Biomolecules

28 pages, 4762 KB

Open AccessArticle

Conditional Ablation of PKCλ/ι in CD4⁺ T Cells Ameliorates Hepatic Fibrosis in Schistosoma japonicum-Infected Mice via T Follicular Helper (Tfh) Cell Suppression Coupled with Increased Follicular Regulatory T (Tfr) and Regulatory B (Breg) Cell Activities

by Congjin Mei, Yingying Yang, Panpan Dong, Julu Lu, Xinyue Zhang, Jingping Li, Lijun Song and Chuanxin Yu

Biomolecules 2025, 15(10), 1430; https://doi.org/10.3390/biom15101430 - 9 Oct 2025

Abstract

To further investigate the role of PKCλ/ι in Schistosoma japonicum-induced hepatic fibrosis, we employed a CD4⁺ T-cell-specific PKCλ/ι conditional knockout (KOSJ) mouse model, with wild-type (WTSJ) mice used as controls. Transcriptomic profiling of hepatic mRNA was used to reveal the immune [...] Read more.

To further investigate the role of PKCλ/ι in Schistosoma japonicum-induced hepatic fibrosis, we employed a CD4⁺ T-cell-specific PKCλ/ι conditional knockout (KOSJ) mouse model, with wild-type (WTSJ) mice used as controls. Transcriptomic profiling of hepatic mRNA was used to reveal the immune regulatory mechanisms underlying the role of PKCλ/ι in the hepatic fibrosis caused by S. japonicum infection. Flow cytometry, RT–qPCR and ELISA were used to analyze the effects of PKCλ/ι on Tfh and Tfr cells, and single-cell RNA sequencing was used to elucidate the interactions between Tfr and B cells. The results showed that PKCλ/ι deficiency led to altered BCR signaling gene expression, reduced germinal center activity, and decreased anti-SEA antibody levels. Tfh cells and key factors including IL-21, CXCR5, and ICOS were downregulated, while Tfr cells and IL-10⁺ B cells increased. Additionally, hepatic neutrophils decreased and Treg/Tfr ratios rose, with enhanced IL-10-mediated cellular crosstalk. These findings indicate that PKCλ/ι deficiency attenuates liver fibrosis by inhibiting Tfh differentiation, promoting Tfr function, and activating IL-10-producing Breg cells, suggesting its potential as a therapeutic target. Full article

(This article belongs to the Section Molecular Medicine)

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34 pages, 4086 KB

Open AccessReview

Neurotransmitter Regulatory Networks: A New Perspective on Cancer Therapy

by Xiaoyu Zhang, Jiaxin Cao, Yishu Zhang, Chuanxiong Li and Yuhong Jing

Biomolecules 2025, 15(10), 1429; https://doi.org/10.3390/biom15101429 - 9 Oct 2025

Abstract

In recent years, the scientific community has increasingly delved into the study of the interaction between the nervous system and tumors, revealing that the nervous system not only regulates bodily functions under physiological conditions, but also assumes a vital part in the emergence [...] Read more.

In recent years, the scientific community has increasingly delved into the study of the interaction between the nervous system and tumors, revealing that the nervous system not only regulates bodily functions under physiological conditions, but also assumes a vital part in the emergence and progression of tumors. Research has demonstrated that the extensive neural network directly regulates tumor progression and can influence tumors by modulating the tumor microenvironment and immune system. Moreover, tumors induce neural networks to provide favorable conditions for their proliferation and metastasis. In the above process, neurotransmitters play a vital role. They directly act or bind to their receptor, activating various classical signaling pathways, among which are PI3K/AKT, MEK/ERK, and WNT/β-catenin, to facilitate tumor advancement. Therefore, this study systematically reviews the regulatory mechanisms of neurotransmitters and their receptors in the advancement of cancer, along with the utilization of targeted drugs. At the same time, we also analyzed that targeting specific receptor subtypes may produce more significant therapeutic effects in different types of cancer. Additionally, this research further explores the limitations of neurotransmitter-based drugs currently used in clinical cancer treatment. In summary, the field of cancer neuroscience is rapidly advancing, constantly revealing the regulatory effects of neurotransmitters on tumor progression and their specific molecular mechanisms, providing broad application prospects for future clinical therapy. Full article

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18 pages, 1224 KB

Open AccessReview

Targeting CRABP1 Signalosomes in Managing Neurodegeneration

by Jennifer Nhieu and Li-Na Wei

Biomolecules 2025, 15(10), 1428; https://doi.org/10.3390/biom15101428 - 9 Oct 2025

Abstract

Retinoic acid (RA) binds RA (RAR) and Retinoid X (RXR) receptors to elicit biological effects by regulating transcription. RA is also known to have non-canonical activities mediated, primarily, by cellular retinoic acid-binding protein 1 (CRABP1) which forms protein complexes named “CRABP1 signalosomes” to [...] Read more.

Retinoic acid (RA) binds RA (RAR) and Retinoid X (RXR) receptors to elicit biological effects by regulating transcription. RA is also known to have non-canonical activities mediated, primarily, by cellular retinoic acid-binding protein 1 (CRABP1) which forms protein complexes named “CRABP1 signalosomes” to regulate cytosolic signaling independent of RARs/RXRs. This review focuses on therapeutic applications in neurodegeneration by targeting CRABP1 signalosomes including CRABP1–MAPK, CRABP1–CaMKII, CRABP1–eIF2α, and others recently identified from our proteomic studies. The mouse Crabp1 gene is regulated by various epigenetic factors and is important for the health of multiple cell types including motor neurons (MNs). In humans, CRABP1 gene expression is reduced in ALS- and SMA-patient MNs. RA is a therapeutic agent for leukemias and dermatological disorders and is being investigated for managing neurodegenerative diseases, but its therapeutic effects are accompanied by RAR-mediated toxic effects. We have uncovered a novel class of synthetic retinoids that bind CRABP1 without acting on RARs, circumventing RAR-mediated toxic effects. These first-generation CRABP1-selective compounds C3, C4, and C32 target CRABP1–MAPK and/or CRABP1–CaMKII signalosomes. This knowledge, together with emerging structural information, sheds lights on the strategies in designing next-generation CRABP1-signalosome-selective retinoids for the management of neurodegenerative diseases. Full article

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13 pages, 2477 KB

Open AccessArticle

Field-Gated Anion Transport in Nanoparticle Superlattices Controlled by Charge Density and Ion Geometry: Insights from Molecular Dynamics Simulations

by Yuexin Su, Jianxiang Huang, Zaixing Yang, Yangwei Jiang and Ruhong Zhou

Biomolecules 2025, 15(10), 1427; https://doi.org/10.3390/biom15101427 - 8 Oct 2025

Abstract

Nanoparticle superlattices—periodic assemblies of uniformly spaced nanocrystals—bridge the nanoscale precision of individual particles with emergent collective properties akin to those of bulk materials. Recent advances demonstrate that multivalent ions and charged polymers can guide the co-assembly of nanoparticles, imparting electrostatic gating and enabling [...] Read more.

Nanoparticle superlattices—periodic assemblies of uniformly spaced nanocrystals—bridge the nanoscale precision of individual particles with emergent collective properties akin to those of bulk materials. Recent advances demonstrate that multivalent ions and charged polymers can guide the co-assembly of nanoparticles, imparting electrostatic gating and enabling semiconductor-like behavior. However, the specific roles of anion geometry, valency, and charge density in mediating ion transport remain unclear. Here, we employ coarse-grained molecular dynamics simulations to investigate how applied electric fields (0–0.40 V/nm) modulate ionic conductivity and spatial distribution in trimethylammonium-functionalized gold nanoparticle superlattices assembled with four phosphate anions of distinct geometries and charges. Our results reveal that linear anions outperform ring-shaped analogues in conductivity due to higher charge densities and weaker interfacial binding. Notably, charge density exerts a greater influence on ion mobility than size alone. Under strong fields, anions accumulate at nanoparticle interfaces, where interfacial adsorption and steric constraints suppress transport. In contrast, local migration is governed by geometrical confinement and field strength. Analyses of transition probability and residence time further indicate that the rigidity and delocalized charge of cyclic anions act as mobility barriers. These findings provide mechanistic insights into the structure–function relationship governing ion transport in superlattices, offering guidance for designing next-generation ion conductors, electrochemical sensors, and energy storage materials through anion engineering. Full article

(This article belongs to the Special Issue Nanomaterials and Their Applications in Biomedicine)

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19 pages, 1467 KB

Open AccessArticle

Landscape Analysis of COL6A1, COL6A2, and COL6A3 Pathogenic Variants in a Large Italian Cohort Presenting with Collagen VI-Related Myopathies: A Nationwide Report

by Fernanda Fortunato, Laura Fiocco, Alice Margutti, Marcella Neri, Adele D’Amico, Enrico Bertini, Enzo Ricci, Eugenio Maria Mercuri, Marika Pane, Roberto Massa, Giulia Greco, Angela Lucia Berardinelli, Cristina Cereda, Antonella Pini, Luciano Merlini, Carlo Fusco, Carmelo Rodolico, Sonia Messina, Chiara Fiorillo, Claudio Bruno, Marina Pedemonte, Monica Traverso, Isabella Moroni, Lorenzo Maggi, Sara Gibertini, Elena Pegoraro, Esther Picillo, Luisa Politano, Marianna Scutifero, Fabiana Vercellino, Francesca Massaro, Massimiliano Filosto, Paolo Gasparini, Federica Ricci, Tiziana Enrica Mongini, Rita Selvatici, Alessandra Ferlini and Francesca Gualandi Show full author list Hide full author list

Biomolecules 2025, 15(10), 1426; https://doi.org/10.3390/biom15101426 - 8 Oct 2025

Abstract

Collagen VI is an extracellular matrix component encoded by COL6A1, COL6A2 and COL6A3 genes. Causative variants in these genes are associated with the following collagen VI-related myopathies: severe Ullrich congenital muscular dystrophy (UCMD), milder Bethlem myopathy (BM) and intermediate phenotypes (INT). We [...] Read more.

Collagen VI is an extracellular matrix component encoded by COL6A1, COL6A2 and COL6A3 genes. Causative variants in these genes are associated with the following collagen VI-related myopathies: severe Ullrich congenital muscular dystrophy (UCMD), milder Bethlem myopathy (BM) and intermediate phenotypes (INT). We report the mutation landscape of COL6A genes in 138 Italian patients affected with a collagen VI-related phenotype. The patient cohort included 44 (32%) UCMD, 9 (7%) INT, 61 (44%) BM and 21 (15%) INT/BM patients; 3 patients (2%) with a myosclerosis myopathy (MM) phenotype were also considered. We identified 104 different variants: 26 in COL6A1 (25%), 52 in COL6A2 (50%) and 26 in COL6A3 (25%). The variant spectrum includes missense, splicing, small indel, frameshifting and nonsense variants. Glycine substitutions in the triple helical domain of the collagen VI protein are the commonest variants and occur in all phenotypes. Our genetic profiling disclosed a unique mutation scenario and phenotypic association of the COL6A2 gene with respect to COL6A1 and COL6A3, which may be related to a different evolutive history. Landscape mutation analysis of variants occurring in ultrarare conditions, such as collagen VI-related myopathies, is crucial to better understand the variations’ profile and to gain insight into fundamental knowledge about gene structure and its evolutive origin. Full article

(This article belongs to the Special Issue State-of-the-Art of Myology 2024–2025)

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19 pages, 2778 KB

Open AccessArticle

Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma

by Alexei A. Maslov, Nicholas H. Trageser, Julia V. Kichina, Haya Elamir, Evelyn Gardner, Frances Teaman, Vera Vishwanath, Scott M. Dugas, Johanna Heid, Alexander Y. Maslov, Henry G. Withers, Anna Bianchi-Smiraglia, Katerina I. Leonova, Mikhail A. Nikiforov and Eugene S. Kandel

Biomolecules 2025, 15(10), 1425; https://doi.org/10.3390/biom15101425 - 7 Oct 2025

Abstract

Uveal melanoma is a melanocyte-derived malignancy of the eye with a high propensity for liver metastasis. Metastatic uveal melanoma is associated with high mortality and is poorly responsive to currently available therapies. Most uveal melanoma cases are driven by activating mutations in GNAQ [...] Read more.

Uveal melanoma is a melanocyte-derived malignancy of the eye with a high propensity for liver metastasis. Metastatic uveal melanoma is associated with high mortality and is poorly responsive to currently available therapies. Most uveal melanoma cases are driven by activating mutations in GNAQ and GNA11 genes, which convey oncogenic signaling through the mitogen-activated protein kinase (MAPK) pathway. Despite promising early results, safe doses of pharmacological inhibitors of the MAPK cascade failed to effectively control uveal melanoma in human trials. Considering the role of the RAC/PAK signaling axis as a co-regulator of the MAPK cascade, we set forth to investigate whether the efficacy of MAPK cascade inhibitors in pre-clinical models may be enhanced by direct inhibition of RAC and PAK proteins, or by indirect control of RAC via inhibition of guanylate biosynthesis. We observed that pharmacological inhibition of RAC, PAK and the key guanylate biosynthesis enzyme IMPDH significantly synergized with various inhibitors of the MAPK cascade in suppressing oncogenic signaling and the growth of uveal melanoma cells. In a mouse model, the addition of an IMPDH inhibitor to the treatment regimen significantly enhanced the ability of a MAPK cascade inhibitor to improve the survival of tumor-bearing animals. Targeting of the RAC/PAK axis provides a new strategy to increase the efficacy of targeted therapies in uveal melanoma. While RAC and PAK inhibitors are still undergoing pre-clinical development, clinically available inhibitors of IMPDH offer an opportunity to test the efficacy of this novel synergistic combination in the context of human disease. Full article

(This article belongs to the Special Issue Advances in Melanoma Targeted Therapy)

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31 pages, 5259 KB

Open AccessArticle

Innovative Therapy with Stem Cell-Derived Extracellular Vesicles on Cardiac Hypertrophy in an Animal Model of Atherosclerosis; Elucidation of the Molecular Mechanisms Involved in the Repair Process

by Alexandra Vîlcu, Ioana Karla Comarița, Alina Constantin, Nicoleta Alexandru, Miruna Nemecz, Florentina Safciuc, Florina Bojin, Virgil Păunescu and Adriana Georgescu

Biomolecules 2025, 15(10), 1424; https://doi.org/10.3390/biom15101424 - 7 Oct 2025

Abstract

(1) Background: The present study investigated the effects of extracellular vesicles (EVs), derived from adipose tissue stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMMSCs), on atherosclerosis-associated cardiac hypertrophy. (2) Methodology: The experiments were performed on hamsters divided into the following groups: [...] Read more.

(1) Background: The present study investigated the effects of extracellular vesicles (EVs), derived from adipose tissue stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMMSCs), on atherosclerosis-associated cardiac hypertrophy. (2) Methodology: The experiments were performed on hamsters divided into the following groups: control (C) fed with a standard diet; hypertensive–hyperlipidemic (HH) generated by combining a diet enriched with 3% cholesterol, 15% butter, and by gavage with 8% NaCl on a daily basis; HH groups injected with EVs (ADSCs) or EVs (BMMSCs), either transfected with Smad2/3 siRNAs or not (HH-EVs (ADSCs), HH-EVs (BMMSCs), HH-EVs (ADSCs) + Smad2/3siRNA, HH-EVs (BMMSCs) + Smad2/3siRNA); and HH group injected with Smad2/3 siRNAs (HH-Smad2/3siRNA). (3) Results: In comparison with the HH group, the findings demonstrated that treatment using EVs (ADSCs or BMMSCs), either with or without Smad2/3 siRNAs, resulted in several significant improvements in the following aspects: the plasma levels of cholesterol, LDL, triglycerides, TGF-β1, and Ang II were decreased; the left ventricular structure and function were recovered; inflammatory markers, ROS, COL1A, α-SMA, Cx43, MIF, ANF, and M1/M2 macrophages, were reduced; the level of key protein NF-κB p50 was diminished. (4) Conclusions: These findings underscore the therapeutic potential of mesenchymal stem cell-derived EVs in atherosclerosis-associated cardiac hypertrophy. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases: 2nd Edition)

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24 pages, 8968 KB

Open AccessArticle

Oncogenic Role of SAMD4B in Breast Cancer Progression by Activating Wnt/β-Catenin Pathway

by Jia-Hui Li, Xin-Ya Wang, Huan-Xi Song, Xiao-Fei Nie and Li-Na Zhang

Biomolecules 2025, 15(10), 1423; https://doi.org/10.3390/biom15101423 - 7 Oct 2025

Abstract

The Sterile alpha motif domain-containing protein 4 (SAMD4) family consists of two evolutionarily conserved and highly homologous RNA-binding proteins, SAMD4A and SAMD4B. Previous studies have established SAMD4A as a tumor suppressor that is downregulated in breast cancer, while the function of SAMD4B in [...] Read more.

The Sterile alpha motif domain-containing protein 4 (SAMD4) family consists of two evolutionarily conserved and highly homologous RNA-binding proteins, SAMD4A and SAMD4B. Previous studies have established SAMD4A as a tumor suppressor that is downregulated in breast cancer, while the function of SAMD4B in tumorigenesis remains poorly defined. In this study, we observed that SAMD4B expression is upregulated in breast cancer. Functional assays demonstrated that SAMD4B facilitated breast cancer cell proliferation, migration, and invasion by inducing epithelial–mesenchymal transition (EMT). Furthermore, SAMD4B accelerated G1-to-S phase cell cycle progression by modulating p53 expression, collectively supporting an oncogenic function of SAMD4B in breast cancer. Mechanistically, we found that SAMD4B enhanced TCF/LEF transcriptional activity and upregulated the expression of β-catenin, Cyclin D1, c-Myc, and Axin2. Further investigations confirmed that SAMD4B activated the Wnt/β-catenin pathway by stabilizing β-catenin mRNA and increasing β-catenin protein expression level. Importantly, treatment with XAV-939, a specific Wnt/β-catenin pathway inhibitor, abrogated the pro-oncogenic effects of SAMD4B overexpression, including Wnt/β-catenin pathway activation, enhanced proliferation, and increased metastatic capacity. These results confirm that SAMD4B promotes the malignant phenotypes of breast cancer cells in a manner dependent on the Wnt/β-catenin pathway. In summary, our findings clarify that SAMD4B exerts an oncogenic role in breast cancer progression by activating the Wnt/β-catenin pathway. These data identify SAMD4B as a potential therapeutic target in breast cancer, although further in vivo investigations are required to validate its clinical relevance. Full article

(This article belongs to the Section Molecular Biomarkers)

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16 pages, 5174 KB

Open AccessArticle

Glucocorticoids Induce an Opposite Metabolic Switch in Human Monocytes Contingent upon Their Polarization

by Elisa Peruzzi, Sophia Heidenreich, Lucas Klaus, Angela Boshnakovska, Agathe Amouret, Tobias Legler, Sybille D. Reichardt, Fred Lühder and Holger M. Reichardt

Biomolecules 2025, 15(10), 1422; https://doi.org/10.3390/biom15101422 - 7 Oct 2025

Abstract

Background: Monocytes can commit to different phenotypes associated with specific features required in inflammation and homeostasis. Classical and alternative activation are two extremes of monocyte polarization and are both influenced by glucocorticoids (GCs). Methods: Human monocytes were sorted from the blood of healthy [...] Read more.

Background: Monocytes can commit to different phenotypes associated with specific features required in inflammation and homeostasis. Classical and alternative activation are two extremes of monocyte polarization and are both influenced by glucocorticoids (GCs). Methods: Human monocytes were sorted from the blood of healthy individuals and activated with LPS or IL-4 and IL-13, either in the absence or presence of dexamethasone (Dex). Metabolic adjustments were analyzed using Seahorse stress tests, SCENITH, and RT-qPCR. Results: LPS enhanced glycolysis and also, to a lesser extent, oxidative phosphorylation (OXPHOS), whereas addition of Dex induced a metabolic switch in favor of the latter. In contrast, activation of monocytes with IL-4 and IL-13 exclusively stimulated OXPHOS, which was suppressed by concomitant Dex treatment. The glycolytic function of monocytes matched alterations in gene expression of glucose transporters and metabolic enzymes, which were upregulated by LPS and inhibited by Dex via interference with the mTORC1 pathway but remained unaltered in response to IL-4 and IL-13. Although the dependency of classically and alternatively activated monocytes on OXPHOS and glucose usage markedly differed, modulation by GCs was limited to the latter polarization state. Conclusions: Our findings unravel a highly selective regulation of human monocyte energy metabolism by different activating stimuli as well as by GCs. Full article

(This article belongs to the Special Issue Transcription Factors in Hematopoiesis and Immunity: From Development to Therapeutic Targeting)

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19 pages, 1062 KB

Open AccessReview

Calcium Signaling and Cardiac Adaptation to Stress: Focus on Pregnancy and Diabetes

by Sathya Velmurugan and Sanda Despa

Biomolecules 2025, 15(10), 1421; https://doi.org/10.3390/biom15101421 - 7 Oct 2025

Abstract

Calcium (Ca²⁺) signaling regulates a wide range of processes in the heart, from contractility and excitability to energy supply and cell growth. Consequently, Ca²⁺ signaling plays a critical role in cardiac adaptation to both physiological and pathophysiological stress. This review [...] Read more.

Calcium (Ca²⁺) signaling regulates a wide range of processes in the heart, from contractility and excitability to energy supply and cell growth. Consequently, Ca²⁺ signaling plays a critical role in cardiac adaptation to both physiological and pathophysiological stress. This review examines the role of Ca²⁺ signaling in the heart’s physiological adaptation to pregnancy and its pathological maladaptation in diabetes. We focus on Ca²⁺-dependent mechanisms involved in hypertrophy, energy imbalance, and electrical remodeling in these two conditions, highlighting shared signaling pathways, functional outcomes, and key knowledge gaps. A deeper understanding of these mechanisms could reveal novel therapeutic targets to improve cardiac health in pregnancy and diabetes. Full article

(This article belongs to the Special Issue The Role of Calcium Signaling in Cardiac and Skeletal Muscle)

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25 pages, 988 KB

Open AccessReview

The NO Pathway as a Target in Patients with Stable and Advanced Heart Failure: An Additional Arrow in Our Quiver!

by Saverio D’Elia, Carmine Gentile, Achille Solimene, Rosa Franzese, Ettore Luisi, Antonio Caiazzo, Luigi Marotta, Simona Covino, Francesco Natale, Francesco S. Loffredo, Paolo Golino and Giovanni Cimmino

Biomolecules 2025, 15(10), 1420; https://doi.org/10.3390/biom15101420 - 6 Oct 2025

Abstract

The nitric oxide (NO) pathway is a fundamental regulator of vascular tone, myocardial function, and inflammation. In heart failure (HF), especially in advanced stages, dysregulation of NO–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling contributes to endothelial dysfunction, increased vascular resistance, myocardial fibrosis, [...] Read more.

The nitric oxide (NO) pathway is a fundamental regulator of vascular tone, myocardial function, and inflammation. In heart failure (HF), especially in advanced stages, dysregulation of NO–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling contributes to endothelial dysfunction, increased vascular resistance, myocardial fibrosis, and impaired cardiac performance. Chronic inflammation further reduces NO bioavailability, exacerbating HF progression This review synthesizes current knowledge on the role of the NO pathway in HF pathophysiology, with a focus on stable and advanced HF. Special attention is given to patient subgroups with comorbidities such as chronic kidney disease, where modulation of NO signaling may be particularly beneficial. We also evaluate therapeutic strategies targeting NO bioavailability and sGC stimulation. Evidence shows that impaired NO signaling promotes systemic and pulmonary vasoconstriction, elevates ventricular afterload, and worsens cardiac remodeling. Pharmacological agents that restore NO levels or activate downstream effectors such as sGC improve vasodilation, reduce fibrosis, and enhance myocardial relaxation. These effects are especially relevant in advanced HF patients and those with renal impairment, who often exhibit limited responses to conventional therapies. The NO pathway represents a promising therapeutic target in both stable and advanced HF. Modulating this pathway could improve outcomes, particularly in complex populations with multiple comorbidities, highlighting the need for further clinical research and tailored treatments. Full article

(This article belongs to the Special Issue Chronic Heart Failure: From Molecular Mechanisms to Therapies Strategies)

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16 pages, 281 KB

Open AccessArticle

Effects of HDL Structure and Function in Peripheral Artery Disease

by Yu-Huang Liao, Semon Wu, Yu-Lin Ko and Ming-Sheng Teng

Biomolecules 2025, 15(10), 1419; https://doi.org/10.3390/biom15101419 - 6 Oct 2025

Abstract

The structure and function of high-density lipoprotein (HDL), rather than its concentration, are more important factors in determining HDL activity. HDL particles (HDL-P) are heterogeneous in their composition, size, and antioxidative function. We investigated the levels of HDL subfractions and oxidized high-density lipoprotein [...] Read more.

The structure and function of high-density lipoprotein (HDL), rather than its concentration, are more important factors in determining HDL activity. HDL particles (HDL-P) are heterogeneous in their composition, size, and antioxidative function. We investigated the levels of HDL subfractions and oxidized high-density lipoprotein (Ox-HDL) and validated their correlation with genetic determinants underlying peripheral artery disease (PAD). We recruited a PAD population stratified by claudication severity (group I) and critical limb ischemia (group II) according to the Rutherford classification. We found that the level of Ox-HDL was significantly increased with Rutherford classification (group II; p = 0.001). Conversely, the levels of high-density lipoprotein cholesterol (HDL-C), HDL-P, and small high-density lipoprotein particles (S-HDL-P) were significantly reduced in group II. Three single nucleotide polymorphisms (SNPs) were differentially associated with HDL particles and Ox-HDL. Briefly, rs117685211 and rs7934858 showed opposing effects, with rs117685211 and rs148877054 being associated with low levels of HDL subfractions; rs148877054 was significantly associated with M and S-HDL-P. Our study indicated the significance of HDL subfractions and Ox-HDL in the pathogenesis of PAD. Full article

(This article belongs to the Section Lipids)

22 pages, 3812 KB

Open AccessReview

Micro- and Nanoplastics Act as Metal Carriers with the Potential to Alter Human Gene Expression Patterns—The Inferences from Bioinformatic Online Tools

by Maja Grabacka and Małgorzata Pierzchalska

Biomolecules 2025, 15(10), 1418; https://doi.org/10.3390/biom15101418 - 6 Oct 2025

Abstract

Micro- and nanoplastic particles (MNPLs) present in the environment have recently become a potential health hazard factor due to the ability to penetrate living organisms, their organs, and cells. MNPLs interact with and absorb chemicals and elements, including metals, such as iron, copper, [...] Read more.

Micro- and nanoplastic particles (MNPLs) present in the environment have recently become a potential health hazard factor due to the ability to penetrate living organisms, their organs, and cells. MNPLs interact with and absorb chemicals and elements, including metals, such as iron, copper, and zinc, and transport them into the cells. The cells subsequently respond with the altered gene expression profiles. In this study, we applied freely accessible online bioinformatic tools to draw out the sets of genes modulated by the metal ions and MNPLs. We focused on the gene interactome as revealed by The Comparative Toxicogenomics Database (CTD). To achieve a deeper insight into the biological processes that are potentially modulated, the retrieved CTD lists of genes, whose expression was influenced by MNPLs and metals, were subsequently analyzed using online tools: Metascape and String database. The genes from the revealed networks were arranged into functional clusters, annotated mainly as inflammation and immune system activity, regulation of apoptosis, oxidative stress response, Wingless-related Integration Site (WNT) signaling and ferroptosis. The complexity of the interactions between the gene sets altered by MNPLs and metal ions illustrates their pleiotropic effects on living systems. Full article

(This article belongs to the Special Issue Molecular Advances in Drug Resistance and Novel Therapies for Cancer)

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17 pages, 2816 KB

Open AccessSystematic Review

The Anti-Inflammatory Effects of Resistance Training in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

by Nikolaos P. E. Kadoglou, Chrysostomos Georgiou, Nikolaos Balaskas, Chrystalla Panayiotou, Michail Vardas, Andreas Mitsis and Constantine N. Antonopoulos

Biomolecules 2025, 15(10), 1417; https://doi.org/10.3390/biom15101417 - 5 Oct 2025

Abstract

Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular risk characterized by low-grade inflammation. The aim of this systematic review and meta-analysis was to assess the effects of resistance exercise training (RET) predominantly on cytokines, along with changes in glucose profile and [...] Read more.

Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular risk characterized by low-grade inflammation. The aim of this systematic review and meta-analysis was to assess the effects of resistance exercise training (RET) predominantly on cytokines, along with changes in glucose profile and body composition in T2DM patients. The present systematic review and meta-analysis was conducted utilizing PubMed, Web of Science, Embase, and the Cochrane Library databases from their inception up to July 2024 (PROSPERO; registration number CRD420251149352). We screened only for randomized controlled trials investigating the effects of systematic, supervised RET on C-reactive protein (CRP) and adipokines: adiponectin, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), along with changes in anthropometric indices and glycemic control in adult T2DM patients. Pooled post-exercise weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated for all outcomes of interest between exercise-treated patients and controls. Sixteen studies involving a total of 668 T2DM patients were retrieved from the databases for meta-analysis. We used the GRADE framework for assessing the certainty of evidence. Cochran Q-score (I²) was used to estimate heterogeneity among studies (level of significance p < 0.10) and risk of bias analysis was also performed. The cumulative results showed that post-RET inflammatory markers were lower in exercise-treated patients compared to controls regarding CRP (mg/L) (WMD: −0.63; 95%CIs: −1.05, −0.20; p < 0.001); adiponectin (μg/mL) (WMD: −0.94; 95%CIs: −1.49, −0.38; p < 0.001). The results from adiponectin are quite conflicting since they derived from only three studies, where one of them had the greater impact. In parallel, we noticed significant amelioration of fasting glucose and HbA1c (p < 0.001), while body weight remained unaltered. Our meta-analysis demonstrated non-significantly lower levels of IL-6 and TNF-α in RET vs. control group. RET can merely reduce the inflammatory burden in T2DM patients by ameliorating the circulating levels of CRP and adiponectin, while in the rest of the biomarkers, non-significant results were obtained. Hence, the overall clinical impact of those anti-inflammatory effects of RET needs to be determined. Full article

(This article belongs to the Special Issue Inflammation—The Surprising Bridge between Diseases)

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15 pages, 1480 KB

Open AccessArticle

Curcumin Alleviates Doxorubicin-Induced Cardiotoxicity by Modulating Apelin Expression

by Baris Akca, Olcay Murat Disli, Nevzat Erdil, Yilmaz Cigremis, Hasan Ozen, Merve Durhan, Selahattin Tunc, Onural Ozhan, Zeynep Ulutas and Feray Akgul Erdil

Biomolecules 2025, 15(10), 1416; https://doi.org/10.3390/biom15101416 - 5 Oct 2025

Abstract

Background: Doxorubicin (Dox)-induced cardiotoxicity is the most important side effect of the drug and significantly limits its use in susceptible patients. Therefore, preventive measures are required to alleviate the Dox-induced cardiac failure. In this study, curcumin, a strong antioxidant agent, was investigated for [...] Read more.

Background: Doxorubicin (Dox)-induced cardiotoxicity is the most important side effect of the drug and significantly limits its use in susceptible patients. Therefore, preventive measures are required to alleviate the Dox-induced cardiac failure. In this study, curcumin, a strong antioxidant agent, was investigated for its potential protective effect on dox-induced cardiotoxicity with its effect on Apelin expression as a mediator of cardiac function. Methods: Wistar albino rats were equally divided into four groups as Control, DOX, CUR, and CUR+DOX. Dox was administered a single dose of 20 mg/kg bw intraperitoneally while 100 mg/kg bw curcumin was given orally for 14 days before the Dox use. Results: DOX group showed a prolonged QT interval on an electrocardiogram and elevated cardiac troponin levels. In biochemical analyses, decreased Superoxide Dismutase activity and increased Malondialdehyde level and Catalase activity were detected in DOX group. Gene expression of Apelin decreased significantly while NF-κB increased in DOX group. Degenerative changes in histopathology, and increased iNOS and nitrotyrosine immunoreactivity were detected in DOX group. However, no significant changes were observed at reduced Glutathione, TNF-, and IL-1β levels. Curcumin use in Dox-given rats altered most of the disturbed parameters investigated in this study, indicating an alleviating effect on Dox-induced cardiotoxicity. Serum and heart Apelin levels and mRNA expression in heart tissue were detected to significantly increase in CUR+DOX group as compared to DOX group. Furthermore, NF-κB mRNA expression was significantly decreased in heart tissue of CUR+DOX group compared with the DOX group. Conclusions: The results suggest that Apelin acts as an important mediator in Dox cardiotoxicity and may be used as a target for treatment of certain cardiomyopathies. By regulating Apelin expression, curcumin may serve as a potential adjunct in cardioprotective approaches. Full article

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

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17 pages, 1533 KB

Open AccessArticle

UHPLC-QTOF-ESI-MS/MS, SNAP-MS Identification, In Silico Prediction of Pharmacokinetic Properties of Constituents from the Stem Bark of Holarrhena floribunda (G. Don) T. Durand and Schinz (Apocynaceae)

by Franck Landry Djila Possi, Mc Jesus Kinyok, Joseph Eric Mbasso Tameko, Bel Youssouf G. Mountessou, Johanne Kevine Jumeta Dongmo, Mariscal Brice Tchatat Tali, Appolinaire Kene Dongmo, Fabrice Fekam Boyom, Jean Jules Kezetas Bankeu, Norbert Sewald, Jean Rodolphe Chouna and Bruno Ndjakou Lenta

Biomolecules 2025, 15(10), 1415; https://doi.org/10.3390/biom15101415 - 4 Oct 2025

Abstract

The present work reports the bioguided isolation of constituents from the ethanol extract of Holarrhena floribunda stem bark, their identification by UHPLC-ESI-QTOF-MS/MS identification, and the in silico prediction of the pharmacokinetic and toxicity parameters. The crude extract, along with its n-hexane and [...] Read more.

The present work reports the bioguided isolation of constituents from the ethanol extract of Holarrhena floribunda stem bark, their identification by UHPLC-ESI-QTOF-MS/MS identification, and the in silico prediction of the pharmacokinetic and toxicity parameters. The crude extract, along with its n-hexane and alkaloid-rich fractions, displayed moderate to good antiplasmodial activity in vitro against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) strains of Plasmodium falciparum, with IC₅₀ values ranging from 6.54 to 43.54 µg/mL. Seventeen steroidal alkaloids (1–17) were identified in the most active fraction using UHPLC-ESI-QTOF-MS/MS, based on their fragmentation patterns and analysis with the Structural Similarity Network Annotation Platform for Mass Spectrometry (SNAP-MS). Furthermore, bioguided isolation of the ethanol extract yielded twenty-one compounds (3, 5, 10, 14–16, 18–31), whose structures were elucidated by spectroscopic methods. Among them, compounds 5, 14, and 27 showed the highest potency against the two strains of P. falciparum, with IC₅₀ values between 25.97 and 55.78 µM. In addition, the in silico prediction of pharmacokinetic parameters and drug-likeness using the SwissADME web tool indicated that most of the evaluated compounds (1, 3–5, and 14–16) complied with Lipinski’s rule of five. Full article

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

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19 pages, 2920 KB

Open AccessReview

Red-Wine Gene Networks Linked to Exceptional Longevity in Humans

by Patricia Lacayo, Alexandria Martignoni, Kenneth Park, Christianne Castro and Shin Murakami

Biomolecules 2025, 15(10), 1414; https://doi.org/10.3390/biom15101414 - 4 Oct 2025

Abstract

Despite the health concerns regarding alcohol and its link to cancer, moderate consumption of red wine has been associated with healthy aging and longevity, defined as up to one drink per day for women and two drinks per day for men (approximately 142 [...] Read more.

Despite the health concerns regarding alcohol and its link to cancer, moderate consumption of red wine has been associated with healthy aging and longevity, defined as up to one drink per day for women and two drinks per day for men (approximately 142 mL or 5 oz per drink). Previous research has revealed the health benefits of red wine, particularly in relation to cardiovascular disease. However, the influence of genetic factors on these benefits remains to be elucidated. In this study, we explored genes linked to red wine and created a curated gene set that intersects with those related to centenarians, which are markers of exceptional longevity. By analyzing literature from over 190 databases, we identified and validated a curated list of 43 genes associated with red wine and centenarians. We conducted gene set enrichment analysis as well as enrichment analysis of diseases and their tissue distributions. The results suggest that these genes play a crucial role in stress response and apoptosis, which are essential for cell survival and renewal. Additionally, these genes were enriched in pathways associated with smooth muscle cell proliferation, neuroinflammation, nucleotide excision repair, and lipoprotein metabolism (false discovery rate, FDR < 3 × 10⁻⁷). Gene set enrichment analysis indicated significant tissue distribution in the gastrointestinal, cardiovascular, and respiratory systems. Furthermore, the disease–gene enrichment analysis pointed to associations with diseases related to tissues and organs, including cardiovascular disease (heart disease and stroke), type 2 diabetes, gastrointestinal diseases and metabolic diseases, immune diseases, and cancer (FDR < 9.37 × 10⁻⁶); notably, cardiovascular diseases, diabetes, and cancer are leading causes of death, suggesting that these genes may be protective against those diseases. Our review of the literature indicates that individuals who do not currently drink alcohol should not be encouraged to start. However, we propose that moderate consumption of red wine, especially for middle-aged to older adults after 40 years old, can provide significant health benefits due to its components and the positive effects of hormesis. Although further research is necessary to uncover additional genes, this study provides the first genetic overview of the health benefits of red wine, emphasizing its potential in supporting healthy aging and longevity. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Life-Extending Biomolecules and Interventions with Medical and Technological Implications)

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15 pages, 2416 KB

Open AccessArticle

Engineering a High-Fidelity MAD7 Variant with Enhanced Specificity for Precision Genome Editing via CcdB-Based Bacterial Screening

by Haonan Zhang, Ying Yang, Tianxiang Yang, Peiyao Cao, Cheng Yu, Liya Liang, Rongming Liu and Zhiying Chen

Biomolecules 2025, 15(10), 1413; https://doi.org/10.3390/biom15101413 - 4 Oct 2025

Abstract

CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated protein) nucleases enable precise genome editing, but off-target cleavage remains a critical challenge. Here, we report the development of MAD7_HF, a high-fidelity variant of the MAD7 nuclease engineered through a bacterial screening system leveraging the [...] Read more.

CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated protein) nucleases enable precise genome editing, but off-target cleavage remains a critical challenge. Here, we report the development of MAD7_HF, a high-fidelity variant of the MAD7 nuclease engineered through a bacterial screening system leveraging the DNA gyrase-targeting toxic gene ccdB. This system couples survival to efficient on-target cleavage and minimal off-target activity, mimicking the transient action required for high-precision editing. Through iterative selection and sequencing validation, we identified MAD7_HF, harboring three substitutions (R187C, S350T, K1019N) that enhanced discrimination between on- and off-target sites. In Escherichia coli assays, MAD7_HF exhibited a >20-fold reduction in off-target cleavage across multiple mismatch contexts while maintaining on-target efficiency comparable to wild-type MAD7. Structural modeling revealed that these mutations stabilize the guide RNA-DNA hybrid at on-target sites and weaken interactions with mismatched sequences. This work establishes a high-throughput bacterial screening strategy that allows the identification of Cas12a variants with improved specificity at a given target site, providing a useful framework for future efforts to develop precision genome-editing tools. Full article

(This article belongs to the Special Issue Advances in Microbial CRISPR Editing)

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13 pages, 2439 KB

Open AccessArticle

2-Hydroxymelatonin Induces Husk-Imposed Vivipary in the Transgenic Rice Overexpressing Melatonin 2-Hydroxylase

by Kyungjin Lee and Kyoungwhan Back

Biomolecules 2025, 15(10), 1412; https://doi.org/10.3390/biom15101412 - 4 Oct 2025

Abstract

Pre-harvest sprouting (PHS) reduces the quality and quantity of crop seeds. PHS can be imposed through the embryo or husk pathway of cereal crops. Most reported PHS seeds are imposed via the embryo pathway. Here, we generated transgenic rice plants overexpressing rice melatonin [...] Read more.

Pre-harvest sprouting (PHS) reduces the quality and quantity of crop seeds. PHS can be imposed through the embryo or husk pathway of cereal crops. Most reported PHS seeds are imposed via the embryo pathway. Here, we generated transgenic rice plants overexpressing rice melatonin 2-hydroxylase (OsM2H), which catalyzes the hydroxylation of melatonin to 2-hydroxymelatonin (2-OHM). OsM2H overexpression (M2H-OE) showed PHS under paddy conditions. Germination assays revealed that intact seeds harvested at 26 and 36 days after heading (DAH) showed PHS, whereas dehusked seeds did not, indicating husk-imposed PHS. Overproduction of 2-OHM was observed in M2H-OE seeds compared to wild-type control. In addition, M2H-OE lines produced more hydrogen peroxide than the wild-type. 2-OHM-induced reactive oxygen species resulted in the induction of OsGA3ox2, a gibberellin (GA) biosynthesis gene, and repression of OsGA2ox3, a GA degradation gene, in caryopses at 2 DAH, but in the induction of the ABA degradation gene OsABA8ox3 in intact seeds at 26 DAH. In addition, M2H-OE seedlings were longer and showed increased levels of hydrogen peroxide and OsGA3ox2 expression versus the wild-type. This is the first report showing that 2-OHM can induce PHS via the husk pathway in rice seeds through the induction of GA biosynthetic and ABA degradation genes. Full article

(This article belongs to the Special Issue New Insights into Hormonal Control of Plant Growth and Development)

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