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Biomolecules
Volume 14
Issue 7
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Biomolecules, Volume 14, Issue 7 (July 2024) – 150 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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10 pages, 4642 KiB  
Article
Rational Design of Chimeric Antisense Oligonucleotides on a Mixed PO–PS Backbone for Splice-Switching Applications
by Bao T. Le, Suxiang Chen and Rakesh N. Veedu
Biomolecules 2024, 14(7), 883; https://doi.org/10.3390/biom14070883 - 22 Jul 2024
Viewed by 329
Abstract
Synthetic antisense oligonucleotides (ASOs) are emerging as an attractive platform to treat various diseases. By specifically binding to a target mRNA transcript through Watson–Crick base pairing, ASOs can alter gene expression in a desirable fashion to either rescue loss of function or downregulate [...] Read more.
Synthetic antisense oligonucleotides (ASOs) are emerging as an attractive platform to treat various diseases. By specifically binding to a target mRNA transcript through Watson–Crick base pairing, ASOs can alter gene expression in a desirable fashion to either rescue loss of function or downregulate pathogenic protein expression. To be clinically relevant, ASOs are generally synthesized using modified analogs to enhance resistance to enzymatic degradation and pharmacokinetic and dynamic properties. Phosphorothioate (PS) belongs to the first generation of modified analogs and has played a vital role in the majority of approved ASO drugs, mainly based on the RNase H mechanism. In contrast to RNase H-dependent ASOs that bind and cleave target mature mRNA, splice-switching oligonucleotides (SSOs) mainly bind and alter precursor mRNA splicing in the cell nucleus. To date, only one approved SSO (Nusinersen) possesses a PS backbone. Typically, the synthesis of PS oligonucleotides generates two types of stereoisomers that could potentially impact the ASO’s pharmaco-properties. This can be limited by introducing the naturally occurring phosphodiester (PO) linkage to the ASO sequence. In this study, towards fine-tuning the current strategy in designing SSOs, we reported the design, synthesis, and evaluation of several stereo-random SSOs on a mixed PO–PS backbone for their binding affinity, biological potency, and nuclease stability. Based on the results, we propose that a combination of PO and PS linkages could represent a promising approach toward limiting undesirable stereoisomers while not largely compromising the efficacy of SSOs. Full article
(This article belongs to the Special Issue RNA Therapeutics)
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28 pages, 2228 KiB  
Review
The Beak of Eukaryotic Ribosomes: Life, Work and Miracles
by Sara Martín-Villanueva, Carla V. Galmozzi, Carmen Ruger-Herreros, Dieter Kressler and Jesús de la Cruz
Biomolecules 2024, 14(7), 882; https://doi.org/10.3390/biom14070882 - 22 Jul 2024
Viewed by 330
Abstract
Ribosomes are not totally globular machines. Instead, they comprise prominent structural protrusions and a myriad of tentacle-like projections, which are frequently made up of ribosomal RNA expansion segments and N- or C-terminal extensions of ribosomal proteins. This is more evident in higher eukaryotic [...] Read more.
Ribosomes are not totally globular machines. Instead, they comprise prominent structural protrusions and a myriad of tentacle-like projections, which are frequently made up of ribosomal RNA expansion segments and N- or C-terminal extensions of ribosomal proteins. This is more evident in higher eukaryotic ribosomes. One of the most characteristic protrusions, present in small ribosomal subunits in all three domains of life, is the so-called beak, which is relevant for the function and regulation of the ribosome’s activities. During evolution, the beak has transitioned from an all ribosomal RNA structure (helix h33 in 16S rRNA) in bacteria, to an arrangement formed by three ribosomal proteins, eS10, eS12 and eS31, and a smaller h33 ribosomal RNA in eukaryotes. In this review, we describe the different structural and functional properties of the eukaryotic beak. We discuss the state-of-the-art concerning its composition and functional significance, including other processes apparently not related to translation, and the dynamics of its assembly in yeast and human cells. Moreover, we outline the current view about the relevance of the beak’s components in human diseases, especially in ribosomopathies and cancer. Full article
(This article belongs to the Special Issue Ribosomal Proteins in Ribosome Assembly)
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28 pages, 948 KiB  
Review
Readers of RNA Modification in Cancer and Their Anticancer Inhibitors
by Fengli Li and Wenjin Li
Biomolecules 2024, 14(7), 881; https://doi.org/10.3390/biom14070881 - 22 Jul 2024
Viewed by 236
Abstract
Cancer treatment has always been a challenge for humanity. The inadequacies of current technologies underscore the limitations of our efforts against this disease. Nevertheless, the advent of targeted therapy has introduced a promising avenue, furnishing us with more efficacious tools. Consequently, researchers have [...] Read more.
Cancer treatment has always been a challenge for humanity. The inadequacies of current technologies underscore the limitations of our efforts against this disease. Nevertheless, the advent of targeted therapy has introduced a promising avenue, furnishing us with more efficacious tools. Consequently, researchers have turned their attention toward epigenetics, offering a novel perspective in this realm. The investigation of epigenetics has brought RNA readers to the forefront, as they play pivotal roles in recognizing and regulating RNA functions. Recently, the development of inhibitors targeting these RNA readers has emerged as a focal point in research and holds promise for further strides in targeted therapy. In this review, we comprehensively summarize various types of inhibitors targeting RNA readers, including non-coding RNA (ncRNA) inhibitors, small-molecule inhibitors, and other potential inhibitors. We systematically elucidate their mechanisms in suppressing cancer progression by inhibiting readers, aiming to present inhibitors of readers at the current stage and provide more insights into the development of anticancer drugs. Full article
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16 pages, 3058 KiB  
Article
Gut Microbiome Dysbiosis in Patients with Pemphigus and Correlation with Pathogenic Autoantibodies
by Si-Zhe Li, Qing-Yang Wu, Yue Fan, Feng Guo, Xiao-Min Hu and Ya-Gang Zuo
Biomolecules 2024, 14(7), 880; https://doi.org/10.3390/biom14070880 - 22 Jul 2024
Viewed by 327
Abstract
Background: Pemphigus is a group of potentially life-threatening autoimmune bullous diseases induced by pathogenic autoantibodies binding to the surface of epidermal cells. The role of the gut microbiota (GM) has been described in various autoimmune diseases. However, the impact of the GM on [...] Read more.
Background: Pemphigus is a group of potentially life-threatening autoimmune bullous diseases induced by pathogenic autoantibodies binding to the surface of epidermal cells. The role of the gut microbiota (GM) has been described in various autoimmune diseases. However, the impact of the GM on pemphigus is less understood. This study aimed to investigate whether there was alterations in the composition and function of the GM in pemphigus patients compared to healthy controls (HCs). Methods: Fecal samples were collected from 20 patients with active pemphigus (AP), 11 patients with remission pemphigus (PR), and 47 HCs. To sequence the fecal samples, 16S rRNA was applied, and bioinformatic analyses were performed. Results: We found differences in the abundance of certain bacterial taxa among the three groups. At the family level, the abundance of Prevotellaceae and Coriobacteriaceae positively correlated with pathogenic autoantibodies. At the genus level, the abundance of Klebsiella, Akkermansia, Bifidobacterium, Collinsella, Gemmiger, and Prevotella positively correlated with pathogenic autoantibodies. Meanwhile, the abundance of Veillonella and Clostridium_XlVa negatively correlated with pathogenic autoantibodies. A BugBase analysis revealed that the sum of potentially pathogenic bacteria was elevated in the AP group in comparison to the PR group. Additionally, the proportion of Gram-negative bacteria in the PR group was statistically significantly lower in comparison to the HC group. Conclusion: The differences in GM composition among the three groups, and the correlation between certain bacterial taxa and pathogenic autoantibodies of pemphigus, support a linkage between the GM and pemphigus. Full article
(This article belongs to the Special Issue Human Gut Microbiome and Diet in Health and Diseases: 2nd Edition)
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16 pages, 8963 KiB  
Article
Radiation-Induced Endothelial Ferroptosis Accelerates Atherosclerosis via the DDHD2-Mediated Nrf2/GPX4 Pathway
by Xi Su, Feng Liang, Ya Zeng, Zhang-Ru Yang, Yue-Zhen Deng, Yun-Hua Xu and Xu-Wei Cai
Biomolecules 2024, 14(7), 879; https://doi.org/10.3390/biom14070879 - 22 Jul 2024
Viewed by 308
Abstract
This study sought to explore potential roles of endothelial ferroptosis in radiation-associated atherosclerosis (RAA) and molecular mechanisms behind this phenomenon. Here, an in vivo RAA mouse model was used and treated with ferroptosis inhibitors. We found that the RAA group had a higher [...] Read more.
This study sought to explore potential roles of endothelial ferroptosis in radiation-associated atherosclerosis (RAA) and molecular mechanisms behind this phenomenon. Here, an in vivo RAA mouse model was used and treated with ferroptosis inhibitors. We found that the RAA group had a higher plaque burden and a reduction in endothelial cells with increased lipid peroxidation compared to the control group, while ameliorated by liproxstatin-1. In vitro experiments further confirmed that radiation induced the occurrence of ferroptosis in human artery endothelial cells (HAECs). Then, proteomics analysis of HAECs identified domain-containing protein 2 (DDHD2) as a co-differentially expressed protein, which was enriched in the lipid metabolism pathway. In addition, the level of lipid peroxidation was elevated in DDHD2-knockdown HAECs. Mechanistically, a significant decrease in the protein and mRNA expression of glutathione peroxidase 4 (GPX4) was observed in HAECs following DDHD2 knockdown. Co-immunoprecipitation assays indicated a potential interaction between DDHD2 and nuclear factor erythroid 2-related factor 2 (Nrf2). The downregulation of Nrf2 protein was also detected in DDHD2-knockdown HAECs. In conclusion, our findings suggest that radiation-induced endothelial ferroptosis accelerates atherosclerosis, and DDHD2 is a potential regulatory protein in radiation-induced endothelial ferroptosis through the Nrf2/GPX4 pathway. Full article
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14 pages, 614 KiB  
Review
Therapeutics Targeting Skeletal Muscle in Amyotrophic Lateral Sclerosis
by Jinghui Gao, Elijah Sterling, Rachel Hankin, Aria Sikal and Yao Yao
Biomolecules 2024, 14(7), 878; https://doi.org/10.3390/biom14070878 - 22 Jul 2024
Viewed by 405
Abstract
Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly skeletal muscle, in disease pathology and treatment. This is evidenced by restricted ALS-like muscle atrophy, which can retrogradely induce neuromuscular junction and motor neuron degeneration. Moreover, therapeutics targeting skeletal muscles can effectively decelerate disease progression by modulating muscle satellite cells for muscle repair, suppressing inflammation, and promoting the recovery or regeneration of the neuromuscular junction. This review summarizes and discusses therapeutic strategies targeting skeletal muscles for ALS treatment. It aims to provide a comprehensive reference for the development of novel therapeutics targeting skeletal muscles, potentially ameliorating the progression of ALS. Full article
(This article belongs to the Special Issue Molecular Pathology of Amyotrophic Lateral Sclerosis)
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14 pages, 603 KiB  
Review
The Role and Function of TRPM8 in the Digestive System
by Zunan Wu, Shuai Peng, Wensha Huang, Yuling Zhang, Yashi Liu, Xiaoyun Yu and Lei Shen
Biomolecules 2024, 14(7), 877; https://doi.org/10.3390/biom14070877 - 21 Jul 2024
Viewed by 380
Abstract
Transient receptor potential (TRP) melastatin member 8 (TRPM8) is a non-selective cation channel that can be activated by low temperatures (8–26 °C), cooling agents (including menthol analogs such as menthol, icilin, and WS-12), voltage, and extracellular osmotic pressure changes. TRPM8 expression has been [...] Read more.
Transient receptor potential (TRP) melastatin member 8 (TRPM8) is a non-selective cation channel that can be activated by low temperatures (8–26 °C), cooling agents (including menthol analogs such as menthol, icilin, and WS-12), voltage, and extracellular osmotic pressure changes. TRPM8 expression has been identified in the digestive system by several research teams, demonstrating its significant involvement in tissue function and pathologies of the digestive system. Specifically, studies have implicated TRPM8 in various physiological and pathological processes of the esophagus, stomach, colorectal region, liver, and pancreas. This paper aims to comprehensively outline the distinct role of TRPM8 in different organs of the digestive system, offering insights for future mechanistic investigations of TRPM8. Additionally, it presents potential therapeutic targets for treating conditions such as digestive tract inflammation, tumors, sensory and functional disorders, and other related diseases. Furthermore, this paper addresses the limitations of existing studies and highlights the research prospects associated with TRPM8. Full article
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13 pages, 7099 KiB  
Article
Assessment of the Ferroptosis Regulators: Glutathione Peroxidase 4, Acyl-Coenzyme A Synthetase Long-Chain Family Member 4, and Transferrin Receptor 1 in Patient-Derived Endometriosis Tissue
by Lidia A. Mielke Cabello, Gabriela Meresman, Dogus Darici, Noelia Carnovale, Birthe Heitkötter, Miriam Schulte, Nancy A. Espinoza-Sánchez, Quang-Khoi Le, Ludwig Kiesel, Sebastian D. Schäfer and Martin Götte
Biomolecules 2024, 14(7), 876; https://doi.org/10.3390/biom14070876 - 21 Jul 2024
Viewed by 340
Abstract
Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a pivotal role in various diseases and is gaining considerable attention in the realm of endometriosis. Considering the classical pathomechanism theories, we hypothesized that ferroptosis, potentially driven by increased iron content at ectopic sites, [...] Read more.
Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a pivotal role in various diseases and is gaining considerable attention in the realm of endometriosis. Considering the classical pathomechanism theories, we hypothesized that ferroptosis, potentially driven by increased iron content at ectopic sites, may contribute to the progression of endometriosis. This retrospective case–control study provides a comprehensive immunohistochemical assessment of the expression and tissue distribution of established ferroptosis markers: GPX4, ACSL4, and TfR1 in endometriosis patients. The case group consisted of 38 women with laparoscopically and histologically confirmed endometriosis and the control group consisted of 18 women with other gynecological conditions. Our study revealed a significant downregulation of GPX4 in stromal cells of endometriosis patients (M = 59.7% ± 42.4 versus 90.0% ± 17.5 in the control group, t (54) = −2.90, p = 0.005). This finding aligned with slightly, but not significantly, higher iron levels detected in the blood of endometriosis patients, using hemoglobin as an indirect predictor (Hb 12.8 (12.2–13.5) g/dL versus 12.5 (12.2–13.4) g/dL in the control group; t (54) = −0.897, p = 0.374). Interestingly, there was no concurrent upregulation of TfR1 (M = 0.7 ± 1.2 versus 0.2 ± 0.4 for EM, t (54) = 2.552, p = 0.014), responsible for iron uptake into cells. Our empirical findings provide support for the involvement of ferroptosis in the context of endometriosis. However, variances in expression patterns within stromal and epithelial cellular subsets call for further in-depth investigations. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)
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20 pages, 459 KiB  
Review
How Transcription Factor Clusters Shape the Transcriptional Landscape
by Rahul Munshi
Biomolecules 2024, 14(7), 875; https://doi.org/10.3390/biom14070875 - 20 Jul 2024
Viewed by 404
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
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19 pages, 2372 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 - 20 Jul 2024
Viewed by 408
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
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15 pages, 7962 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 - 20 Jul 2024
Viewed by 310
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)
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20 pages, 2345 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 398
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)
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16 pages, 2313 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 292
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)
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18 pages, 3903 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 268
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
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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 341
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 346
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 336
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 238
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 290
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 293
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 614
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 422
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
(This article belongs to the Special Issue Exploring the Dynamics of Protein Lysine Methylation and Its Implication in Disease)
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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 362
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, 2587 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 299
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 317
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
(This article belongs to the Special Issue Advances in Protein–Protein Interactions and Reversible Self-Association)
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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 387
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 450
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 468
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 423
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 479
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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