
Abstract
Background: AT-MSCs display great immunoregulatory features, making them potential candidates for cell-based therapy. This study aimed to evaluate the “RBC lysis buffer” isolation protocol and immunological profiling of the so-obtained AT-MSCs. Methods: We established an immune-comparative screening of AT-MSCs throughout in vitro cell [...] Read more.
Background: AT-MSCs display great immunoregulatory features, making them potential candidates for cell-based therapy. This study aimed to evaluate the “RBC lysis buffer” isolation protocol and immunological profiling of the so-obtained AT-MSCs. Methods: We established an immune-comparative screening of AT-MSCs throughout in vitro cell expansion (PM, P1, P2, P3, P4) and inflammatory priming regarding the expression of 28 cell-surface markers, 6 cytokines/chemokines, and 10 TLR patterns. Findings: AT-MSCs were highly expandable and sensitive to microenvironment challenges, hereby showing plasticity in distinct expression profiles. Both cell expansion and inflammation differentially modulated the expression profile of CD34, HLA-DR, CD40, CD62L, CD200 and CD155, CD252, CD54, CD58, CD106, CD274 and CD112. Inflammation resulted in a significant increase in the expression of the cytokines IL-6, IL-8, IL-1β, IL-1Ra, CCL5, and TNFα. Depending on the culture conditions, the expression of the TLR pattern was distinctively altered with TLR1–4, TLR7, and TLR10 being increased, whereas TLR6 was downregulated. Protein network and functional enrichment analysis showed that several trophic and immune responses are likely linked to these immunological changes. Conclusions: AT-MSCs may sense and actively respond to tissue challenges by modulating distinct and specific pathways to create an appropriate immuno-reparative environment. These mechanisms need to be further characterized to identify and assess a molecular target that can enhance or impede the therapeutic ability of AT-MSCs, which therefore will help improve the quality, safety, and efficacy of the therapeutic strategy. Full article
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19 pages, 2491 KiB  
Article
Assessment of Antimicrobial and Cytotoxic Activities of Liposomes Loaded with Curcumin and Lippia origanoides Essential Oil
by Juan Pablo Bedoya-Agudelo, Jhon Esteban López-Carvajal, Edwin Stiven Quiguanás-Guarín, Nestor Cardona, Leonardo Padilla-Sanabria and Jhon Carlos Castaño-Osorio
Biomolecules 2024, 14(7), 851; https://doi.org/10.3390/biom14070851 - 15 Jul 2024
Viewed by 474
Abstract
(1) Introduction: Curcumin and Lippia origanoides essential oils have a broad spectrum of biological activities; however, their physicochemical instability, low solubility, and high volatility limit their therapeutic use. Encapsulation in liposomes has been reported as a feasible approach to increase the physicochemical stability [...] Read more.
(1) Introduction: Curcumin and Lippia origanoides essential oils have a broad spectrum of biological activities; however, their physicochemical instability, low solubility, and high volatility limit their therapeutic use. Encapsulation in liposomes has been reported as a feasible approach to increase the physicochemical stability of active substances, protect them from interactions with the environment, modulate their release, reduce their volatility, improve their bioactivity, and reduce their toxicity. To date, there are no reports on the co-encapsulation of curcumin and Lippia origanoides essential oils in liposomes. Therefore, the objective of this work is to prepare and physiochemical characterize liposomes loaded with the mixture of these compounds and to evaluate different in vitro biological activities. (2) Methods: Liposomes were produced using the thin-layer method and physiochemical characteristics were calculated. The antimicrobial and cytotoxic activities of both encapsulated and non-encapsulated compounds were evaluated. (3) Results: Empty and loaded nanometric-sized liposomes were obtained that are monodisperse and have a negative zeta potential. They inhibited the growth of Staphylococcus aureus and did not exhibit cytotoxic activity against mammalian cells. (4) Conclusions: Encapsulation in liposomes was demonstrated to be a promising strategy for natural compounds possessing antimicrobial activity. Full article
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13 pages, 1180 KiB  
Article
Hepatic Gene Expression and Metabolite Profiles of Androstenone and Skatole Relative to Plasma Estrone Sulfate Levels in Boars
by Christine Bone and E. James Squires
Biomolecules 2024, 14(7), 850; https://doi.org/10.3390/biom14070850 - 15 Jul 2024
Viewed by 371
Abstract
Testicular steroids can alter the activity and expression of enzymes within the liver and may influence the metabolism of skatole and androstenone, which are responsible for boar taint. Plasma levels of estrone sulfate (E1S) are indicative of the steroidogenic capacity of [...] Read more.
Testicular steroids can alter the activity and expression of enzymes within the liver and may influence the metabolism of skatole and androstenone, which are responsible for boar taint. Plasma levels of estrone sulfate (E1S) are indicative of the steroidogenic capacity of the boar and are variable between animals of similar live weights at slaughter. This study aimed to characterize the relationship between steroidogenic capacity and the metabolism of boar taint compounds by relating plasma E1S levels at slaughter weight to the expression levels of genes regulating the metabolism of androstenone and skatole, along with their respective metabolite profiles. RT-qPCR was used to evaluate gene expression in the liver. Hepatocytes were also isolated and treated with androstenone or skatole, with metabolite levels in the incubation media quantified by high-performance liquid chromatography. Plasma E1S levels ranged from 2.2–108.5 ng/mL and were positively correlated with overall skatole metabolism (p = 0.038), the production of metabolites 3-methyloxindole (p = 0.026) and 3-hydroxy-3-methyloxindole (p = 0.036), and expression levels of key genes involved in skatole metabolism, specifically CYP2C33 (p = 0.0042), CYP2C49 (p = 0.022), and CYB5R1 (p = 0.017). There was no association between androstenone metabolism and plasma E1S concentrations; however, there was evidence of possible co-regulation amongst genes involved in the metabolism of androstenone, skatole, and estrogens. These findings indicate that steroidogenic capacity is related to the rate of skatole, but not androstenone metabolism, in slaughter-weight boars. Full article
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16 pages, 3429 KiB  
Article
Biocatalytic Method for Producing an Affinity Resin for the Isolation of Immunoglobulins
by Mikhail N. Tereshin, Tatiana D. Melikhova, Barbara Z. Eletskaya, Elena A. Ivanova, Lyudmila V. Onoprienko, Dmitry A. Makarov, Mikhail V. Razumikhin, Igor V. Myagkikh, Igor P. Fabrichniy and Vasiliy N. Stepanenko
Biomolecules 2024, 14(7), 849; https://doi.org/10.3390/biom14070849 - 14 Jul 2024
Viewed by 366
Abstract
Affinity chromatography is a widely used technique for antibody isolation. This article presents the successful synthesis of a novel affinity resin with a mutant form of protein A (BsrtA) immobilized on it as a ligand. The key aspect of the described process is [...] Read more.
Affinity chromatography is a widely used technique for antibody isolation. This article presents the successful synthesis of a novel affinity resin with a mutant form of protein A (BsrtA) immobilized on it as a ligand. The key aspect of the described process is the biocatalytic immobilization of the ligand onto the matrix using the sortase A enzyme. Moreover, we used a matrix with primary amino groups without modification, which greatly simplifies the synthesis process. The resulting resin shows a high dynamic binding capacity (up to 50 mg IgG per 1 mL of sorbent). It also demonstrates high tolerance to 0.1 M NaOH treatment and maintains its effectiveness even after 100 binding, elution, and sanitization cycles. Full article
(This article belongs to the Section Synthetic Biology and Bioengineering)
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27 pages, 4324 KiB  
Review
Role of Type I Interferons during Mycobacterium tuberculosis and HIV Infections
by Elsa Anes, José Miguel Azevedo-Pereira and David Pires
Biomolecules 2024, 14(7), 848; https://doi.org/10.3390/biom14070848 - 14 Jul 2024
Viewed by 327
Abstract
Tuberculosis and AIDS remain two of the most relevant human infectious diseases. The pathogens that cause them, Mycobacterium tuberculosis (Mtb) and HIV, individually elicit an immune response that treads the line between beneficial and detrimental to the host. Co-infection further complexifies this response [...] Read more.
Tuberculosis and AIDS remain two of the most relevant human infectious diseases. The pathogens that cause them, Mycobacterium tuberculosis (Mtb) and HIV, individually elicit an immune response that treads the line between beneficial and detrimental to the host. Co-infection further complexifies this response since the different cytokines acting on one infection might facilitate the dissemination of the other. In these responses, the role of type I interferons is often associated with antiviral mechanisms, while for bacteria such as Mtb, their importance and clinical relevance as a suitable target for manipulation are more controversial. In this article, we review the recent knowledge on how these interferons play distinct roles and sometimes have opposite consequences depending on the stage of the pathogenesis. We highlight the dichotomy between the acute and chronic infections displayed by both infections and how type I interferons contribute to an initial control of each infection individually, while their chronic induction, particularly during HIV infection, might facilitate Mtb primo-infection and progression to disease. We expect that further findings and their systematization will allow the definition of windows of opportunity for interferon manipulation according to the stage of infection, contributing to pathogen clearance and control of immunopathology. Full article
(This article belongs to the Collection Feature Papers in Section Molecular Medicine)
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20 pages, 2799 KiB  
Review
Blood-Derived Extracellular Vesicles as a Promising Liquid Biopsy Diagnostic Tool for Early Cancer Detection
by Dan He, Bozhou Cui, Hongkai Lv, Shuxian Lu, Yuan Zhu, Yuqiang Cheng, Lin Dang and Hong Zhang
Biomolecules 2024, 14(7), 847; https://doi.org/10.3390/biom14070847 - 14 Jul 2024
Viewed by 285
Abstract
Cancer poses a significant public health challenge worldwide, and timely screening has the potential to mitigate cancer progression and reduce mortality rates. Currently, early identification of most tumors relies on imaging techniques and tissue biopsies. However, the use of low-cost, highly sensitive, non-invasive [...] Read more.
Cancer poses a significant public health challenge worldwide, and timely screening has the potential to mitigate cancer progression and reduce mortality rates. Currently, early identification of most tumors relies on imaging techniques and tissue biopsies. However, the use of low-cost, highly sensitive, non-invasive detection methods for early cancer screening has become more attractive. Extracellular Vesicles (EVs) released by all living cells contain distinctive biological components, such as nucleic acids, proteins, and lipids. These vesicles play crucial roles in the tumor microenvironment and intercellular communication during tumor progression, rendering liquid biopsy a particularly suitable method for diagnosis. Nevertheless, challenges related to purification methods and validation of efficacy currently hinder its widespread clinical implementation. These limitations underscore the importance of refining isolation techniques and conducting comprehensive investigations on EVs. This study seeks to evaluate the potential of liquid biopsy utilizing blood-derived EVs as a practical, cost-effective, and secure approach for early cancer detection. Full article
(This article belongs to the Topic Extracellular Vesicles in Cancer Diagnosis and Treatment)
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14 pages, 3273 KiB  
Article
Metformin Restrains the Proliferation of CD4+ T Lymphocytes by Inducing Cell Cycle Arrest in Normo- and Hyperglycemic Conditions
by Ricardo Cartes-Velásquez, Agustín Vera, Bárbara Antilef, Sergio Sanhueza, Liliana Lamperti, Marcelo González-Ortiz and Estefanía Nova-Lamperti
Biomolecules 2024, 14(7), 846; https://doi.org/10.3390/biom14070846 - 14 Jul 2024
Viewed by 432
Abstract
CD4+ T lymphocytes play a key role in the modulation of the immune response by orchestrating both effector and regulatory functions. The effect of metformin on the immunometabolism of CD4+ T lymphocytes has been scarcely studied, and its impact under high glucose conditions, [...] Read more.
CD4+ T lymphocytes play a key role in the modulation of the immune response by orchestrating both effector and regulatory functions. The effect of metformin on the immunometabolism of CD4+ T lymphocytes has been scarcely studied, and its impact under high glucose conditions, particularly concerning effector responses and glucose metabolism, remains unknown. This study aims to evaluate the effect of metformin on the modulation of the effector functions and glucose metabolism of CD4+ T lymphocytes under normo- and hyperglycemic conditions. CD4+ T lymphocytes, obtained from peripheral blood from healthy volunteers, were anti-CD3/CD28-activated and cultured for 4 days with three concentrations of metformin (0.1 mM, 1 mM, and 5 mM) under normoglycemic (5.5 mM) and hyperglycemic (25 mM) conditions. Effector functions such as proliferation, cell count, cell cycle analysis, activation markers and cytokine secretion were analyzed by flow cytometry. Glucose uptake was determined using the 2-NBDG assay, and levels of glucose, lactate, and phosphofructokinase (PFK) activity were assessed by colorimetric assays. Metformin at 5 mM restrained the cell counts and proliferation of CD4+ T lymphocytes by arresting the cell cycle in the S/G2 phase at the beginning of the cell culture, without affecting cell activation, cytokine production, and glucose metabolism. In fact, CD69 expression and IL4 secretion by CD4+ T lymphocytes was higher in the presence of 5 mM than the untreated cells in both glucose conditions. Overall, metformin inhibited proliferation through mechanisms associated with cell cycle arrest, leading to an increase in the S/G2 phases at the expense of G1 in activated CD4+ T lymphocytes in normo- and hyperglycemic conditions. Despite the cell cycle arrest, activated CD4+ T lymphocytes remained metabolically, functionally, and phenotypically activated. Full article
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