Biomolecules

15 pages, 1791 KiB

Open AccessReview

Exploring the Antiangiogenic and Anti-Inflammatory Potential of Homoisoflavonoids: Target Identification Using Biotin Probes

by **ang Fei, Sangil Kwon, **young Jang, Minyoung Seo, Seongwon Yu, Timothy W. Corson and Seung-Yong Seo

Biomolecules 2024, 14(7), 785; https://doi.org/10.3390/biom14070785 (registering DOI) - 30 Jun 2024

Abstract

Chemical proteomics using biotin probes of natural products have significantly advanced our understanding of molecular targets and therapeutic potential. This review highlights recent progress in the application of biotin probes of homoisoflavonoids for identifying binding proteins and elucidating mechanisms of action. Notably, homoisoflavonoids [...] Read more.

Chemical proteomics using biotin probes of natural products have significantly advanced our understanding of molecular targets and therapeutic potential. This review highlights recent progress in the application of biotin probes of homoisoflavonoids for identifying binding proteins and elucidating mechanisms of action. Notably, homoisoflavonoids exhibit antiangiogenic, anti-inflammatory, and antidiabetic effects. A combination of biotin probes, pull-down assays, mass spectrometry, and molecular modeling has revealed how natural products and their derivatives interact with several proteins such as ferrochelatase (FECH), soluble epoxide hydrolase (sEH), inosine monophosphate dehydrogenase 2 (IMPDH2), phosphodiesterase 4 (PDE4), and deoxyhypusine hydroxylase (DOHH). These target identification approaches pave the way for new therapeutic avenues, especially in the fields of oncology and ophthalmology. Future research aimed at expanding the repertoire of target identification using biotin probes of homoisoflavonoids promises to further elucidate the complex mechanisms and develop new drug candidates. Full article

(This article belongs to the Special Issue Biomolecules and Their Impact on Biology and Translational Applications: Celebrating the Pioneering Work of Prof. Ho Jeong Kwon)

20 pages, 556 KiB

Open AccessReview

Advances in Molecular Research on Hip Joint Im**ement—A Vascular Perspective

by Riana Maria Huzum, Marius Valeriu Hînganu, Bogdan Huzum and Delia Hînganu

Biomolecules 2024, 14(7), 784; https://doi.org/10.3390/biom14070784 (registering DOI) - 30 Jun 2024

Abstract

With the rise in longevity within the population, medicine continues to encounter fresh hurdles necessitating prompt actions, among which are those associated with hip joint aging. Age-related arthropathies encompass damage to bones’ articulating extremities and their supporting structures, such as articular cartilage, and [...] Read more.

With the rise in longevity within the population, medicine continues to encounter fresh hurdles necessitating prompt actions, among which are those associated with hip joint aging. Age-related arthropathies encompass damage to bones’ articulating extremities and their supporting structures, such as articular cartilage, and alterations in the quantity and quality of synovial fluid. This study aims to summarize the biomolecular methods of hip joint evaluation focused on its vascularization, using data correlated with biomolecular research on other joints and tissues, in order to reach an objective opinion of the study prospects in this field. Following a retrospective study on most modern biomolecular research methods on the synovium, the capsule, and the articular cartilage of the hip joint, we have hereby concretized certain future research directions in this field that will improve the qualitative and morphofunctional management of the hip joint at an advanced age, even within population categories at risk of develo** various degenerative joint pathologies. Full article

(This article belongs to the Section Molecular Medicine)

28 pages, 1998 KiB

Open AccessReview

Third-Generation Tetracyclines: Current Knowledge and Therapeutic Potential

by Dimitris Kounatidis, Maria Dalamaga, Eugenia Grivakou, Irene Karampela, Petros Koufopoulos, Vasileios Dalopoulos, Nikolaos Adamidis, Eleni Mylona, Aikaterini Kaziani and Natalia G. Vallianou

Biomolecules 2024, 14(7), 783; https://doi.org/10.3390/biom14070783 (registering DOI) - 30 Jun 2024

Abstract

Tetracyclines constitute a unique class of antibiotic agents, widely prescribed for both community and hospital infections due to their broad spectrum of activity. Acting by disrupting protein synthesis through tight binding to the 30S ribosomal subunit, their interference is typically reversible, rendering them [...] Read more.

Tetracyclines constitute a unique class of antibiotic agents, widely prescribed for both community and hospital infections due to their broad spectrum of activity. Acting by disrupting protein synthesis through tight binding to the 30S ribosomal subunit, their interference is typically reversible, rendering them bacteriostatic in action. Resistance to tetracyclines has primarily been associated with changes in pump efflux or ribosomal protection mechanisms. To address this challenge, tetracycline molecules have been chemically modified, resulting in the development of third-generation tetracyclines. These novel tetracyclines offer significant advantages in treating infections, whether used alone or in combination therapies, especially in hospital settings. Beyond their conventional antimicrobial properties, research has highlighted their potential non-antibiotic properties, including their impact on immunomodulation and malignancy. This review will focus on third-generation tetracyclines, namely tigecycline, eravacycline, and omadacycline. We will delve into their mechanisms of action and resistance, while also evaluating their pros and cons over time. Additionally, we will explore their therapeutic potential, analyzing their primary indications of prescription, potential future uses, and non-antibiotic features. This review aims to provide valuable insights into the clinical applications of third-generation tetracyclines, thereby enhancing understanding and guiding optimal clinical use. Full article

(This article belongs to the Special Issue Feature Papers in the Natural and Bio-Inspired Molecules Section)

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20 pages, 6046 KiB

Open AccessArticle

Green Synthesis of Silver Nanoparticles with Extracts from Kalanchoe fedtschenkoi: Characterization and Bioactivities

by Jorge L. Mejía-Méndez, Gildardo Sánchez-Ante, Mónica Cerro-López, Yulianna Minutti-Calva, Diego E. Navarro-López, J. Daniel Lozada-Ramírez, Horacio Bach, Edgar R. López-Mena and Eugenio Sánchez-Arreola

Biomolecules 2024, 14(7), 782; https://doi.org/10.3390/biom14070782 (registering DOI) - 30 Jun 2024

Abstract

In this work, the hexane, chloroform, and methanol extracts from Kalanchoe fedtschenkoi were utilized to green-synthesize silver nanoparticles (Kf₁-, Kf₂-, and Kf₃-AgNPs). The Kf₁-, Kf₂-, and Kf₃-AgNPs were characterized by spectroscopy [...] Read more.

In this work, the hexane, chloroform, and methanol extracts from Kalanchoe fedtschenkoi were utilized to green-synthesize silver nanoparticles (Kf₁-, Kf₂-, and Kf₃-AgNPs). The Kf₁-, Kf₂-, and Kf₃-AgNPs were characterized by spectroscopy and microscopy techniques. The antibacterial activity of AgNPs was studied against bacteria strains, utilizing the microdilution assay. The DPPH and H₂O₂ assays were considered to assess the antioxidant activity of AgNPs. The results revealed that Kf₁-, Kf₂-, and Kf₃-AgNPs exhibit an average diameter of 39.9, 111, and 42 nm, respectively. The calculated ζ-potential of Kf₁-, Kf₂-, and Kf₃-AgNPs were −20.5, −10.6, and −7.9 mV, respectively. The UV-vis analysis of the three samples demonstrated characteristic absorption bands within the range of 350–450 nm, which confirmed the formation of AgNPs. The FTIR analysis of AgNPs exhibited a series of bands from 3500 to 750 cm⁻¹, related to the presence of extracts on their surfaces. SEM observations unveiled that Kf₁- and Kf₂-AgNPs adopted structural arrangements related to nano-popcorns and nanoflowers, whereas Kf₃-AgNPs were spherical in shape. It was determined that treatment with Kf₁-, Kf₂-, and Kf₃-AgNPs was demonstrated to inhibit the growth of E. coli, S. aureus, and P. aeruginosa in a dose-dependent manner (50–300 μg/mL). Within the same range, treatment with Kf₁-, Kf₂-, and Kf₃-AgNPs decreased the generation of DPPH (IC₅₀ 57.02–2.09 μg/mL) and H₂O₂ (IC₅₀ 3.15–3.45 μg/mL) radicals. This study highlights the importance of using inorganic nanomaterials to improve the biological performance of plant extracts as an efficient nanotechnological approach. Full article

(This article belongs to the Special Issue Bionanomaterials: Synthesis, Characterization, Toxicity and Biomedical Applications (Volume II))

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15 pages, 2489 KiB

Open AccessArticle

Guanidinium Chloride-Induced Haemolysis Assay to Measure New Permeation Pathway Functionality in Rodent Malaria Plasmodium berghei

by Mitchell L. Trickey, Natalie A. Counihan, Joyanta K. Modak and Tania F. de Koning-Ward

Biomolecules 2024, 14(7), 781; https://doi.org/10.3390/biom14070781 (registering DOI) - 30 Jun 2024

Abstract

Parasite-derived new permeation pathways (NPPs) expressed at the red blood cell (RBC) membrane enable Plasmodium parasites to take up nutrients from the plasma to facilitate their survival. Thus, NPPs represent a potential novel therapeutic target for malaria. The putative channel component of the [...] Read more.

Parasite-derived new permeation pathways (NPPs) expressed at the red blood cell (RBC) membrane enable Plasmodium parasites to take up nutrients from the plasma to facilitate their survival. Thus, NPPs represent a potential novel therapeutic target for malaria. The putative channel component of the NPP in the human malaria parasite P. falciparum is encoded by mutually exclusively expressed clag3.1/3.2 genes. Complicating the study of the essentiality of these genes to the NPP is the addition of three clag paralogs whose contribution to the P. falciparum channel is uncertain. Rodent malaria P. berghei contains only two clag genes, and thus studies of P. berghei clag genes could significantly aid in dissecting their overall contribution to NPP activity. Previous methods for determining NPP activity in a rodent model have utilised flux-based assays of radioisotope-labelled substrates or patch clam**. This study aimed to ratify a streamlined haemolysis assay capable of assessing the functionality of P. berghei NPPs. Several isotonic lysis solutions were tested for their ability to preferentially lyse infected RBCs (iRBCs), leaving uninfected RBCs (uRBCs) intact. The osmotic lysis assay was optimised and validated in the presence of NPP inhibitors to demonstrate the uptake of the lysis solution via the NPPs. Guanidinium chloride proved to be the most efficient reagent to use in an osmotic lysis assay to establish NPP functionality. Furthermore, following treatment with guanidinium chloride, ring-stage parasites could develop into trophozoites and schizonts, potentially enabling use of guanidinium chloride for parasite synchronisation. This haemolysis assay will be useful for further investigation of NPPs in P. berghei and could assist in validating its protein constituents. Full article

17 pages, 4250 KiB

Open AccessArticle

Molecular Diversity from Longipinenes of Santolina viscosa Lag. through Acid Catalysis: Biocidal Activity

by Irene Torres-García, José F. Quílez del Moral, Alejandro F. Barrero, Azucena González-Coloma, María Fe Andrés, José L. López-Pérez, Miriam Álvarez-Corral, Ignacio Rodríguez-García and Manuel Muñoz-Dorado

Biomolecules 2024, 14(7), 780; https://doi.org/10.3390/biom14070780 (registering DOI) - 30 Jun 2024

Abstract

The search for new compounds with biocidal potential was carried out, focusing on the longipinenes 1–7 from the plant species Santolina viscosa Lag. Compounds 1, 2, and 5 showed remarkable molecular diversity when treated in acidic reaction conditions. Protonic, [...] Read more.

The search for new compounds with biocidal potential was carried out, focusing on the longipinenes 1–7 from the plant species Santolina viscosa Lag. Compounds 1, 2, and 5 showed remarkable molecular diversity when treated in acidic reaction conditions. Protonic, Lewis, and heterogeneous compounds were used in the treatment. Three main models of reaction have been observed: isomerization of the double bond (8–10); rearrangements to longibornane-based skeleton (11–15) and ring-opening to himachalane-based skeleton (16–18). Secolongibornane aldehydes 23 and 24 were obtained after epoxide opening under the same reaction conditions. The elucidation of the structures of the new compounds was carried out using spectroscopic data and was supported by computational theoretical calculations of ¹³C NMR spectra. Additionally, high-resolution mass spectrometry and single-crystal X-ray diffraction analysis were employed for certain compounds. Natural longipinenes 4–7, methyl esters 1–3 of corresponding natural carboxylic acids and the isomerized and derivatives compounds 8–19 exhibit moderate to high insecticidal activity against R. padi and M. persicae insects. Longipinene 5 shows potent inhibition against the root growth of the plants L. perenne and L. sativa, as well as compound 2 on the leaves of L. perenne. Furthermore, significant ixocidal and nematicidal activity was found for this latter compound. Full article

(This article belongs to the Special Issue Research into Bioactive Natural Compounds: New Molecules, Bioinspired Syntheses, Biotechnological Methods and Bioassays—Celebrating the Pioneering Work of Prof. Alejandro Fernandez Barrero)

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21 pages, 1331 KiB

Open AccessArticle

Anti-Biofilm Perspectives of Propolis against Staphylococcus epidermidis Infections

by Virginia Vadillo-Rodríguez, Irene Fernández-Babiano, Ciro Pérez-Giraldo and María Coronada Fernández-Calderón

Biomolecules 2024, 14(7), 779; https://doi.org/10.3390/biom14070779 (registering DOI) - 29 Jun 2024

Abstract

Staphylococcus epidermis has emerged as the main causative agent of medical device-related infections. Their major pathogenicity factor lies in its ability to adhere to surfaces and proliferate into biofilms, which increase their resistance to antibiotics. The main objective of this study was to [...] Read more.

Staphylococcus epidermis has emerged as the main causative agent of medical device-related infections. Their major pathogenicity factor lies in its ability to adhere to surfaces and proliferate into biofilms, which increase their resistance to antibiotics. The main objective of this study was to evaluate the use and the mechanism of action of an ethanolic extract of Spanish propolis (EESP) as a potential alternative for preventing biofilm-related infections caused by S. epidermidis. The chemical composition of propolis is reported and its antibacterial activity against several strains of S. epidermidis with different biofilm-forming capacities evaluated. The influence of sub-inhibitory concentrations (sub-MICs) of EESP on their growth, physicochemical surface properties, adherence, and biofilm formation were studied. EESP interferes with planktonic cells, homogenizing their physicochemical surface properties and introducing a significant delay in their growth. The adherence and biofilms at the EESP concentrations investigated were decreased up to 90.5% among the strains. Microscopic analysis indicated that the planktonic cells that survived the treatment were the ones that adhere and proliferate on the surfaces. The results obtained suggest that the EESP has a high potential to be used as an inhibitor of both the adhesion and biofilm formation of S. epidermidis. Full article

(This article belongs to the Special Issue Research into Bioactive Natural Compounds: New Molecules, Bioinspired Syntheses, Biotechnological Methods and Bioassays—Celebrating the Pioneering Work of Prof. Alejandro Fernandez Barrero)

24 pages, 1214 KiB

Open AccessArticle

Identification of Potential New Genes Related to the SREBP Pathway in Xanthophyllomyces dendrorhous

by Maximiliano Venegas, Alejandro Durán, Sebastián Campusano, Salvador Barahona, Dionisia Sepúlveda, Marcelo Baeza, Víctor Cifuentes and Jennifer Alcaíno

Biomolecules 2024, 14(7), 778; https://doi.org/10.3390/biom14070778 (registering DOI) - 29 Jun 2024

Abstract

The sterol regulatory element-binding protein (SREBP) pathway is an integral cellular mechanism that regulates lipid homeostasis, in which transcriptional activator SREBPs regulate the expression of various genes. In the carotenogenic yeast Xanthophyllomyces dendrorhous, Sre1 (the yeast SREBP homolog) regulates lipid biosynthesis and [...] Read more.

The sterol regulatory element-binding protein (SREBP) pathway is an integral cellular mechanism that regulates lipid homeostasis, in which transcriptional activator SREBPs regulate the expression of various genes. In the carotenogenic yeast Xanthophyllomyces dendrorhous, Sre1 (the yeast SREBP homolog) regulates lipid biosynthesis and carotenogenesis, among other processes. Despite the characterization of several components of the SREBP pathway across various eukaryotes, the specific elements of this pathway in X. dendrorhous remain largely unknown. This study aimed to explore the potential regulatory mechanisms of the SREBP pathway in X. dendrorhous using the strain CBS.cyp61^- as a model, which is known to have Sre1 in its active state under standard culture conditions, resulting in a carotenoid-overproducing phenotype. This strain was subjected to random mutagenesis with N-methyl-N’-nitro-N-nitrosoguanidine (NTG), followed by a screening methodology that focused on identifying mutants with altered Sre1 activation phenotypes. Single-nucleotide polymorphism (SNP) analysis of 20 selected mutants detected 5439 single-nucleotide variants (SNVs), narrowing them down to 1327 SNPs of interest after a series of filters. Classification based on SNP impact identified 116 candidate genes, including 49 genes with high impact and 68 genes with deleterious moderate-impact mutations. BLAST, InterProScan, and gene ontology enrichment analyses highlighted 25 genes as potential participants in regulating Sre1 in X. dendrorhous. The key findings of this study include the identification of genes potentially encoding proteins involved in protein import/export to the nucleus, sterol biosynthesis, the ubiquitin–proteasome system, protein regulatory activities such as deacetylases, a subset of kinases and proteases, as well as transcription factors that could be influential in SREBP regulation. These findings are expected to significantly contribute to the current understanding of the intricate regulation of the transcription factor Sre1 in X. dendrorhous, providing valuable groundwork for future research and potential biotechnological applications. Full article

(This article belongs to the Special Issue Sterol Biosynthesis and Function in Organisms)

17 pages, 2415 KiB

Open AccessArticle

COMT and Neuregulin 1 Markers for Personalized Treatment of Schizophrenia Spectrum Disorders Treated with Risperidone Monotherapy

by Mariana Bondrescu, Liana Dehelean, Simona Sorina Farcas, Ion Papava, Vlad Nicoras, Dana Violeta Mager, Anca Eliza Grecescu, Petre Adrian Podaru and Nicoleta Ioana Andreescu

Biomolecules 2024, 14(7), 777; https://doi.org/10.3390/biom14070777 (registering DOI) - 29 Jun 2024

Abstract

Pharmacogenetic markers are current targets for the personalized treatment of psychosis. Limited data exist on COMT and NRG1 polymorphisms in relation to risperidone treatment. This study focuses on the impact of COMT rs4680 and NRG1 (rs35753505, rs3924999) polymorphisms on risperidone treatment in schizophrenia [...] Read more.

Pharmacogenetic markers are current targets for the personalized treatment of psychosis. Limited data exist on COMT and NRG1 polymorphisms in relation to risperidone treatment. This study focuses on the impact of COMT rs4680 and NRG1 (rs35753505, rs3924999) polymorphisms on risperidone treatment in schizophrenia spectrum disorders (SSDs). This study included 103 subjects with SSD treated with risperidone monotherapy. COMT rs4680, NRG1 rs35753505, and rs3924999 were analyzed by RT-PCR. Participants were evaluated via the Positive and Negative Syndrome Scale (PANSS) after six weeks. Socio-demographic and clinical characteristics were collected. COMT rs4680 genotypes significantly differed in PANSS N scores at admission: AG>AA genotypes (p = 0.03). After six weeks of risperidone, PANSS G improvement was AA>GG (p = 0.05). The PANSS total score was as follows: AA>AG (p = 0.04), AA>GG (p = 0.02). NRG1 rs35753504 genotypes significantly differed across educational levels, with CC>CT (p = 0.02), and regarding the number of episodes, TT>CC, CT>CC (p = 0.01). The PANSS total score after six weeks of treatment showed a better improvement for TT<CT genotypes (p = 0.01). NRG1 rs3924999 genotypes revealed GG<AG (p = 0.02) for PANSS G scores after six weeks, with AG and GG requiring higher doses (p = 0.007, p = 0.02). Overall, our study suggests that the genetic polymorphisms COMT rs4680, NRG1 rs35753505, and rs3924999 significantly impact the treatment response to risperidone in patients with SSD. Full article

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20 pages, 2006 KiB

Open AccessArticle

Skin Rejuvenation Efficacy and Safety Evaluation of Kaempferia parviflora Standardized Extract (BG100) in Human 3D Skin Models and Clinical Trial

by Wannita Klinngam, Phetploy Rungkamoltip, Ratjika Wongwanakul, Jaruwan Joothamongkhon, Sakkarin Du-a-man, Mattaka Khongkow, Udom Asawapirom, Tawin Iempridee and Uracha Ruktanonchai

Biomolecules 2024, 14(7), 776; https://doi.org/10.3390/biom14070776 (registering DOI) - 29 Jun 2024

Abstract

Polymethoxyflavones from Kaempferia parviflora rhizomes have been shown to effectively combat aging in skin cells and tissues by inhibiting senescence, reducing oxidative stress, and enhancing skin structure and function. This study assessed the anti-aging effects and safety of standardized K. parviflora extract (BG100), [...] Read more.

Polymethoxyflavones from Kaempferia parviflora rhizomes have been shown to effectively combat aging in skin cells and tissues by inhibiting senescence, reducing oxidative stress, and enhancing skin structure and function. This study assessed the anti-aging effects and safety of standardized K. parviflora extract (BG100), enriched with polymethoxyflavones including 5,7-dimethoxyflavone, 5,7,4’-trimethoxyflavone, 3,5,7,3’,4’-pentamethoxyflavone, 3,5,7-trimethoxyflavone, and 3,5,7,4ʹ-tetramethoxyflavone. We evaluated BG100’s impact on skin rejuvenation and antioxidant properties using photoaged human 3D full-thickness skin models. The potential for skin irritation and sensitization was also assessed through studies on reconstructed human epidermis and clinical trials. Additionally, in vitro genotoxicity testing was performed following OECD guidelines. Results indicate that BG100 promotes collagen and hyaluronic acid production, reduces oxidative stress, and minimizes DNA damage in photoaged full-thickness 3D skin models. Furthermore, it exhibited non-irritating and non-sensitizing properties, as supported by tests on reconstructed human epidermis and clinical settings. BG100 also passed in vitro genotoxicity tests, adhering to OECD guidelines. These results underscore BG100′s potential as a highly effective and safe, natural anti-aging agent, suitable for inclusion in cosmeceutical and nutraceutical products aimed at promoting skin rejuvenation. Full article

(This article belongs to the Section Natural and Bio-inspired Molecules)

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32 pages, 14477 KiB

Open AccessArticle

De Novo Design of Inhibitors of DNA Methyltransferase 1: A Critical Comparison of Ligand- and Structure-Based Approaches

by Diana L. Prado-Romero, Fernanda I. Saldívar-González, Iván López-Mata, Pedro A. Laurel-García, Adrián Durán-Vargas, Enrique García-Hernández, Norberto Sánchez-Cruz and José L. Medina-Franco

Biomolecules 2024, 14(7), 775; https://doi.org/10.3390/biom14070775 (registering DOI) - 28 Jun 2024

Abstract

Designing and develo** inhibitors against the epigenetic target DNA methyltransferase (DNMT) is an attractive strategy in epigenetic drug discovery. DNMT1 is one of the epigenetic enzymes with significant clinical relevance. Structure-based de novo design is a drug discovery strategy that was used in [...] Read more.

Designing and develo** inhibitors against the epigenetic target DNA methyltransferase (DNMT) is an attractive strategy in epigenetic drug discovery. DNMT1 is one of the epigenetic enzymes with significant clinical relevance. Structure-based de novo design is a drug discovery strategy that was used in combination with similarity searching to identify a novel DNMT inhibitor with a novel chemical scaffold and warrants further exploration. This study aimed to continue exploring the potential of de novo design to build epigenetic-focused libraries targeted toward DNMT1. Herein, we report the results of an in-depth and critical comparison of ligand- and structure-based de novo design of screening libraries focused on DNMT1. The newly designed chemical libraries focused on DNMT1 are freely available on GitHub. Full article

(This article belongs to the Special Issue Chemoinformatics and Molecular Modeling of Pharmacologically Active Biomolecules: A Themed Issue in Honor of Prof. José L. Medina-Franco)

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21 pages, 7608 KiB

Open AccessArticle

Oligomer Formation by Physiologically Relevant C-Terminal Isoforms of Amyloid β-Protein

by Rachit Pandey and Brigita Urbanc

Biomolecules 2024, 14(7), 774; https://doi.org/10.3390/biom14070774 (registering DOI) - 28 Jun 2024

Abstract

Alzheimer’s disease (AD) is a neurological disorder associated with amyloid

β

-protein (A

β

) assembly into toxic oligomers. In addition to the two predominant alloforms, A

β_{1 - 40}

and A

β_{1 - 42}

, other C-terminally truncated A

β

[...] Read more.

Alzheimer’s disease (AD) is a neurological disorder associated with amyloid

β

-protein (A

β

) assembly into toxic oligomers. In addition to the two predominant alloforms, A

β_{1 - 40}

and A

β_{1 - 42}

, other C-terminally truncated A

β

peptides, including A

β_{1 - 38}

and A

β_{1 - 43}

, are produced in the brain. Here, we use discrete molecular dynamics (DMD) and a four-bead protein model with amino acid-specific hydropathic interactions, DMD4B-HYDRA, to examine oligomer formation of A

β_{1 - 38}

, A

β_{1 - 40}

, A

β_{1 - 42}

, and A

β_{1 - 43}

. Self-assembly of 32 unstructured monomer peptides into oligomers is examined using 32 replica DMD trajectories for each of the four peptides. In a quasi-steady state, A

β_{1 - 38}

and A

β_{1 - 40}

adopt similar unimodal oligomer size distributions with a maximum at trimers, whereas A

β_{1 - 42}

and A

β_{1 - 43}

oligomer size distributions are multimodal with the dominant maximum at trimers or tetramers, and additional maxima at hexamers and unidecamers (for A

β_{1 - 42}

) or octamers and pentadecamers (for A

β_{1 - 43}

). The free energy landscapes reveal isoform- and oligomer-order specific structural and morphological features of oligomer ensembles. Our results show that oligomers of each of the four isoforms have unique features, with A

β_{1 - 42}

alone resulting in oligomers with disordered and solvent-exposed N-termini. Our findings help unravel the structure–function paradigm governing oligomers formed by various A

β

isoforms. Full article

(This article belongs to the Special Issue New Insights into Protein Aggregation in Condensed and Amyloid States)

16 pages, 1770 KiB

Open AccessReview

Zinc, Copper, and Calcium: A Triangle in the Synapse for the Pathogenesis of Vascular-Type Senile Dementia

by Masahiro Kawahara, Ken-ichiro Tanaka and Midori Kato-Negishi

Biomolecules 2024, 14(7), 773; https://doi.org/10.3390/biom14070773 (registering DOI) - 28 Jun 2024

Abstract

Zinc (Zn) and copper (Cu) are essential for normal brain functions. In particular, Zn and Cu are released to synaptic clefts during neuronal excitation. Synaptic Zn and Cu regulate neuronal excitability, maintain calcium (Ca) homeostasis, and play central roles in memory formation. However, [...] Read more.

Zinc (Zn) and copper (Cu) are essential for normal brain functions. In particular, Zn and Cu are released to synaptic clefts during neuronal excitation. Synaptic Zn and Cu regulate neuronal excitability, maintain calcium (Ca) homeostasis, and play central roles in memory formation. However, in pathological conditions such as transient global ischemia, excess Zn is secreted to synaptic clefts, which causes neuronal death and can eventually trigger the pathogenesis of a vascular type of senile dementia. We have previously investigated the characteristics of Zn-induced neurotoxicity and have demonstrated that low concentrations of Cu can exacerbate Zn neurotoxicity. Furthermore, during our pharmacological approaches to clarify the molecular pathways of Cu-enhanced Zn-induced neurotoxicity, we have revealed the involvement of Ca homeostasis disruption. In the present review, we discuss the roles of Zn and Cu in the synapse, as well as the crosstalk between Zn, Cu, and Ca, which our study along with other recent studies suggest may underlie the pathogenesis of vascular-type senile dementia. Full article

(This article belongs to the Special Issue Zinc in Health and Disease Conditions II)

18 pages, 1663 KiB

Open AccessArticle

Helicobacter pylori-Induced Decrease in Membrane Expression of Na,K-ATPase Leads to Gastric Injury

by Olga Vagin, Elmira Tokhtaeva, Muriel Larauche, Joshua Davood and Elizabeth A. Marcus

Biomolecules 2024, 14(7), 772; https://doi.org/10.3390/biom14070772 (registering DOI) - 28 Jun 2024

Abstract

Helicobacter pylori is a highly prevalent human gastric pathogen that causes gastritis, ulcer disease, and gastric cancer. It is not yet fully understood how H. pylori injures the gastric epithelium. The Na,K-ATPase, an essential transporter found in virtually all mammalian cells, has been [...] Read more.

Helicobacter pylori is a highly prevalent human gastric pathogen that causes gastritis, ulcer disease, and gastric cancer. It is not yet fully understood how H. pylori injures the gastric epithelium. The Na,K-ATPase, an essential transporter found in virtually all mammalian cells, has been shown to be important for maintaining the barrier function of lung and kidney epithelia. H. pylori decreases levels of Na,K-ATPase in the plasma membrane of gastric epithelial cells, and the aim of this study was to demonstrate that this reduction led to gastric injury by impairing the epithelial barrier. Similar to H. pylori infection, the inhibition of Na,K-ATPase with ouabain decreased transepithelial electrical resistance and increased paracellular permeability in cell monolayers of human gastric cultured cells, 2D human gastric organoids, and gastric epithelium isolated from gerbils. Similar effects were caused by a partial shRNA silencing of Na,K-ATPase in human gastric organoids. Both H. pylori infection and ouabain exposure disrupted organization of adherens junctions in human gastric epithelia as demonstrated by E-cadherin immunofluorescence. Functional and structural impairment of epithelial integrity with a decrease in Na,K-ATPase amount or activity provides evidence that the H. pylori-induced downregulation of Na,K-ATPase plays a role in the complex mechanism of gastric disease induced by the bacteria. Full article

(This article belongs to the Special Issue The Role of P-type ATPases in Health and Diseases)

26 pages, 1691 KiB

Open AccessArticle

Functional Characterization of the Lysosomal Peptide/Histidine Transporter PHT1 (SLC15A4) by Solid Supported Membrane Electrophysiology (SSME)

by Jonai Pujol-Giménez, Sven P. Baumann, Tin Manh Ho, Bartlomiej Augustynek and Matthias A. Hediger

Biomolecules 2024, 14(7), 771; https://doi.org/10.3390/biom14070771 - 28 Jun 2024

Abstract

The peptide/histidine transporter PHT1 (SLC15A4) is expressed in the lysosomal membranes of immune cells where it plays an important role in metabolic and inflammatory signaling. PHT1 is an H⁺-coupled/histidine symporter that can transport a wide range of oligopeptides, including [...] Read more.

The peptide/histidine transporter PHT1 (SLC15A4) is expressed in the lysosomal membranes of immune cells where it plays an important role in metabolic and inflammatory signaling. PHT1 is an H⁺-coupled/histidine symporter that can transport a wide range of oligopeptides, including a variety of bacterial-derived peptides. Moreover, it enables the scaffolding of various metabolic signaling molecules and interacts with key regulatory elements of the immune response. Not surprisingly, PHT1 has been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Unfortunately, the pharmacological development of PHT1 modulators has been hampered by the lack of suitable transport assays. To address this shortcoming, a novel transport assay based on solid-supported membrane-based electrophysiology (SSME) is presented. Key findings of the present SSME studies include the first recordings of electrophysiological properties, a pH dependence analysis, an assessment of PHT1 substrate selectivity, as well as the transport kinetics of the identified substrates. In contrast to previous work, PHT1 is studied in its native lysosomal environment. Moreover, observed substrate selectivity is validated by molecular docking. Overall, this new SSME-based assay is expected to contribute to unlocking the pharmacological potential of PHT1 and to deepen the understanding of its functional properties. Full article

(This article belongs to the Section Cellular Biochemistry)

16 pages, 850 KiB

Open AccessReview

The Sweet Relationship between the Endometrium and Protein Glycosylation

by Linyu Zhang, Ying Feng, Yue Zhang, **nrui Sun, Qianhong Ma and Fang Ma

Biomolecules 2024, 14(7), 770; https://doi.org/10.3390/biom14070770 - 27 Jun 2024

Abstract

The endometrium is an important part of women’s bodies for menstruation and pregnancy. Various proteins are widely expressed on the surface of endometrial cells, and glycosylation is an important post-translational modification of proteins. Glycosylation modification is closely related not only to endometrial receptivity [...] Read more.

The endometrium is an important part of women’s bodies for menstruation and pregnancy. Various proteins are widely expressed on the surface of endometrial cells, and glycosylation is an important post-translational modification of proteins. Glycosylation modification is closely related not only to endometrial receptivity but also to common diseases related to endometrial receptivity. Glycosylation can improve endometrial receptivity, promote embryo localization and trophoblast cell adhesion and invasion, and contribute to successful implantation. Two diseases related to endometrial receptivity include endometriosis and endometrial cancer. As a common benign disease in women, endometriosis is often accompanied by an increased menstrual volume, prolonged menstrual periods, progressive and aggravated dysmenorrhea, and may be accompanied by infertility. Protein glycosylation modification of the endometrial surface indicates the severity of the disease and may be an important pathogenesis of endometriosis. In cancer, glycosylation modifications on the surface of tumor cells can be a marker to distinguish the type and severity of endometrial cancer. This review highlights the role of protein glycosylation in embryo–maternal endometrial dialogue and explores its potential mechanisms in diseases related to endometrial receptivity, which could provide a new clinical approach for their diagnosis and treatment. Full article

(This article belongs to the Collection Feature Papers in Molecular Reproduction)

16 pages, 2180 KiB

Open AccessArticle

Phloridzin Docosahexaenoate, an Omega-3 Fatty Acid Ester of a Flavonoid Precursor, Inhibits Angiogenesis by Suppressing Endothelial Cell Proliferation, Migration, and Differentiation

by Wasundara Fernando, Emma MacLean, Susan Monro, Melanie R. Power Coombs, Paola Marcato, H. P. Vasantha Rupasinghe and David W. Hoskin

Biomolecules 2024, 14(7), 769; https://doi.org/10.3390/biom14070769 - 27 Jun 2024

Abstract

Angiogenesis is a normal physiological process that also contributes to diabetic retinopathy-related complications and facilitates tumor metastasis by promoting the hematogenic dissemination of malignant cells from solid tumors. Here, we investigated the in vitro, ex vivo, and in vivo anti-angiogenic activity of phloridzin [...] Read more.

Angiogenesis is a normal physiological process that also contributes to diabetic retinopathy-related complications and facilitates tumor metastasis by promoting the hematogenic dissemination of malignant cells from solid tumors. Here, we investigated the in vitro, ex vivo, and in vivo anti-angiogenic activity of phloridzin docosahexaenoate (PZ-DHA), a novel ω-3 fatty acid ester of a flavonoid precursor. Human umbilical vein endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC) treated with a sub-cytotoxic concentration of PZ-DHA to assess in vitro anti-angiogenic activity showed impaired tubule formation on a Matrigel matrix. Ex vivo angiogenesis was measured using rat thoracic aortas, which exhibited reduced vessel sprouting and tubule formation in the presence of PZ-DHA. Female BALB/c mice bearing VEGF₁₆₅- and basic fibroblast growth factor-containing Matrigel plugs showed a significant reduction in blood vessel development following PZ-DHA treatment. PZ-DHA inhibited HUVEC and HMVEC proliferation, as well as the migration of HUVECs in gap closure and trans-well cell migration assays. PZ-DHA inhibited upstream and downstream components of the Akt pathway and vascular endothelial growth factor (VEGF₁₆₅)-induced overexpression of small molecular Rho GTPases in HUVECs, suggesting a decrease in actin cytoskeletal-mediated stress fiber formation and migration. Taken together, these findings reveal the potential of combined food biomolecules in PZ-DHA to inhibit angiogenesis. Full article

(This article belongs to the Special Issue The Value of Natural Compounds as Therapeutic Agents)

20 pages, 640 KiB

Open AccessArticle

Concentrations of Glypican-4, Irisin and Total Antioxidant Status in Women with Metabolic Syndrome: Influence of Physical Activity

by Teresa Grzelak, Marcelina Sperling, Marta Pelczyńska, Aniceta Ada Mikulska-Sauermann, Paweł Bogdański, Krystyna Czyżewska and Edyta Mądry

Biomolecules 2024, 14(7), 768; https://doi.org/10.3390/biom14070768 - 27 Jun 2024

Abstract

Glypican-4 belongs to a group of poorly understood adipokines, with potential importance in people with metabolic syndrome, especially in groups of patients with glucose metabolism disorder. This study aimed to assess the effect of physical activity on serum glypican-4 and irisin levels and [...] Read more.

Glypican-4 belongs to a group of poorly understood adipokines, with potential importance in people with metabolic syndrome, especially in groups of patients with glucose metabolism disorder. This study aimed to assess the effect of physical activity on serum glypican-4 and irisin levels and total antioxidant status (TAS) in plasma and saliva in women with metabolic syndrome (MetS). Seventy-two Caucasian women aged 25–60 were included in the study (36 women with MetS and 36 women without MetS (control group, CONTR)). The glypican-4 and irisin concentrations, total antioxidant status, glycemia, lipid profile, anthropometric parameters, and blood pressure were analyzed before and after 28 days of controlled physical activity. Serum glypican-4 and plasma TAS levels were higher (p = 0.006 and p = 0.043, respectively) on the 28th day than on the first day of the study only in the CONTR group. In the MetS group, 28 days of physical activity caused a reduction in body fat mass (p = 0.049) without changes in glypican-4, irisin, or TAS levels. In both groups, glypican-4 levels correlated positively with irisin levels and negatively with Waist-Hip Ratio (WHR), while irisin levels correlated positively with High-Density Lipoprotein Cholesterol (HDL-C) levels and negatively with waist circumference (WC) and WHR values on the 28th day of the study. To summarize, a 28-day moderate training, accompanied by a reduction in body fat mass, stabilized glypican-4 levels and TAS in female patients with MetS. Full article

(This article belongs to the Special Issue Advances in Cardiometabolic Health)

12 pages, 1307 KiB

Open AccessArticle

mRCat: A Novel CatBoost Predictor for the Binary Classification of mRNA Subcellular Localization by Fusing Large Language Model Representation and Sequence Features

by **ao Wang, Lixiang Yang and Rong Wang

Biomolecules 2024, 14(7), 767; https://doi.org/10.3390/biom14070767 - 27 Jun 2024

Abstract

The subcellular localization of messenger RNAs (mRNAs) is a pivotal aspect of biomolecules, tightly linked to gene regulation and protein synthesis, and offers innovative insights into disease diagnosis and drug development in the field of biomedicine. Several computational methods have been proposed to [...] Read more.

The subcellular localization of messenger RNAs (mRNAs) is a pivotal aspect of biomolecules, tightly linked to gene regulation and protein synthesis, and offers innovative insights into disease diagnosis and drug development in the field of biomedicine. Several computational methods have been proposed to predict the subcellular localization of mRNAs within cells. However, there remains a deficiency in the accuracy of these predictions. In this study, we propose an mRCat predictor based on the gradient boosting tree algorithm specifically to predict whether mRNAs are localized in the nucleus or in the cytoplasm. This predictor firstly uses large language models to thoroughly explore hidden information within sequences and then integrates traditional sequence features to collectively characterize mRNA gene sequences. Finally, it employs CatBoost as the base classifier for predicting the subcellular localization of mRNAs. The experimental validation on an independent test set demonstrates that mRCat obtained accuracy of 0.761, F1 score of 0.710, MCC of 0.511, and AUROC of 0.751. The results indicate that our method has higher accuracy and robustness compared to other state-of-the-art methods. It is anticipated to offer deep insights for biomolecular research. Full article

(This article belongs to the Special Issue Artificial Intelligence (AI) in Biomedicine)

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