Journal Description
Biomolecules
Biomolecules
is a peer-reviewed, open access journal on structures and functions of bioactive and biogenic substances, molecular mechanisms with biological and medical implications as well as biomaterials and their applications. Biomolecules is published monthly online by MDPI. The Spanish Society for Biochemistry and Molecular Biology (SEBBM) is affiliated with Biomolecules and their members receive discounts on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q1 (Biochemistry & Molecular Biology) / CiteScore - Q1 (Biochemistry)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 16.9 days after submission; acceptance to publication is undertaken in 2.9 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Sections: published in 19 topical sections.
- Testimonials: See what our editors and authors say about Biomolecules.
- Companion journal: Receptors.
Impact Factor:
5.5 (2022);
5-Year Impact Factor:
5.8 (2022)
Latest Articles
Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases
Biomolecules 2024, 14(5), 588; https://doi.org/10.3390/biom14050588 (registering DOI) - 15 May 2024
Abstract
Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase
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Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.
Full article
(This article belongs to the Special Issue The Role of Cholinesterases in Alzheimer’s Disease and Other Neurodegenerative Disorders)
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Open AccessArticle
A Practical Guide for the Quality Evaluation of Fluobodies/Chromobodies
by
Urša Štrancar, Claudia D’Ercole, Lucia Cikatricisová, Mirna Nakić, Matteo De March and Ario de Marco
Biomolecules 2024, 14(5), 587; https://doi.org/10.3390/biom14050587 (registering DOI) - 15 May 2024
Abstract
Background: Fluorescent proteins (FPs) are pivotal reagents for flow cytometry analysis or fluorescent microscopy. A new generation of immunoreagents (fluobodies/chromobodies) has been developed by fusing recombinant nanobodies to FPs. Methods: We analyzed the quality of such biomolecules by a combination of gel filtration
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Background: Fluorescent proteins (FPs) are pivotal reagents for flow cytometry analysis or fluorescent microscopy. A new generation of immunoreagents (fluobodies/chromobodies) has been developed by fusing recombinant nanobodies to FPs. Methods: We analyzed the quality of such biomolecules by a combination of gel filtration and SDS-PAGE to identify artefacts due to aggregation or material degradation. Results: In the SDS-PAGE run, unexpected bands corresponding to separate fluobodies were evidenced and characterized as either degradation products or artefacts that systematically resulted in the presence of specific FPs and some experimental conditions. The elimination of N-terminal methionine from FPs did not impair the appearance of FP fragments, whereas the stability and migration characteristics of some FP constructs were strongly affected by heating in loading buffer, which is a step samples undergo before electrophoretic separation. Conclusions: In this work, we provide explanations for some odd results observed during the quality control of fluobodies and summarize practical suggestions for the choice of the most convenient FPs to fuse to antibody fragments.
Full article
(This article belongs to the Special Issue Conventional and In Silico-Based Approaches for the Optimization of Nanobody Biophysical Characteristics)
Open AccessArticle
SKGQA, a Peptide Derived from the ANA/BTG3 Protein, Cleaves Amyloid-β with Proteolytic Activity
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Yusuke Hatakawa, Rina Nakamura, Toshifumi Akizawa, Motomi Konishi, Akira Matsuda, Tomoyuki Oe, Motoaki Saito and Fumiaki Ito
Biomolecules 2024, 14(5), 586; https://doi.org/10.3390/biom14050586 (registering DOI) - 15 May 2024
Abstract
Despite the extensive research conducted on Alzheimer’s disease (AD) over the years, no effective drug for AD treatment has been found. Therefore, the development of new drugs for the treatment of AD is of the utmost importance. We recently reported the proteolytic activities
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Despite the extensive research conducted on Alzheimer’s disease (AD) over the years, no effective drug for AD treatment has been found. Therefore, the development of new drugs for the treatment of AD is of the utmost importance. We recently reported the proteolytic activities of JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMA), synthetic peptides of nine amino acids each, derived from the Box A region of Tob1 and ANA/BTG3 proteins, respectively. Furthermore, two components of ANA-TA9, ANA-YA4 (YRMI) at the C-terminus end and ANA-SA5 (SKGQA) at the N-terminus end of ANA-TA9, exhibited proteolytic activity against amyloid-β (Aβ) fragment peptides. In this study, we identified the active center of ANA-SA5 using AEBSF, a serine protease inhibitor, and a peptide in which the Ser residue of ANA-SA5 was replaced with Leu. In addition, we demonstrate the proteolytic activity of ANA-SA5 against the soluble form Aβ42 (a-Aβ42) and solid insoluble form s-Aβ42. Furthermore, ANA-SA5 was not cytotoxic to A549 cells. These results indicate that ANA-SA5 is a promising Catalytide and a potential candidate for the development of new peptide drugs targeting Aβ42 for AD treatment.
Full article
(This article belongs to the Special Issue Amyloid-Beta (Aβ) Production/Clearance Balance and Aβ Neurotoxicity in Alzheimer’s Disease: From Mechanisms to Therapy)
Open AccessReview
Oncogenic Pathways and Targeted Therapies in Ovarian Cancer
by
Carolina Lliberos, Gary Richardson and Antonella Papa
Biomolecules 2024, 14(5), 585; https://doi.org/10.3390/biom14050585 (registering DOI) - 15 May 2024
Abstract
Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment.
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Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments.
Full article
Open AccessReview
Glyoxalase System in Breast and Ovarian Cancers: Role of MEK/ERK/SMAD1 Pathway
by
Muhanad Alhujaily
Biomolecules 2024, 14(5), 584; https://doi.org/10.3390/biom14050584 - 15 May 2024
Abstract
The glyoxalase system, comprising GLO1 and GLO2 enzymes, is integral in detoxifying methylglyoxal (MGO) generated during glycolysis, with dysregulation implicated in various cancer types. The MEK/ERK/SMAD1 signaling pathway, crucial in cellular processes, influences tumorigenesis, metastasis, and angiogenesis. Altered GLO1 expression in cancer showcases
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The glyoxalase system, comprising GLO1 and GLO2 enzymes, is integral in detoxifying methylglyoxal (MGO) generated during glycolysis, with dysregulation implicated in various cancer types. The MEK/ERK/SMAD1 signaling pathway, crucial in cellular processes, influences tumorigenesis, metastasis, and angiogenesis. Altered GLO1 expression in cancer showcases its complex role in cellular adaptation and cancer aggressiveness. GLO2 exhibits context-dependent functions, contributing to both proapoptotic and antiapoptotic effects in different cancer scenarios. Research highlights the interconnected nature of these systems, particularly in ovarian cancer and breast cancer. The glyoxalase system’s involvement in drug resistance and its impact on the MEK/ERK/SMAD1 signaling cascade underscore their clinical significance. Furthermore, this review delves into the urgent need for effective biomarkers, exemplified in ovarian cancer, where the RAGE-ligand pathway emerges as a potential diagnostic tool. While therapeutic strategies targeting these pathways hold promise, this review emphasizes the challenges posed by context-dependent effects and intricate crosstalk within the cellular milieu. Insights into the molecular intricacies of these pathways offer a foundation for developing innovative therapeutic approaches, providing hope for enhanced cancer diagnostics and tailored treatment strategies.
Full article
(This article belongs to the Section Biological Factors)
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Open AccessArticle
Nerve Bundle Density and Expression of NGF and IL-1β Are Intra-Individually Heterogenous in Subtypes of Endometriosis
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Mahfuza Sreya, Dwayne R. Tucker, Jennifer Yi, Fahad T. Alotaibi, Anna F. Lee, Heather Noga and Paul J. Yong
Biomolecules 2024, 14(5), 583; https://doi.org/10.3390/biom14050583 - 15 May 2024
Abstract
Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin–1β (IL-1β). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes
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Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin–1β (IL-1β). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes of endometriosis (deep, superficial peritoneal, endometrioma) at surgery, with at least two surgically excised subtypes available for analysis. Immunolocalization for nerve bundle density around endometriosis using protein gene product 9.5 (PGP9.5), as well as NGF and IL-1β histoscores in endometriosis epithelium/stroma, was performed to evaluate differences in scores between lesions and anatomic subtypes per patient. Intra-individual heterogeneity in scores across lesions was assessed using the coefficient of variation (CV). The degree of score variability between subtypes was evaluated using the percentage difference between mean scores from one subtype to another subtype for each marker. PGP9.5 nerve bundle density was heterogenous across multiple subtypes of endometriosis, ranging from 50.0% to 173.2%, where most patients (8/12) showed CV ≥ 100%. The percentage difference in scores showed that PGP9.5 nerve bundle density and NGF and IL-1β expression were heterogenous between anatomic subtypes within the same patient. Based on these observations of intra-individual heterogeneity, we conclude that markers of neuroproliferation in endometriosis should be stratified by anatomic subtype in future studies of clinical correlation.
Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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Open AccessCommunication
Comparative Analysis of Posiphen Pharmacokinetics across Different Species—Similar Absorption and Metabolism in Mouse, Rat, Dog and Human
by
Maria L. Maccecchini and Diane R. Mould
Biomolecules 2024, 14(5), 582; https://doi.org/10.3390/biom14050582 - 15 May 2024
Abstract
Posiphen is a small molecule that exhibits neuroprotective properties by targeting multiple neurotoxic proteins involved in axonal transport, synaptic transmission, neuroinflammation, and cell death. Its broad-spectrum effects make it a promising candidate for treating neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases. Despite extensive
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Posiphen is a small molecule that exhibits neuroprotective properties by targeting multiple neurotoxic proteins involved in axonal transport, synaptic transmission, neuroinflammation, and cell death. Its broad-spectrum effects make it a promising candidate for treating neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases. Despite extensive investigation with animal models and human subjects, a comprehensive comparative analysis of Posiphen’s pharmacokinetics across studies remains elusive. Here, we address this gap by examining the metabolic profiles of Posiphen and its breakdown into two primary metabolites—N1 and N8—across species by measuring their concentrations in plasma, brain, and CSF using the LC-MS/MS method. While all three compounds effectively inhibit neurotoxic proteins, the N1 metabolite is associated with adverse effects. Our findings reveal the species-specific behavior of Posiphen, with both Posiphen and N8 being predominant in various species, while N1 remains a minor constituent, supporting the drug’s safety. Moreover, in plasma, Posiphen consistently showed fast clearance of all metabolites within 8 h in animal models and in human subjects, whereas in CSF or brain, the compound has an extended half-life of over 12 h. Combining all our human data and analyzing them by population pharmacokinetics showed that there are no differences between healthy volunteers, Alzheimer’s, and Parkinson’s patients. It also showed that Posiphen is absorbed and metabolized in a similar fashion across all animal species and human groups tested. These observations have critical implications for understanding the drug’s safety, therapeutic effect, and clinical translation.
Full article
(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)
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Open AccessArticle
Novel Angiotensin-Converting Enzyme-Inhibitory Peptides Obtained from Trichiurus lepturus: Preparation, Identification and Potential Antihypertensive Mechanism
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Jiaming Cao, Boyuan Xiang, Baojie Dou, Jingfei Hu, Lei Zhang, Xinxin Kang, Mingsheng Lyu and Shujun Wang
Biomolecules 2024, 14(5), 581; https://doi.org/10.3390/biom14050581 - 15 May 2024
Abstract
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Peptides possessing antihypertensive attributes via inhibiting the angiotensin-converting enzyme (ACE) were derived through the enzymatic degradation of Trichiurus lepturus (ribbonfish) using alkaline protease. The resulting mixture underwent filtration using centrifugation, ultrafiltration tubes, and Sephadex G-25 gels. Peptides exhibiting ACE-inhibitory properties and DPPH free-radical-scavenging
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Peptides possessing antihypertensive attributes via inhibiting the angiotensin-converting enzyme (ACE) were derived through the enzymatic degradation of Trichiurus lepturus (ribbonfish) using alkaline protease. The resulting mixture underwent filtration using centrifugation, ultrafiltration tubes, and Sephadex G-25 gels. Peptides exhibiting ACE-inhibitory properties and DPPH free-radical-scavenging abilities were isolated and subsequently purified via LC/MS-MS, leading to the identification of over 100 peptide components. In silico screening yielded five ACE inhibitory peptides: FAGDDAPR, QGPIGPR, IFPRNPP, AGFAGDDAPR, and GPTGPAGPR. Among these, IFPRNPP and AGFAGDDAPR were found to be allergenic, while FAGDDAPRR, QGPIGPR, and GPTGPAGP showed good ACE-inhibitory effects. IC50 values for the latter peptides were obtained from HUVEC cells: FAGDDAPRR (IC50 = 262.98 μM), QGPIGPR (IC50 = 81.09 μM), and GPTGPAGP (IC50 = 168.11 μM). Peptide constituents derived from ribbonfish proteins effectively modulated ACE activity, thus underscoring their therapeutic potential. Molecular docking and modeling corroborated these findings, emphasizing the utility of functional foods as a promising avenue for the treatment and prevention of hypertension, with potential ancillary health benefits and applications as substitutes for synthetic drugs.
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Open AccessArticle
Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model
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Ana Sofia Zabala, Rocío Ayelem Conforti, María Belén Delsouc, Verónica Filippa, Maria Magdalena Montt-Guevara, Andrea Giannini, Tommaso Simoncini, Sandra Silvina Vallcaneras and Marilina Casais
Biomolecules 2024, 14(5), 580; https://doi.org/10.3390/biom14050580 - 15 May 2024
Abstract
Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus, and it is associated with alterations in the expression of hormone receptors and inflammation. Estetrol (E4) is a weak estrogen that recently has been approved for contraception. We evaluated
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Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus, and it is associated with alterations in the expression of hormone receptors and inflammation. Estetrol (E4) is a weak estrogen that recently has been approved for contraception. We evaluated the effect of E4 on the growth of endometriotic-like lesions and the expression of TNF-α, estrogen receptors (ERs), and progesterone receptors (PRs) in an in vivo murine model. Endometriosis was induced surgically in female C57BL/6 mice. E4 was delivered via Alzet pump (3 mg/kg/day) from the 15th postoperative day for 4 weeks. E4 significantly reduced the volume (p < 0.001) and weight (p < 0.05) of ectopic lesions. Histologically, E4 did not affect cell proliferation (PCNA immunohistochemistry) but it did increase cell apoptosis (TUNEL assay) (p < 0.05). Furthermore, it modulated oxidative stress (SOD, CAT, and GPX activity, p < 0.05) and increased lipid peroxidation (TBARS/MDA, p < 0.01). Molecular analysis showed mRNA (RT-qPCR) and protein (ELISA) expression of TNF-α decreased (p < 0.05) and mRNA expression of Esr2 reduced (p < 0.05), in contrast with the increased expression of Esr1 (p < 0.01) and Pgr (p < 0.05). The present study demonstrates for the first time that E4 limited the development and progression of endometriosis in vivo.
Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)
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Open AccessArticle
BSA Binding and Aggregate Formation of a Synthetic Amino Acid with Potential for Promoting Fibroblast Proliferation: An In Silico, CD Spectroscopic, DLS, and Cellular Study
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Hayarpi Simonyan, Rosanna Palumbo, Satenik Petrosyan, Anna Mkrtchyan, Armen Galstyan, Ashot Saghyan, Pasqualina Liana Scognamiglio, Caterina Vicidomini, Marta Fik-Jaskólka and Giovanni N. Roviello
Biomolecules 2024, 14(5), 579; https://doi.org/10.3390/biom14050579 - 14 May 2024
Abstract
This study presents the chemical synthesis, purification, and characterization of a novel non-natural synthetic amino acid. The compound was synthesized in solution, purified, and characterized using NMR spectroscopy, polarimetry, and melting point determination. Dynamic Light Scattering (DLS) analysis demonstrated its ability to form
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This study presents the chemical synthesis, purification, and characterization of a novel non-natural synthetic amino acid. The compound was synthesized in solution, purified, and characterized using NMR spectroscopy, polarimetry, and melting point determination. Dynamic Light Scattering (DLS) analysis demonstrated its ability to form aggregates with an average size of 391 nm, extending to the low micrometric size range. Furthermore, cellular biological assays revealed its ability to enhance fibroblast cell growth, highlighting its potential for tissue regenerative applications. Circular dichroism (CD) spectroscopy showed the ability of the synthetic amino acid to bind serum albumins (using bovine serum albumin (BSA) as a model), and CD deconvolution provided insights into the changes in the secondary structures of BSA upon interaction with the amino acid ligand. Additionally, molecular docking using HDOCK software elucidated the most likely binding mode of the ligand inside the BSA structure. We also performed in silico oligomerization of the synthetic compound in order to obtain a model of aggregate to investigate computationally. In more detail, the dimer formation achieved by molecular self-docking showed two distinct poses, corresponding to the lowest and comparable energies, with one pose exhibiting a quasi-coplanar arrangement characterized by a close alignment of two aromatic rings from the synthetic amino acids within the dimer, suggesting the presence of π-π stacking interactions. In contrast, the second pose displayed a non-coplanar configuration, with the aromatic rings oriented in a staggered arrangement, indicating distinct modes of interaction. Both poses were further utilized in the self-docking procedure. Notably, iterative molecular docking of amino acid structures resulted in the formation of higher-order aggregates, with a model of a 512-mer aggregate obtained through self-docking procedures. This model of aggregate presented a cavity capable of hosting therapeutic cargoes and biomolecules, rendering it a potential scaffold for cell adhesion and growth in tissue regenerative applications. Overall, our findings highlight the potential of this synthetic amino acid for tissue regenerative therapeutics and provide valuable insights into its molecular interactions and aggregation behavior.
Full article
(This article belongs to the Special Issue Protein Structure Prediction in Drug Discovery II)
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Open AccessArticle
Effect of Flavonols of Aronia melanocarpa Fruits on Morphofunctional State of Immunocompetent Organs of Rats under Cyclophosphamide-Induced Immunosuppression
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Kseniya Bushmeleva, Alexandra Vyshtakalyuk, Dmitriy Terenzhev, Timur Belov, Evgeniy Nikitin and Vladimir Zobov
Biomolecules 2024, 14(5), 578; https://doi.org/10.3390/biom14050578 - 14 May 2024
Abstract
Aronia melanocarpa berries contain many compounds with potential benefits for human health. The food flavonoids quercetin and rutin, found in significant amounts in the fruits of A. melanocarpa, are known to have favourable effects on animal and human organisms. However, data on
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Aronia melanocarpa berries contain many compounds with potential benefits for human health. The food flavonoids quercetin and rutin, found in significant amounts in the fruits of A. melanocarpa, are known to have favourable effects on animal and human organisms. However, data on the effect of flavonols isolated from black chokeberry on immune functions during immunosuppression are not available in the literature. Thus, the aim of this study was to evaluate the effect of flavonol fraction isolated from A. melanocarpa fruits, in comparison with pure quercetin and rutin substances, on the dysfunctional state of rat thymus and spleen in immunodeficiency. The study was performed on Wistar rats. The animals were orally administered solutions of the investigated substances for 7 days: water, a mixture of quercetin and rutin and flavonol fraction of A. melanocarpa. For induction of immunosuppression, the animals were injected once intraperitoneally with cyclophosphamide. Substance administration was then continued for another 7 days. The results showed that under the influence of flavonols, there was a decrease in cyclophosphamide-mediated reaction of lipid peroxidation enhancement and stimulation of proliferation of lymphocytes of thymus and spleen in rats. At that, the effect of the flavonol fraction of aronia was more pronounced.
Full article
(This article belongs to the Special Issue Plant Polyphenols in the Immune and Inflammatory Responses - Volume II)
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Open AccessReview
NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases
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Jiafan Xu, Wang Jiang, Tian Hu, Yan Long and Yueming Shen
Biomolecules 2024, 14(5), 577; https://doi.org/10.3390/biom14050577 - 13 May 2024
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Protein ubiquitination is an enzymatic cascade reaction and serves as an important protein post-translational modification (PTM) that is involved in the vast majority of cellular life activities. The key enzyme in the ubiquitination process is E3 ubiquitin ligase (E3), which catalyzes the binding
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Protein ubiquitination is an enzymatic cascade reaction and serves as an important protein post-translational modification (PTM) that is involved in the vast majority of cellular life activities. The key enzyme in the ubiquitination process is E3 ubiquitin ligase (E3), which catalyzes the binding of ubiquitin (Ub) to the protein substrate and influences substrate specificity. In recent years, the relationship between the subfamily of neuron-expressed developmental downregulation 4 (NEDD4), which belongs to the E3 ligase system, and digestive diseases has drawn widespread attention. Numerous studies have shown that NEDD4 and NEDD4L of the NEDD4 family can regulate the digestive function, as well as a series of related physiological and pathological processes, by controlling the subsequent degradation of proteins such as PTEN, c-Myc, and P21, along with substrate ubiquitination. In this article, we reviewed the appropriate functions of NEDD4 and NEDD4L in digestive diseases including cell proliferation, invasion, metastasis, chemotherapeutic drug resistance, and multiple signaling pathways, based on the currently available research evidence for the purpose of providing new ideas for the prevention and treatment of digestive diseases.
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Open AccessArticle
Apigenin Provides Structural Protection to Human Fibrinogen against Nitrosative Stress: Biochemical and Molecular Insights
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Aisha Farhana, Abdullah Alsrhani, Yusuf Saleem Khan, Mohammad Salahuddin, Mohammed Ubaidullah Sayeed and Zafar Rasheed
Biomolecules 2024, 14(5), 576; https://doi.org/10.3390/biom14050576 - 13 May 2024
Abstract
Background: Peroxynitrite (ONOO−) is an oxidant linked with several human pathologies. Apigenin, a natural flavonoid known for its health benefits, remains unexplored in relation to ONOO− effects. This study investigated the potential of apigenin to structurally protect fibrinogen, an essential
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Background: Peroxynitrite (ONOO−) is an oxidant linked with several human pathologies. Apigenin, a natural flavonoid known for its health benefits, remains unexplored in relation to ONOO− effects. This study investigated the potential of apigenin to structurally protect fibrinogen, an essential blood clotting factor, from ONOO−-induced damage. Methods: Multi-approach analyses were carried out where fibrinogen was exposed to ONOO− generation while testing the efficacy of apigenin. The role of apigenin against ONOO−-induced modifications in fibrinogen was investigated using UV spectroscopy, tryptophan or tyrosine fluorescence, protein hydrophobicity, carbonylation, and electrophoretic analyses. Results: The findings demonstrate that apigenin significantly inhibits ONOO−-induced oxidative damage in fibrinogen. ONOO− caused reduced UV absorption, which was reversed by apigenin treatment. Moreover, ONOO− diminished tryptophan and tyrosine fluorescence, which was effectively restored by apigenin treatment. Apigenin also reduced the hydrophobicity of ONOO−-damaged fibrinogen. Moreover, apigenin exhibited protective effects against ONOO−-induced protein carbonylation. SDS-PAGE analyses revealed that ONOO−treatment eliminated bands corresponding to fibrinogen polypeptide chains Aα and γ, while apigenin preserved these changes. Conclusions: This study highlights, for the first time, the role of apigenin in structural protection of human fibrinogen against peroxynitrite-induced nitrosative damage. Our data indicate that apigenin offers structural protection to all three polypeptide chains (Aα, Bβ, and γ) of human fibrinogen. Specifically, apigenin prevents the dislocation or breakdown of the amino acids tryptophan, tyrosine, lysine, arginine, proline, and threonine and also prevents the exposure of hydrophobic sites in fibrinogen induced by ONOO−.
Full article
(This article belongs to the Special Issue Bioactive Molecules in the Control of Oxidative Stress and Oxidative Stress-Related Diseases)
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Open AccessReview
Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration
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Katarzyna Budzynska, Maria Siemionow, Katarzyna Stawarz, Lucile Chambily and Krzysztof Siemionow
Biomolecules 2024, 14(5), 575; https://doi.org/10.3390/biom14050575 - 13 May 2024
Abstract
Chimerism-based strategies represent a pioneering concept which has led to groundbreaking advancements in regenerative medicine and transplantation. This new approach offers therapeutic potential for the treatment of various diseases, including inherited disorders. The ongoing studies on chimeric cells prompted the development of Dystrophin-Expressing
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Chimerism-based strategies represent a pioneering concept which has led to groundbreaking advancements in regenerative medicine and transplantation. This new approach offers therapeutic potential for the treatment of various diseases, including inherited disorders. The ongoing studies on chimeric cells prompted the development of Dystrophin-Expressing Chimeric (DEC) cells which were introduced as a potential therapy for Duchenne Muscular Dystrophy (DMD). DMD is a genetic condition that leads to premature death in adolescent boys and remains incurable with current methods. DEC therapy, created via the fusion of human myoblasts derived from normal and DMD-affected donors, has proven to be safe and efficacious when tested in experimental models of DMD after systemic–intraosseous administration. These studies confirmed increased dystrophin expression, which correlated with functional and morphological improvements in DMD-affected muscles, including cardiac, respiratory, and skeletal muscles. Furthermore, the application of DEC therapy in a clinical study confirmed its long-term safety and efficacy in DMD patients. This review summarizes the development of chimeric cell technology tested in preclinical models and clinical studies, highlighting the potential of DEC therapy in muscle regeneration and repair, and introduces chimeric cell-based therapies as a promising, novel approach for muscle regeneration and the treatment of DMD and other neuromuscular disorders.
Full article
(This article belongs to the Special Issue Skeletal Muscle Homeostasis and Regeneration)
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Open AccessReview
A Survey of Deep Learning Methods for Estimating the Accuracy of Protein Quaternary Structure Models
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Xiao Chen, Jian Liu, Nolan Park and Jianlin Cheng
Biomolecules 2024, 14(5), 574; https://doi.org/10.3390/biom14050574 - 13 May 2024
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The quality prediction of quaternary structure models of a protein complex, in the absence of its true structure, is known as the Estimation of Model Accuracy (EMA). EMA is useful for ranking predicted protein complex structures and using them appropriately in biomedical research,
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The quality prediction of quaternary structure models of a protein complex, in the absence of its true structure, is known as the Estimation of Model Accuracy (EMA). EMA is useful for ranking predicted protein complex structures and using them appropriately in biomedical research, such as protein–protein interaction studies, protein design, and drug discovery. With the advent of more accurate protein complex (multimer) prediction tools, such as AlphaFold2-Multimer and ESMFold, the estimation of the accuracy of protein complex structures has attracted increasing attention. Many deep learning methods have been developed to tackle this problem; however, there is a noticeable absence of a comprehensive overview of these methods to facilitate future development. Addressing this gap, we present a review of deep learning EMA methods for protein complex structures developed in the past several years, analyzing their methodologies, data and feature construction. We also provide a prospective summary of some potential new developments for further improving the accuracy of the EMA methods.
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Open AccessReview
Failure of Autophagy in Pompe Disease
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Hung Do, Naresh K. Meena and Nina Raben
Biomolecules 2024, 14(5), 573; https://doi.org/10.3390/biom14050573 - 13 May 2024
Abstract
Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective
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Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles. The autophagic pathway is largely responsible for the delivery of cytosolic glycogen to the lysosome where it is degraded to glucose via acid α-glucosidase. Although the physiological role of lysosomal glycogenolysis is not fully understood, its significance is highlighted by the manifestations of Pompe disease, which is caused by a deficiency of this lysosomal enzyme. Pompe disease is a severe lysosomal glycogen storage disorder that affects skeletal and cardiac muscles most. In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. Finally, we outline how autophagic pathology in the diseased muscles can be used as a tool to fast track the efficacy of therapeutic interventions.
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(This article belongs to the Special Issue Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini)
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Open AccessReview
The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond
by
Meng-Yao Niu, Yan-Jun Liu, Jin-Jin Shi, Ru-Yi Chen, Shun Zhang, Chang-Yun Li, Jia-Feng Cao, Guan-Jun Yang and Jiong Chen
Biomolecules 2024, 14(5), 572; https://doi.org/10.3390/biom14050572 - 12 May 2024
Abstract
The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and
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The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.
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(This article belongs to the Special Issue Emerging Roles of Epigenetic Regulators in Inflammatory Diseases)
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Open AccessArticle
Hypermethylation of the Gene Body in SRCIN1 Is Involved in Breast Cancer Cell Proliferation and Is a Potential Blood-Based Biomarker for Early Detection and a Poor Prognosis
by
Hsieh-Tsung Shen, Chin-Sheng Hung, Clilia Davis, Chih-Ming Su, Li-Min Liao, Hsiu-Ming Shih, Kuan-Der Lee, Muhamad Ansar and Ruo-Kai Lin
Biomolecules 2024, 14(5), 571; https://doi.org/10.3390/biom14050571 - 12 May 2024
Abstract
Breast cancer is a leading cause of cancer mortality in women worldwide. Using the Infinium MethylationEPIC BeadChip, we analyzed plasma sample methylation to identify the SRCIN1 gene in breast cancer patients. We assessed SRCIN1-related roles and pathways for their biomarker potential. To
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Breast cancer is a leading cause of cancer mortality in women worldwide. Using the Infinium MethylationEPIC BeadChip, we analyzed plasma sample methylation to identify the SRCIN1 gene in breast cancer patients. We assessed SRCIN1-related roles and pathways for their biomarker potential. To verify the methylation status, quantitative methylation-specific PCR (qMSP) was performed on genomic DNA and circulating cell-free DNA samples, and mRNA expression analysis was performed using RT‒qPCR. The results were validated in a Western population; for this analysis, the samples included plasma samples from breast cancer patients from the USA and from The Cancer Genome Atlas (TCGA) cohort. To study the SRCIN1 pathway, we conducted cell viability assays, gene manipulation and RNA sequencing. SRCIN1 hypermethylation was identified in 61.8% of breast cancer tissues from Taiwanese patients, exhibiting specificity to this malignancy. Furthermore, its presence correlated significantly with unfavorable 5-year overall survival outcomes. The levels of methylated SRCIN1 in the blood of patients from Taiwan and the USA correlated with the stage of breast cancer. The proportion of patients with high methylation levels increased from 0% in healthy individuals to 63.6% in Stage 0, 80% in Stage I and 82.6% in Stage II, with a sensitivity of 78.5%, an accuracy of 90.3% and a specificity of 100%. SRCIN1 hypermethylation was significantly correlated with increased SRCIN1 mRNA expression (p < 0.001). Knockdown of SRCIN1 decreased the viability of breast cancer cells. SRCIN1 silencing resulted in the downregulation of ESR1, BCL2 and various cyclin protein expressions. SRCIN1 hypermethylation in the blood may serve as a noninvasive biomarker, facilitating early detection and prognosis evaluation, and SRCIN1-targeted therapies could be used in combination regimens for breast cancer patients.
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(This article belongs to the Special Issue DNA Methylation in Human Diseases)
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Disruption of Transmembrane Phosphatidylserine Asymmetry by HIV-1 Incorporated SERINC5 Is Not Responsible for Virus Restriction
by
Gokul Raghunath, Elizabeth H. Abbott, Mariana Marin, Hui Wu, Judith Mary Reyes Ballista, Melinda A. Brindley and Gregory B. Melikyan
Biomolecules 2024, 14(5), 570; https://doi.org/10.3390/biom14050570 - 10 May 2024
Abstract
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Host restriction factor SERINC5 (SER5) incorporates into the HIV-1 membrane and inhibits infectivity by a poorly understood mechanism. Recently, SER5 was found to exhibit scramblase-like activity leading to the externalization of phosphatidylserine (PS) on the viral surface, which has been proposed to be
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Host restriction factor SERINC5 (SER5) incorporates into the HIV-1 membrane and inhibits infectivity by a poorly understood mechanism. Recently, SER5 was found to exhibit scramblase-like activity leading to the externalization of phosphatidylserine (PS) on the viral surface, which has been proposed to be responsible for SER5’s antiviral activity. This and other reports that document modulation of HIV-1 infectivity by viral lipid composition prompted us to investigate the role of PS in regulating SER5-mediated HIV-1 restriction. First, we show that the level of SER5 incorporation into virions correlates with an increase in PS levels in the outer leaflet of the viral membrane. We developed an assay to estimate the PS distribution across the viral membrane and found that SER5, but not SER2, which lacks antiviral activity, abrogates PS asymmetry by externalizing this lipid. Second, SER5 incorporation diminished the infectivity of pseudoviruses produced from cells lacking a flippase subunit CDC50a and, therefore, exhibited a higher baseline level of surface-accessible PS. Finally, exogenous manipulation of the viral PS levels utilizing methyl-alpha-cyclodextrin revealed a lack of correlation between external PS and virion infectivity. Taken together, our study implies that the increased PS exposure to SER5-containing virions itself is not directly linked to HIV-1 restriction.
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Open AccessFeature PaperArticle
Risk and Resilience Variants in the Retinoic Acid Metabolic and Developmental Pathways Associated with Risk of FASD Outcomes
by
Leo McKay, Berardino Petrelli, Molly Pind, James N. Reynolds, Richard F. Wintle, Albert E. Chudley, Britt Drögemöller, Abraham Fainsod, Stephen W. Scherer, Ana Hanlon-Dearman and Geoffrey G. Hicks
Biomolecules 2024, 14(5), 569; https://doi.org/10.3390/biom14050569 - 10 May 2024
Abstract
Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or
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Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or understood. In this study, using a candidate gene approach, we performed a genetic variant analysis of retinoic acid (RA) metabolic and developmental signaling pathway genes on whole exome sequencing data of 23 FASD-diagnosed individuals. We found risk and resilience alleles in ADH and ALDH genes known to normally be involved in alcohol detoxification at the expense of RA production, causing RA deficiency, following PAE. Risk and resilience variants were also identified in RA-regulated developmental pathway genes, especially in SHH and WNT pathways. Notably, we also identified significant variants in the causative genes of rare neurodevelopmental disorders sharing comorbidities with FASD, including STRA6 (Matthew–Wood), SOX9 (Campomelic Dysplasia), FDG1 (Aarskog), and 22q11.2 deletion syndrome (TBX1). Although this is a small exploratory study, the findings support PAE-induced RA deficiency as a major etiology underlying FASD and suggest risk and resilience variants may be suitable biomarkers to determine the risk of FASD outcomes following PAE.
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(This article belongs to the Special Issue New Insight into the Molecular Genetics of Neurodevelopmental Disorders)
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