Biomolecules

15 pages, 1276 KiB

Open AccessReview

Atypical Metastases from Prostate Cancer: Alpha-Methylacyl-Coenzyme A Racemase (AMACR) as a Potential Molecular Target in Prostate-Specific Membrane Antigen-Negative Prostate Adenocarcinoma

by Ilham Badrane, Angelo Castello, Matteo Brunelli, Corrado Cittanti, Sara Adamantiadis, Ilaria Bagni, Noemi Mindicini, Federica Lancia, Massimo Castellani, Licia Uccelli, Mirco Bartolomei and Luca Urso

Biomolecules 2025, 15(1), 17; https://doi.org/10.3390/biom15010017 (registering DOI) - 26 Dec 2024

Abstract

Prostate cancer (PCa) is a high-prevalence disease usually characterized by metastatic spread to the pelvic lymph nodes and bones and the development of visceral metastases only in the late stages of disease. Positron Emission Tomography (PET) plays a key role in the detection [...] Read more.

Prostate cancer (PCa) is a high-prevalence disease usually characterized by metastatic spread to the pelvic lymph nodes and bones and the development of visceral metastases only in the late stages of disease. Positron Emission Tomography (PET) plays a key role in the detection of PCa metastases. Several PET radiotracers are used in PCa patients according to the stage and pathological features of the disease, in particular ⁶⁸Ga/¹⁸F-prostate-specific membrane antigen (PSMA) ligands. Moreover, 2-deoxy-2-[18F]fluoro-D-glucose ¹⁸F-FDG PET usually shows metastases in the late stages of disease, when dedifferentiated neoplastic clones lose PSMA expression. In some cases, PCa patients may present atypical sites of metastases, with uncommon appearance at PET imaging with different radiotracers. We present the case of a patient with biochemical recurrence of PCa (ISUP Grade Group IV; PSA 4.7 ng/mL) showing atypical sites of metastases (the testis and multiple lung nodules) with absent PSMA expression and high [¹⁸F]FDG avidity. The patient showed diffuse positivity to alpha-methylacyl-coenzyme A racemase (AMACR). Moreover, a literature review was performed by collecting cases of PCa patients with atypical metastatic spread detected via PET imaging, with the aim of highlighting the relationship between atypical sites of metastases, imaging presentation, and pathology findings. Full article

(This article belongs to the Special Issue Advances in the Pathology of Prostate Cancer)

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14 pages, 3107 KiB

Open AccessArticle

IL-18 Blockage Reduces Neuroinflammation and Promotes Functional Recovery in a Mouse Model of Spinal Cord Injury

by Easmin Begum, Md Rashel Mahmod, Md Mahbobur Rahman, Fumiko Fukuma, Takeshi Urano and Yuki Fujita

Biomolecules 2025, 15(1), 16; https://doi.org/10.3390/biom15010016 (registering DOI) - 26 Dec 2024

Abstract

The prognosis of spinal cord injury (SCI) is closely linked to secondary injury processes, predominantly driven by neuroinflammation. Interleukin-18 (IL-18) plays a pivotal role in this inflammatory response. In previous work, we developed an anti-IL-18 antibody capable of neutralizing the active form of [...] Read more.

The prognosis of spinal cord injury (SCI) is closely linked to secondary injury processes, predominantly driven by neuroinflammation. Interleukin-18 (IL-18) plays a pivotal role in this inflammatory response. In previous work, we developed an anti-IL-18 antibody capable of neutralizing the active form of IL-18. This study evaluated the functional effects of this antibody in a mouse model of SCI. IL-18 expression was significantly upregulated in the spinal cord following injury. In a mouse model of SCI (C57BL/6J strain), mice were administered 150 μg of the anti-IL-18 antibody intraperitoneally. IL-18 inhibition via antibody treatment facilitated motor functional recovery post-injury. This intervention reduced neuronal death, reactive gliosis, microglia/macrophage activation, and neutrophil infiltration. Additionally, IL-18 inhibition lowered the expression of pro-inflammatory factors, such as IL-1β and the M1 microglia/macrophage marker Ccl17, while enhancing the expression of the M2 microglia/macrophage marker Arginase 1. Collectively, our findings demonstrate that IL-18 inhibition promotes motor recovery and facilitates the polarization of M1 microglia/macrophages to the M2 phenotype, thereby fostering a neuroprotective immune microenvironment in mice with SCI. Full article

(This article belongs to the Section Cellular Biochemistry)

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35 pages, 1450 KiB

Open AccessReview

Epigenetic Properties of Compounds Contained in Functional Foods Against Cancer

by Giulia Casari, Brenda Romaldi, Andrea Scirè, Cristina Minnelli, Daniela Marzioni, Gianna Ferretti and Tatiana Armeni

Biomolecules 2025, 15(1), 15; https://doi.org/10.3390/biom15010015 - 26 Dec 2024

Abstract

Epigenetics encompasses reversible and heritable genomic changes in histones, DNA expression, and non-coding RNAs that occur without modifying the nucleotide DNA sequence. These changes play a critical role in modulating cell function in both healthy and pathological conditions. Dysregulated epigenetic mechanisms are implicated [...] Read more.

Epigenetics encompasses reversible and heritable genomic changes in histones, DNA expression, and non-coding RNAs that occur without modifying the nucleotide DNA sequence. These changes play a critical role in modulating cell function in both healthy and pathological conditions. Dysregulated epigenetic mechanisms are implicated in various diseases, including cardiovascular disorders, neurodegenerative diseases, obesity, and mainly cancer. Therefore, to develop innovative therapeutic strategies, research for compounds able to modulate the complex epigenetic landscape of cancer is rapidly surging. Dietary phytochemicals, mostly flavonoids but also tetraterpenoids, organosulfur compounds, and isothiocyanates, represent biologically active molecules found in vegetables, fruits, medicinal plants, and beverages. These natural organic compounds exhibit epigenetic modulatory properties by influencing the activity of epigenetics key enzymes, such as DNA methyltransferases, histone acetyltransferases and deacetylases, and histone methyltransferases and demethylases. Due to the reversibility of the modifications that they induce, their minimal adverse effects, and their potent epigenetic regulatory activity, dietary phytochemicals hold significant promise as antitumor agents and warrant further investigation. This review aims to consolidate current data on the diverse epigenetic effects of the six major flavonoid subclasses, as well as other natural compounds, in the context of cancer. The goal is to identify new therapeutic epigenetic targets for drug development, whether as stand-alone treatments or in combination with conventional antitumor approaches. Full article

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

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19 pages, 14588 KiB

Open AccessArticle

Integrated Proteomic and Metabolomic Analysis of Muscle Atrophy Induced by Hindlimb Unloading

by Yuan Wang, Xi Li, Na Li, Jiawei Du, Xiaodong Qin, Xiqing Sun, Yongchun Wang and Chengfei Li

Biomolecules 2025, 15(1), 14; https://doi.org/10.3390/biom15010014 - 26 Dec 2024

Abstract

Skeletal muscle atrophy, which is induced by factors such as disuse, spaceflight, certain medications, neurological disorders, and malnutrition, is a global health issue that lacks effective treatment. Hindlimb unloading is a commonly used model of muscle atrophy. However, the underlying mechanism of muscle [...] Read more.

Skeletal muscle atrophy, which is induced by factors such as disuse, spaceflight, certain medications, neurological disorders, and malnutrition, is a global health issue that lacks effective treatment. Hindlimb unloading is a commonly used model of muscle atrophy. However, the underlying mechanism of muscle atrophy induced by hindlimb unloading remains unclear, particularly from the perspective of the myocyte proteome and metabolism. We first used mass spectrometry for proteomic sequencing and untargeted metabolomics to analyze soleus muscle changes in rats with hindlimb unloading. The study found 1052 proteins and 377 metabolites (with the MS2 name) that were differentially expressed between the hindlimb unloading group and the control group. Proteins like ACTN3, MYH4, MYBPC2, and MYOZ1, typically found in fast-twitch muscles, were upregulated, along with metabolism-related proteins GLUL, GSTM4, and NDUFS4. Metabolites arachidylcarnitine and 7,8-dihydrobiopterin, as well as pathways like histidine, taurine, and hypotaurine metabolism, were linked to muscle atrophy. Protein and metabolism joint analyses revealed that some pathways, such as glutathione metabolism, ferroptosis, and lysosome pathways, were likely to be involved in soleus atrophy. In this study, we have applied integrated deep proteomic and metabolomic analyses. The upregulation of proteins that are expressed in fast-twitch fibers indicates the conversion of slow-twitch fibers to fast-twitch fibers under hindlimb unloading. In addition, some differentially abundant metabolites and pathways revealed the important role of metabolism in muscle atrophy of the soleus. As shown in the graphical abstract, our study provides insights into the pathogenesis and treatment of muscle atrophy that results from unloading by integrating proteomics and metabolomics of the soleus muscles. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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4 pages, 149 KiB

Open AccessEditorial

Ribosomal Proteins in Ribosome Assembly

by Brigitte Pertschy and Ingrid Zierler

Biomolecules 2025, 15(1), 13; https://doi.org/10.3390/biom15010013 - 26 Dec 2024

Abstract

Ribosomes are the cellular machinery responsible for translating mRNA into proteins, a process fundamental to all domains of life from bacteria to eukaryotes [...] Full article

(This article belongs to the Special Issue Ribosomal Proteins in Ribosome Assembly)

17 pages, 3068 KiB

Open AccessArticle

Etoricoxib–NLC Mitigates Radiation-Induced Ovarian Damage in Rats: Insights into Pro-Inflammatory Cytokines, Antioxidant Activity, and Hormonal Responses

by Sahar Khateeb

Biomolecules 2025, 15(1), 12; https://doi.org/10.3390/biom15010012 - 25 Dec 2024

Abstract

Radiotherapy is a critical treatment for cancer but poses significant risks to ovarian tissue, particularly in young females, leading to premature ovarian failure (POF). This study examines the therapeutic potential of etoricoxib nanostructured lipid carriers (ETO-NLC) in mitigating radiation-induced ovarian damage in female [...] Read more.

Radiotherapy is a critical treatment for cancer but poses significant risks to ovarian tissue, particularly in young females, leading to premature ovarian failure (POF). This study examines the therapeutic potential of etoricoxib nanostructured lipid carriers (ETO-NLC) in mitigating radiation-induced ovarian damage in female Wistar rats. Twenty-four female rats were randomly assigned to four groups: a control group receiving normal saline, a group exposed to a single dose of whole-body gamma radiation (6 Gy), a group treated with etoricoxib (10 mg/kg) post-radiation, and a group treated with ETO-NLC for 14 days following radiation. Histopathological evaluations and oxidative stress biomarker assessments were conducted, including ELISAs for reactive oxygen species (ROS), pro-inflammatory cytokines (IL-1β, TNF-α), and signaling molecules (PI3K, AKT, P38MAPK, AMH). Serum levels of estrogen, FSH, and LH were measured, and gene expression analysis for TGF-β and Nrf2 was performed using qRT-PCR. The findings indicate that ETO-NLC has the potential to ameliorate the harmful effects of ovarian damage induced by γ-radiation. These therapeutic effects were achieved through the modulation of oxidative stress, inflammation, augmentation of antioxidant defenses (including Nrf2 activation), support for cell survival pathways (via PI3K/Akt signaling), regulation of MAPK, mitigation of fibrosis (TGF-β), and preservation of ovarian reserve (as evidenced by AMH, FSH/LH, and estrogen levels). ETO-NLC shows promise as an effective strategy for attenuating radiation-induced ovarian damage, highlighting the need for further research to enhance therapeutic interventions aimed at preserving ovarian function during cancer treatment. Full article

(This article belongs to the Section Cellular Biochemistry)

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13 pages, 2356 KiB

Open AccessViewpoint

A Refined Nomenclature System to Better Discriminate Endo- and Exo-Type Fructanases and Glucanases

by Laura Leaerts, Jaime Ricardo Porras-Domínguez, Maxime Versluys and Wim Van den Ende

Biomolecules 2025, 15(1), 11; https://doi.org/10.3390/biom15010011 - 25 Dec 2024

Abstract

Distinguishing between endo- and exo-type enzymes within the glycoside hydrolase (GH) classification presents significant challenges. Traditional methods, often based on endpoint activity measurements, do not capture the full range of products generated, leading to inconsistencies in classification. Not all exo-acting fructanases and glucanases [...] Read more.

Distinguishing between endo- and exo-type enzymes within the glycoside hydrolase (GH) classification presents significant challenges. Traditional methods, often based on endpoint activity measurements, do not capture the full range of products generated, leading to inconsistencies in classification. Not all exo-acting fructanases and glucanases produce monosaccharides (like fructose or glucose), while endo-acting enzymes do not solely produce higher-degree polymerization oligosaccharides. In practice, both enzyme types can yield a variety of products throughout the reaction, complicating classification efforts. To address these challenges, we propose a refined nomenclature system for GH enzymes, including fructanases and glucanases, based on good practices and initial product formation. This system classifies enzymes into four categories for each type: Fr, Fn, Fn,n+1 and F1 for fructanases, and Gr, Gn, Gn,n+1 and G1 for glucanases, based on their mode of action (endo- or exo-based) and initial product profiles. Our refined nomenclature system will advance enzyme structure–function research and support the production and application of fructan and glucan oligosaccharides as prebiotics, priming agents, and potential signaling molecules in microbe–microbe and plant–microbe interactions. Ultimately, this system could benefit agronomy and the food industry, contributing to health improvements. Full article

(This article belongs to the Special Issue Recent Advances in the Enzymatic Synthesis of Bioactive Compounds)

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25 pages, 1456 KiB

Open AccessReview

The Role of Neuroglia in the Development and Progression of Schizophrenia

by Neha S. Rawani, Allen W. Chan, Kathryn G. Todd, Glen B. Baker and Serdar M. Dursun

Biomolecules 2025, 15(1), 10; https://doi.org/10.3390/biom15010010 - 25 Dec 2024

Abstract

Schizophrenia is a complex heterogenous disorder thought to be caused by interactions between genetic and environmental factors. The theories developed to explain the etiology of schizophrenia have focused largely on the dysfunction of neurotransmitters such as dopamine, serotonin and glutamate with their receptors, [...] Read more.

Schizophrenia is a complex heterogenous disorder thought to be caused by interactions between genetic and environmental factors. The theories developed to explain the etiology of schizophrenia have focused largely on the dysfunction of neurotransmitters such as dopamine, serotonin and glutamate with their receptors, although research in the past several decades has indicated strongly that other factors are also involved and that the role of neuroglial cells in psychotic disorders including schizophrenia should be given more attention. Although glia were originally thought to be present in the brain only to support neurons in a physical, metabolic and nutritional capacity, it has become apparent that these cells have a variety of important physiological roles and that abnormalities in their function may make significant contributions to the symptoms of schizophrenia. In the present paper, we review the interactions of brain microglia, astrocytes and oligodendroglia with aspects such as transmitter dysregulation, neuro-inflammation, oxidative stress, synaptic function, the gut microbiome, myelination and the blood–brain barrier that appear to affect the cause, development and treatment of schizophrenia. We also review crosstalk between microglia, astrocytes and oligodendrocytes and the effects of antipsychotics on neuroglia. Problems associated with studies on specific biomarkers for glia in schizophrenia are discussed. Full article

(This article belongs to the Section Cellular Biochemistry)

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21 pages, 3504 KiB

Open AccessArticle

G Protein-Coupled Receptor 17 Inhibits Glucagon-like Peptide-1 Secretion via a Gi/o-Dependent Mechanism in Enteroendocrine Cells

by Jason M. Conley, Alexander Jochim, Carmella Evans-Molina, Val J. Watts and Hongxia Ren

Biomolecules 2025, 15(1), 9; https://doi.org/10.3390/biom15010009 - 25 Dec 2024

Abstract

Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. [...] Read more.

Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. However, the GPR17-mediated molecular signaling pathways in EECs have yet to be fully deciphered. Here, we expressed the human GPR17 long isoform (hGPR17L) in GLUTag cells, a murine EEC line, and we used the GPR17 synthetic agonist MDL29,951 together with pharmacological probes and genetic approaches to quantitatively assess the contribution of GPR17 signaling to GLP-1 secretion. Constitutive hGPR17L activity inhibited GLP-1 secretion, and MDL29,951 treatment further inhibited this secretion, which was attenuated by treatment with the GPR17 antagonist HAMI3379. MDL29,951 promoted both Gi/o and Gq protein coupling to mediate cyclic AMP (cAMP) and calcium signaling. hGPR17L regulation of GLP-1 secretion appeared to be Gq-independent and dependent upon Gi/o signaling, but was not correlated with MDL29,951-induced whole-cell cAMP signaling. Our studies revealed key signaling mechanisms underlying the role of GPR17 in regulating GLP-1 secretion and suggest future opportunities for pharmacologically targeting GPR17 with inverse agonists to maximize GLP-1 secretion. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Metabolic Regulation Used by G Protein-Coupled Receptors)

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11 pages, 1653 KiB

Open AccessArticle

Neurofilament Light Chain Levels in Serum and Cerebrospinal Fluid Do Not Correlate with Survival Times in Patients with Prion Disease

by Mika Shimamura, Kong Weijie, Toshiaki Nonaka, Koki Kosami, Ryusuke Ae, Koji Fujita, Taiki Matsubayashi, Tadashi Tsukamoto, Nobuo Sanjo and Katsuya Satoh

Biomolecules 2025, 15(1), 8; https://doi.org/10.3390/biom15010008 - 25 Dec 2024

Abstract

Prion diseases, including Creutzfeldt–Jakob disease (CJD), are deadly neurodegenerative disorders characterized by the buildup of abnormal prion proteins in the brain. This accumulation disrupts neuronal functions, leading to the rapid onset of psychiatric symptoms, ataxia, and cognitive decline. The urgency of timely diagnosis [...] Read more.

Prion diseases, including Creutzfeldt–Jakob disease (CJD), are deadly neurodegenerative disorders characterized by the buildup of abnormal prion proteins in the brain. This accumulation disrupts neuronal functions, leading to the rapid onset of psychiatric symptoms, ataxia, and cognitive decline. The urgency of timely diagnosis for effective treatment necessitates the identification of strongly correlated biomarkers in bodily fluids, which makes our research crucial. In this study, we employed a fully automated multiplex ELISA (Ella^®) to measure the concentrations of 14-3-3 protein, total tau protein, and neurofilament light chain (NF-L) in cerebrospinal fluid (CSF) and serum samples from patients with prion disease and analyzed their link to disease prognosis. However, in North American and European cases, we did not confirm a correlation between NF-L levels and survival time. This discrepancy is believed to stem from differences in treatment policies and measurement methods between Japan and the United States. Nonetheless, our findings suggest that NF-L concentrations could be an early diagnostic marker for CJD patients with further enhancements. The potential impact of our findings on the early diagnosis of CJD patients is significant. Future research should focus on increasing the number of sCJD cases studied in Japan and gathering additional evidence using next-generation measurement techniques. Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 6429 KiB

Open AccessArticle

Discovery and Characterization of Two Selective Inhibitors for a Mu-Class Glutathione S-Transferase of 25 kDa from Taenia solium Using Computational and Bioinformatics Tools

by César Sánchez-Juárez, Roberto Flores-López, Lluvia de Carolina Sánchez-Pérez, Ponciano García-Gutiérrez, Lucía Jiménez, Abraham Landa and Rafael A. Zubillaga

Biomolecules 2025, 15(1), 7; https://doi.org/10.3390/biom15010007 - 25 Dec 2024

Abstract

Glutathione S-transferases (GSTs) are promising pharmacological targets for developing antiparasitic agents against helminths, as they play a key role in detoxifying cytotoxic xenobiotics and managing oxidative stress. Inhibiting GST activity can compromise parasite viability. This study reports the successful identification of two selective [...] Read more.

Glutathione S-transferases (GSTs) are promising pharmacological targets for developing antiparasitic agents against helminths, as they play a key role in detoxifying cytotoxic xenobiotics and managing oxidative stress. Inhibiting GST activity can compromise parasite viability. This study reports the successful identification of two selective inhibitors for the mu-class glutathione S-transferase of 25 kDa (Ts25GST) from Taenia solium, named i11 and i15, using a computationally guided approach. The workflow involved modeling and refining the 3D structure from the sequence using the AlphaFold algorithm and all-atom molecular dynamics simulations with an explicit solvent. Representative structures from these simulations and a putative binding site with low conservation relative to human GSTs, identified via the SILCS methodology, were employed for virtual screening through ensemble docking against a commercial compound library. The two compounds were found to reduce the enzyme’s activity by 50–70% under assay conditions, while showing a reduction of only 30–35% for human mu-class GSTM1, demonstrating selectivity for Ts25GST. Notable, i11 displayed competitive inhibition with CDNB, while i15 exhibited a non-competitive inhibition type. Full article

(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery: 2nd Edition)

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32 pages, 1556 KiB

Open AccessReview

Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia

by Amanda Louise White, Grant M. Talkington, Blake Ouvrier, Saifudeen Ismael, Rebecca J. Solch-Ottaiano and Gregory Bix

Biomolecules 2025, 15(1), 6; https://doi.org/10.3390/biom15010006 - 25 Dec 2024

Abstract

Vascular dementia (VaD) is a progressive neurodegenerative condition prevalent among elderly adults marked by cognitive decline resulting from injured and/or improperly functioning cerebrovasculature with resultant disruptions in cerebral blood flow. Currently, VaD has no specific therapeutics and the exact pathobiology is still being [...] Read more.

Vascular dementia (VaD) is a progressive neurodegenerative condition prevalent among elderly adults marked by cognitive decline resulting from injured and/or improperly functioning cerebrovasculature with resultant disruptions in cerebral blood flow. Currently, VaD has no specific therapeutics and the exact pathobiology is still being investigated. VaD has been shown to develop when reactive oxygen species (ROS) form from damaged targets at different levels of organization—mitochondria, endothelial cells, or cerebrovasculature. In this review, we highlight how specific ROS molecules may be important in the development of VaD and how they can be targeted as a potential therapeutic for VaD. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment (2nd Edition))

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22 pages, 1019 KiB

Open AccessArticle

Effect of Satureja montana Essential Oil on Model Lipid Membranes

by Simona Sennato, Silvia Trabalzini, Maria Gioia Fabiano, Domenico Truzzolillo, Edouard Chauveau, Cecilia Bombelli, Federica Rinaldi and Maria Carafa

Biomolecules 2025, 15(1), 5; https://doi.org/10.3390/biom15010005 - 24 Dec 2024

Abstract

Satureja montana essential oil is a natural substance able to inhibit the growth of several pathogens. This antimicrobial effect is often attributed to its ability to penetrate cellular structures and disrupt them. Although these properties are recognized as playing a key role in [...] Read more.

Satureja montana essential oil is a natural substance able to inhibit the growth of several pathogens. This antimicrobial effect is often attributed to its ability to penetrate cellular structures and disrupt them. Although these properties are recognized as playing a key role in the mechanism of action of this substance, many unresolved issues still exist, and fundamental studies focused on such aspects are scarce. In this framework, we investigated the interaction of SEO with lipid monolayers, which represent simplified models of cell membranes, using the Langmuir monolayer technique, complemented by fluorescence anisotropy and differential scanning calorimetry on lipid bilayers. By focusing on packing conditions that approximate those of biological membranes and using lipids with different polar heads and structures, such as the ones occurring in bacterial membranes, we aim to clarify the effect of this essential oil on the lipid membrane. Our results show that Satureja montana essential oil consistently manages to insert into the membrane and interfere with the lipid–lipid interactions, thereby altering the lipid packing and significantly increasing the membrane fluidity, depending on the oil concentration and the nature of the lipid. Full article

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

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19 pages, 1313 KiB

Open AccessArticle

Cardiovascular Risk Biomarkers in Women with and Without Polycystic Ovary Syndrome

by Manjula Nandakumar, Priya Das, Thozhukat Sathyapalan, Alexandra E. Butler and Stephen L. Atkin

Biomolecules 2025, 15(1), 4; https://doi.org/10.3390/biom15010004 - 24 Dec 2024

Abstract

Objective: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder with an increased risk for cardiovascular disease (CVD) that is enhanced by obesity. This study sought to determine whether a panel of cardiovascular risk proteins (CVRPs) would be dysregulated in overweight/obese PCOS patients, [...] Read more.

Objective: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder with an increased risk for cardiovascular disease (CVD) that is enhanced by obesity. This study sought to determine whether a panel of cardiovascular risk proteins (CVRPs) would be dysregulated in overweight/obese PCOS patients, highlighting potential biomarkers for CVD in PCOS. Methods: In this exploratory cross-sectional study, plasma levels of 54 CVRPs were analyzed in women with PCOS (n = 147) and controls (n = 97). CVRPs were measured using the SOMAscan proteomic platform (version 3.1), with significant proteins identified through linear models, regression analysis, and receiver operating characteristic (ROC) analysis. Analysis on BMI-matched subsets of the cohort were undertaken. Functional enrichment and protein–protein interaction analyses elucidated the pathways involved. Results: Eleven CVRPs were dysregulated in PCOS (whole set, without matching for body mass index (BMI) or insulin resistance (IR)): leptin, Interleukin-1 receptor antagonist protein (IL-1Ra), polymeric immunoglobulin receptor (PIGR), interleukin-18 receptor (IL-18Ra), C-C motif chemokine 3 (MIP-1a), and angiopoietin-1 (ANGPT1) were upregulated whilst advanced glycosylation end product-specific receptor, soluble (sRAGE), bone morphogenetic protein 6 (BMP6); growth/differentiation factor 2 (GDF2), superoxide dismutase [Mn] mitochondrial (MnSOD), and SLAM family member 5 (SLAF5) were downregulated versus the controls. In BMI-matched (overweight/obese, BMI ≥ 26 kg/m²) subset analysis, six CVRPs were common to the whole set: ANGPT1 and IL-1Ra were upregulated; and sRAGE, BMP6, GDF2, and Mn-SOD were downregulated. In addition, lymphotactin (XCL1) was upregulated and placenta growth factor (PIGF), alpha-L-iduronidase (IDUA), angiopoietin-1 receptor, and soluble (sTie-2) and macrophage metalloelastase (MMP12) were downregulated. A subset analysis of BMI-matched plus insulin resistance (IR)-matched women revealed only upregulation of tissue factor (TF) and renin in PCOS, potentially serving as biomarkers for cardiovascular risk in overweight/obese women with PCOS. Conclusions: A combination of upregulated obesity-related CVRPs (ANGPT1/IL/1Ra/XCL1) and downregulated cardioprotective proteins (sRAGE/BMP6/Mn-SOD/GDF2) in overweight/obese PCOS women may contribute to the increased risk for CVD. TF and renin upregulation observed in the BMI- and IR-matched limited sample PCOS subgroup indicates their potential risk of CVD. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

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14 pages, 2758 KiB

Open AccessReview

The Expression Regulation and Cancer-Promoting Roles of RACGAP1

by Jiacheng Lin, Yuhao Zhu, Zhaoping Lin, Jindong Yu, Xiaobing Lin, Weiyuan Lai, Beibei Tong, Liyan Xu, Enmin Li and Lin Long

Biomolecules 2025, 15(1), 3; https://doi.org/10.3390/biom15010003 - 24 Dec 2024

Abstract

RACGAP1 is a Rho-GTPase-activating protein originally discovered in male germ cells to inactivate Rac, RhoA and Cdc42 from the GTP-bound form to the GDP-bound form. GAP has traditionally been known as a tumor suppressor. However, studies increasingly suggest that overexpressed RACGAP1 activates Rac [...] Read more.

RACGAP1 is a Rho-GTPase-activating protein originally discovered in male germ cells to inactivate Rac, RhoA and Cdc42 from the GTP-bound form to the GDP-bound form. GAP has traditionally been known as a tumor suppressor. However, studies increasingly suggest that overexpressed RACGAP1 activates Rac and RhoA in multiple cancers to mediate downstream oncogene overexpression by assisting in the nuclear translocation of signaling molecules and to promote cytokinesis by regulating the cytoskeleton or serving as a component of the central spindle. Contradictorily, it was also reported that RACGAP1 in gastric cancer could inactivate Rac and RhoA. In addition, studies have revealed that RACGAP1 can be a biomarker for prognosis, and its role in reducing doxorubicin sensitivity poses difficulties for treatment, while the current drug targets mainly focus on its downstream molecule. This article mainly reviews the expression regulation of RACGAP1 and its cancer-promoting functions through oncogene expression mediation and Rho-GTPase activation. Full article

(This article belongs to the Section Molecular Biology)

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18 pages, 2132 KiB

Open AccessArticle

Synthesis and Anti-Cancer Activity In Vitro of Synephrine Derivatives

by Ekaterina M. Zhidkova, Evgeniya S. Oleynik, Ekaterina A. Mikhina, Daria V. Stepanycheva, Diana D. Grigoreva, Lyubov E. Grebenkina, Kirill V. Gordeev, Ekaterina D. Savina, Andrey V. Matveev, Marianna G. Yakubovskaya and Ekaterina A. Lesovaya

Biomolecules 2025, 15(1), 2; https://doi.org/10.3390/biom15010002 - 24 Dec 2024

Abstract

Glucocorticoids (GCs) are routinely used to treat hematological malignancies; however, long-term treatment with GCs can lead to atrophic and metabolic adverse effects. Selective glucocorticoid receptor agonists (SEGRAs) with reduced side effects may act as a superior alternative to GCs. More than 30 SEGRAs [...] Read more.

Glucocorticoids (GCs) are routinely used to treat hematological malignancies; however, long-term treatment with GCs can lead to atrophic and metabolic adverse effects. Selective glucocorticoid receptor agonists (SEGRAs) with reduced side effects may act as a superior alternative to GCs. More than 30 SEGRAs have been described so far, yet none of them reached clinical trials for anti-cancer treatment. In the present work, we propose a novel approach to increase the number of potential SEGRAs by obtaining derivatives of synephrine, a molecule of natural origin. We synthesized 26 novel compounds from the class of synephrine derivatives and characterized them by HRMS, and ¹H and ¹³C NMR. We evaluated in vitro anti-cancer effects in leukemia K562 and lymphoma Granta cells using the MTT assay and studied their potential affinity for the glucocorticoid receptor (GR) in silico using the molecular docking approach. The novel derivative 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2) with the highest GR affinity in silico exhibited cytotoxic activity against K562 and Granta cells after 24 h of treatment at the concentration of approximately 13 µM which correlated with its highest MolDock Score. The other compound with high GR affinity, 2-(hexylamino)-1-(4-nitrophenyl)ethanol (13S-G2), demonstrated cytotoxicity in both cell lines at concentrations of 50–70 µM. Overall, our results may provide a solid rationale for developing and further investigating synephrine derivatives as SEGRAs with anti-cancer activity. Full article

(This article belongs to the Topic Novel Discoveries in Oncology)

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13 pages, 2170 KiB

Open AccessArticle

The Difference a Year Can Make: How Antibiotic Resistance Mechanisms in Pseudomonas aeruginosa Have Changed in Northwestern Transylvania

by Matei-Ștefan Dobrescu, Dan-Alexandru Țoc, Adrian-Gabriel Pană, Carmen Costache and Anca Butiuc-Keul

Biomolecules 2025, 15(1), 1; https://doi.org/10.3390/biom15010001 - 24 Dec 2024

Abstract

This study examines the prevalence and the mechanisms of antibiotic resistance in Pseudomonas aeruginosa isolates collected from healthcare units in Northwestern Transylvania, Romania, between 2022 and 2023. Given the alarming rise in antibiotic resistance, the study screened 34 isolates for resistance to 10 [...] Read more.

This study examines the prevalence and the mechanisms of antibiotic resistance in Pseudomonas aeruginosa isolates collected from healthcare units in Northwestern Transylvania, Romania, between 2022 and 2023. Given the alarming rise in antibiotic resistance, the study screened 34 isolates for resistance to 10 antibiotics, 46 ARGs, and integrase genes using PCR analysis. The results reveal a concerning increase in multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates over the two-year period. Notably, the prevalence of ARGs encoding resistance to sulfonamides and beta-lactams, particularly sul1 and bla_OXA-50, has shown a significant rise. Furthermore, the study detected the emergence of new resistance mechanisms in the same time interval. These include target protection and even more specific mechanisms, such as metallo-beta-lactamases or enzymes involved in the methylation of 23S rRNA. Statistical analysis further confirmed the correlation between Class I integrons and several ARGs, underscoring the role of horizontal gene transfer in the dissemination of resistance. These findings emphasize the urgent need for updated treatment strategies and monitoring programs to effectively combat the spread of ARGs in clinical settings. Full article

(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance)

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23 pages, 1332 KiB

Open AccessReview

Gut Microbiota Modulation: A Novel Strategy for Rheumatoid Arthritis Therapy

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

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

Abstract

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

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

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

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13 pages, 918 KiB

Open AccessReview

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

by Andreas Rinne and Moritz Bünemann

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

Abstract

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

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

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

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