Biomolecules

18 pages, 3514 KiB

Open AccessArticle

Baicalin Relieves Glaesserella parasuis-Triggered Immunosuppression Through Polarization via MIF/CD74 Signaling Pathway in Piglets

by Shulin Fu, Qiaoli Dong, Yunjian Fu, Ronghui Luo, Jingyang Li, Yamin Sun, Siyu Liu, Yinsheng Qiu, Ling Guo and Jin Hu

Biomolecules 2025, 15(5), 640; https://doi.org/10.3390/biom15050640 (registering DOI) - 29 Apr 2025

Abstract

Glaesserella parasuis (G. parasuis) infection is responsible for Glässer’s disease in pigs. G. parasuis could trigger piglet immunosuppression, but the mechanism of inducing immunosuppression by G. parasuis remains unknown. Macrophage migration inhibitory factor (MIF)/CD74 axis has been shown to participate in [...] Read more.

Glaesserella parasuis (G. parasuis) infection is responsible for Glässer’s disease in pigs. G. parasuis could trigger piglet immunosuppression, but the mechanism of inducing immunosuppression by G. parasuis remains unknown. Macrophage migration inhibitory factor (MIF)/CD74 axis has been shown to participate in inflammation response and immunosuppression, but the function of MIF/CD74 during immunosuppression elicited by G. parasuis has not been fully explored. This experiment explored the efficacy of baicalin on immunosuppression elicited by G. parasuis alleviation through regulating polarization via the MIF/CD74 signaling pathway. Our data indicated that baicalin reduced IL-1β, IL-6, IL-8, IL-18, TNF-α, and COX-2 expression, and regulated MIF/CD74 axis expression in the spleen. Immunohistochemistry analysis showed that baicalin enhanced CD74 protein levels in the spleen of piglets induced by G. parasuis. Baicalin regulated the PI3K/Akt/mTOR signaling pathway and RAF/MEK/ERK signaling activation, modified the expression of the autophagy-related proteins Beclin-1, P62, and LC3B, promoted M2 polarization to M1 polarization, and enhanced CD3, CD4, CD8, and TIM3 levels in the spleen of piglets elicited by G. parasuis. Our study reveals the important functions of the MIF/CD74 axis in G. parasuis-induced immunosuppression and may offer a new therapeutic method to control G. parasuis infection. Full article

(This article belongs to the Topic Recent Advances in Veterinary Pharmacology and Toxicology)

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23 pages, 714 KiB

Open AccessReview

Bispecific Antibodies, Nanobodies and Extracellular Vesicles: Present and Future to Cancer Target Therapy

by Asier Lizama-Muñoz and Julio Plaza-Diaz

Biomolecules 2025, 15(5), 639; https://doi.org/10.3390/biom15050639 (registering DOI) - 29 Apr 2025

Abstract

Cancer remains one of the leading causes of mortality worldwide, with a growing need for precise and effective treatments. Traditional therapies such as chemotherapy and radiotherapy have limitations, including off-target effects and drug resistance. In recent years, targeted therapies have emerged as promising [...] Read more.

Cancer remains one of the leading causes of mortality worldwide, with a growing need for precise and effective treatments. Traditional therapies such as chemotherapy and radiotherapy have limitations, including off-target effects and drug resistance. In recent years, targeted therapies have emerged as promising alternatives, aiming to improve treatment specificity and reduce systemic toxicity. Among the most innovative approaches, bispecific antibodies, nanobodies, and extracellular vesicles offer distinct and complementary mechanisms for cancer therapy. Bispecific antibodies enhance immune responses and enable dual-targeting of cancer cells, nanobodies provide superior tumor penetration due to their small size, and extracellular vesicles present a novel platform for drug and RNA delivery. This work aims to review and analyze these three approaches, assessing their current applications, advantages, challenges, and future perspectives. Full article

(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms in Immuno-Oncology and Onco-Hematology)

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25 pages, 1105 KiB

Open AccessReview

From Obesity to Mitochondrial Dysfunction in Peripheral Tissues and in the Central Nervous System

by Francesca Marino, Lidia Petrella, Fabiano Cimmino, Amelia Pizzella, Antonietta Monda, Salvatore Allocca, Roberta Rotondo, Margherita D’Angelo, Nadia Musco, Piera Iommelli, Angela Catapano, Carmela Bagnato, Barbara Paolini and Gina Cavaliere

Biomolecules 2025, 15(5), 638; https://doi.org/10.3390/biom15050638 (registering DOI) - 29 Apr 2025

Abstract

Obesity is a condition of chronic low-grade inflammation affecting peripheral organs of the body, as well as the central nervous system. The adipose tissue dysfunction occurring under conditions of obesity is a key factor in the onset and progression of a variety of [...] Read more.

Obesity is a condition of chronic low-grade inflammation affecting peripheral organs of the body, as well as the central nervous system. The adipose tissue dysfunction occurring under conditions of obesity is a key factor in the onset and progression of a variety of diseases, including neurodegenerative disorders. Mitochondria, key organelles in the production of cellular energy, play an important role in this tissue dysfunction. Numerous studies highlight the close link between obesity and adipocyte mitochondrial dysfunction, resulting in excessive ROS production and adipose tissue inflammation. This inflammation is transmitted systemically, leading to metabolic disorders that also impact the central nervous system, where pro-inflammatory cytokines impair mitochondrial and cellular functions in different areas of the brain, leading to neurodegenerative diseases. To date, several bioactive compounds are able to prevent and/or slow down neurogenerative processes by acting on mitochondrial functions. Among these, some molecules present in the Mediterranean diet, such as polyphenols, carotenoids, and omega-3 PUFAs, exert a protective action due to their antioxidant and anti-inflammatory ability. The aim of this review is to provide an overview of the involvement of adipose tissue dysfunction in the development of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, emphasizing the central role played by mitochondria, the main actors in the cross-talk between adipose tissue and the central nervous system. Full article

(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders: 3rd Edition)

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24 pages, 16643 KiB

Open AccessArticle

Ngn2-Induced Differentiation of the NG108-15 Cell Line Enhances Motor Neuronal Differentiation and Neuromuscular Junction Formation

by Madeline Meli, Kristy Swiderski, Jinchao Gu, Ben Rollo, Ben Bartlett, Marissa K. Caldow, Gordon S. Lynch, Patrick Kwan, Huseyin Sumer and Brett Cromer

Biomolecules 2025, 15(5), 637; https://doi.org/10.3390/biom15050637 (registering DOI) - 29 Apr 2025

Abstract

The neuronal progenitor NG108-15 neuroblastoma x glioma cell line proliferates indefinitely in vitro and is capable of directed differentiation into cholinergic neurons. The cell line is a robust model for investigating neuronal differentiation and function in vitro. The lineage-specific transcription factor-mediated differentiation of [...] Read more.

The neuronal progenitor NG108-15 neuroblastoma x glioma cell line proliferates indefinitely in vitro and is capable of directed differentiation into cholinergic neurons. The cell line is a robust model for investigating neuronal differentiation and function in vitro. The lineage-specific transcription factor-mediated differentiation of pluripotent stem cell lines (PSCs) leads to more rapid, efficient, and functional neurons. In this study, we tested the hypothesis that transcription factors could also drive the fate of an immortalised cell line. We first established a stable NG108-15 cell line, by piggyBac (pBac) transposition, that conditionally expresses neurogenin-2 (Ngn2), a common transcription factor for specifying neuronal fate. Following doxycycline-induction of Ngn2, we observed more rapid and efficient differentiation, and improved neurite outgrowth and viability compared with the WT cell line. Moreover, when co-cultured with C2C12 mouse myotubes, the modified NG108-15 cells resulted in significantly larger acetylcholine receptor (AChR) aggregates, suggesting enhanced neuromuscular junction (NMJ) formation. These findings describe a novel methodology for differentiating NG108-15 cells more efficiently, to enhance the usefulness of the cell line as a motor neuron model. Full article

(This article belongs to the Section Biological Factors)

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23 pages, 4085 KiB

Open AccessArticle

Microbial Composition, Disease Trajectory and Genetic Background in a Slow Onset Model of Frontotemporal Lobar Degeneration

by Nathalie Daude, Ivana Machado, Luis Arce, Jing Yang and David Westaway

Biomolecules 2025, 15(5), 636; https://doi.org/10.3390/biom15050636 (registering DOI) - 29 Apr 2025

Abstract

Slow-onset neurodegenerative disease in a low-expresser 2N4R P301L transgenic (Tg) mouse model is marked by neuroinflammation and by differing patterns of CNS deposition and accumulation of tau conformers, with such heterogeneities present even within inbred backgrounds. Gut microbial genotypes were notably divergent within [...] Read more.

Slow-onset neurodegenerative disease in a low-expresser 2N4R P301L transgenic (Tg) mouse model is marked by neuroinflammation and by differing patterns of CNS deposition and accumulation of tau conformers, with such heterogeneities present even within inbred backgrounds. Gut microbial genotypes were notably divergent within C57BL6/Tac or 129SvEv/Tac congenic (Cg) sublines of TgTau^P301L mice, and these sublines differed when challenged with antibiotic treatment and fecal microbial transplantation. Whereas aged, transplanted Cg 129SvEv/Tac TgTau^P301L mice had neuroanatomical deposition of tau resembling controls, transplanted Cg C57BL6/Tac TgTau^P301L mice had different proportions of rostral versus caudal tau accumulation (p = 0.0001). These data indicate the potential for environmental influences on tau neuropathology in this model. Furthermore, Cg C57BL6/Tac TgTau^P301L cohorts differed from 129SvEv/Tac counterparts by showing 28% versus 9% net intercurrent loss (p = 0.0027). While the origin of this phenomenon is not established, it offers a parallel to differing patterns of frailty observed in C57BL6 versus 129 SvEv Tg mice expressing the 695 amino acid isoform of human amyloid precursor protein. We infer that generalized responses to protein aggregation might account for similar reductions in viability even when expressing different human proteins in the same inbred strain background. Full article

(This article belongs to the Special Issue Molecular and Genetic Basis of Neurodegenerative Diseases)

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13 pages, 2563 KiB

Open AccessArticle

Structural and Functional Analysis of the Human IQSEC2 S1474Qfs*133 Mutation

by Yonat Israel, Aaron Lowenkamp, Michael Shokhen, Shai Netser, Shlomo Wagner, Joseph Zarowin, Shaun Orth, Veronika Borisov, Orit Lache, Nina S. Levy and Andrew P. Levy

Biomolecules 2025, 15(5), 635; https://doi.org/10.3390/biom15050635 (registering DOI) - 29 Apr 2025

Abstract

IQSEC2 is a guanine nucleotide exchange factor that modulates synaptic transmission, the excitatory/inhibitor balance and memory consolidation. Pathogenic mutations in the IQSEC2 gene result in epilepsy, cognitive dysfunction and autism spectrum disorder. The most common de novo IQSEC2 mutation in the IQSEC2 gene, [...] Read more.

IQSEC2 is a guanine nucleotide exchange factor that modulates synaptic transmission, the excitatory/inhibitor balance and memory consolidation. Pathogenic mutations in the IQSEC2 gene result in epilepsy, cognitive dysfunction and autism spectrum disorder. The most common de novo IQSEC2 mutation in the IQSEC2 gene, associated with a particularly severe phenotype in males as compared to other IQSEC2 mutations, is due to a frameshift mutation near the C terminus, resulting in an extension of the open reading frame [IQSEC2 S1474Qfs*133]. The objective of this study was to understand the pathophysiology of this specific IQSEC2 mutation using molecular modeling protein–protein interaction assays and a conditional transgenic mouse model of the mutation. Molecular modeling studies showed that the mutation results in the generation of a new domain that may bind ATP. The mutant IQSEC2 protein failed to interact with proteins that normally interact with IQSEC2, most notably with PSD-95. Finally, mice expressing the human mutation displayed marked developmental delays and abnormal social behavior. We conclude that diseases associated with the IQSEC2 S1474Qfs*133 may be due not only to the loss of function of IQSEC2 but also to the appearance of new detrimental activity. The conditional mouse model will allow for the identification of brain regions that are critical for IQSEC2 expression and will serve as a platform for the development of personalized therapies for this disease. Full article

(This article belongs to the Special Issue Protein Structure Prediction in Drug Discovery: 2nd Edition)

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12 pages, 2016 KiB

Open AccessArticle

Ionic Strength Investigation on the Interaction Between miR-155 and a PNA-Based Probe by Atomic Force Spectroscopy

by Davide Atzei, Francesco Lavecchia di Tocco and Anna Rita Bizzarri

Biomolecules 2025, 15(5), 634; https://doi.org/10.3390/biom15050634 (registering DOI) - 28 Apr 2025

Abstract

Peptide nucleic acids (PNAs) are synthetic analogues of DNA/RNA characterized by the absence of negative phosphate groups, which confer a low sensitivity to ionic strength for hybridization with respect to the canonical counterpart. PNAs are a suitable probe for miRNAs, as well as [...] Read more.

Peptide nucleic acids (PNAs) are synthetic analogues of DNA/RNA characterized by the absence of negative phosphate groups, which confer a low sensitivity to ionic strength for hybridization with respect to the canonical counterpart. PNAs are a suitable probe for miRNAs, as well as endogenous molecules of single-strand non-coding RNA whose dysregulation is often linked to several diseases. The interaction forces between PNA and microRNA-155 (miR-155), a multifunctional microRNA overexpressed in a variety of tumors, were investigated by Atomic Force Spectroscopy (AFS) in fluid under different conditions. We found that the unbinding forces acquired at the ionic strength of 150 mM for a rather wide range of loading rates (ΔF/Δt) can be described using the Bell–Evans model. This allows us to extract information on the kinetics and thermodynamic properties of the miR-155/PNA duplex. Additionally, we probed the unbinding forces and the target recognition times between miR-155 and PNA in the 50–300 mM ionic strength range. Our results indicate that both of these parameters are practically independent from the ionic strength in the analyzed range. The results provide information that is useful for a wider use of PNA in biosensors for diagnostics and therapeutics, even in situ. Full article

(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)

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16 pages, 261 KiB

Open AccessReview

Noninvasive Urinary Biomarkers for Obesity-Related Metabolic Diseases: Diagnostic Applications and Future Directions

by Shumin Zhan, Xuelian Zhou and Junfen Fu

Biomolecules 2025, 15(5), 633; https://doi.org/10.3390/biom15050633 (registering DOI) - 28 Apr 2025

Viewed by 19

Abstract

Obesity-related metabolic diseases include conditions linked to obesity, such as type 2 diabetes, hypertension, steatotic liver disease, and polycystic ovary syndrome. These disorders are primarily caused by insulin resistance, chronic inflammation, and excessive fat accumulation. They represent significant health challenges and often remain [...] Read more.

Obesity-related metabolic diseases include conditions linked to obesity, such as type 2 diabetes, hypertension, steatotic liver disease, and polycystic ovary syndrome. These disorders are primarily caused by insulin resistance, chronic inflammation, and excessive fat accumulation. They represent significant health challenges and often remain asymptomatic during their early stages. Traditional diagnostic tools, including blood glucose, lipid levels, blood pressure, and uric acid measurements, provide valuable insights but fall short of fully capturing the complexity of metabolic dysfunction. Consequently, there is a growing need for noninvasive, easily accessible biomarkers, especially those found in urine, to enable more accurate, sensitive, and patient-friendly diagnostic methods. Urine, with its diverse range of metabolites that reflect the body’s metabolic changes, is an ideal sample for early detection. Recent advancements in urine metabolomics and proteomics have highlighted the potential of urinary biomarkers for diagnosing obesity-related metabolic diseases. Despite challenges such as the need for standardized detection techniques and clinical validation, the integration of artificial intelligence and multi-omics approaches holds significant promise for enhancing diagnostic accuracy and advancing disease management strategies. Full article

(This article belongs to the Special Issue Non-Invasive Biomarkers in Saliva or Urine: Technical and Biological Variability)

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Graphical abstract

32 pages, 3209 KiB

Open AccessReview

CD99: A Key Regulator in Immune Response and Tumor Microenvironment

by Maria Cristina Manara, Valentina Fiori, Angelo Sparti and Katia Scotlandi

Biomolecules 2025, 15(5), 632; https://doi.org/10.3390/biom15050632 (registering DOI) - 28 Apr 2025

Viewed by 13

Abstract

CD99 is a membrane protein critical for various immunological functions, including T-cell activation, protein trafficking, cell apoptosis, and leukocyte movement. It is also highly expressed in certain malignant tumors, contributing to the development, invasion, immune evasion, and adaptation of tumor cells to stress [...] Read more.

CD99 is a membrane protein critical for various immunological functions, including T-cell activation, protein trafficking, cell apoptosis, and leukocyte movement. It is also highly expressed in certain malignant tumors, contributing to the development, invasion, immune evasion, and adaptation of tumor cells to stress stimuli, including drug resistance. CD99 is crucial at the intersection of normal biological processes and pathological conditions like cancer. While research indicates that CD99 may interact homotypically, there is evidence of some heterotypic ligands that align with its roles. The development of multiple anti-CD99 antibodies has shed light on its functions, particularly regarding interactions between tumor cells that overexpress CD99 and immune cells expressing the same protein within the microenvironment. Anti-CD99 antibodies effectively eliminate tumors and attract immune cells to the tumor area. Additionally, CD99 influences the expression of specific immune checkpoint molecules, such as CD47, paving the way for potential combinations of anti-CD99 with immune checkpoint inhibitors. This review explores CD99’s role in normal physiology and cancer biology, focusing on how monoclonal antibodies affect CD99 expression and activity, thereby influencing cancer cells’ interactions with their microenvironment. It summarizes key findings about how these changes impact cancer cell behavior and the effectiveness of treatments. Full article

(This article belongs to the Section Biological Factors)

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18 pages, 2980 KiB

Open AccessArticle

The Wheat Intrinsically Disordered Protein TdRL1 Negatively Regulates the Type One Protein Phosphatase TdPP1

by Fatma Amor, Mariem Bradai, Ikram Zaidi, Vitor Amorim-Silva, Nabil Miled, Moez Hanin and Chantal Ebel

Biomolecules 2025, 15(5), 631; https://doi.org/10.3390/biom15050631 (registering DOI) - 28 Apr 2025

Viewed by 10

Abstract

Type 1 protein phosphatases (PP1s) are crucial in various plant cellular processes. Their function is controlled by regulators known as PP1-interacting proteins (PIPs), often intrinsically disordered, such as Inhibitor 2 (I2), conserved across kingdoms. The durum wheat TdRL1 acts as a positive [...] Read more.

Type 1 protein phosphatases (PP1s) are crucial in various plant cellular processes. Their function is controlled by regulators known as PP1-interacting proteins (PIPs), often intrinsically disordered, such as Inhibitor 2 (I2), conserved across kingdoms. The durum wheat TdRL1 acts as a positive regulator of plant stress tolerance, presumably by inhibiting PP1 activity. In this work, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays demonstrate that the durum wheat TdPP1 interacts with both TdRL1 and At-I2 in vivo. YFP fluorescence restored after TdRL1-TdPP1 interaction decorated specifically the microtubular network of the tobacco co-infiltrated cells. In vitro phosphatase assays revealed that TdRL1 inhibited the activity of wild-type TdPP1 and two mutant forms (T243M and H135A) in a concentration-dependent manner, showing a novel and potent inhibition mechanism. Structural modeling of the TdPP1-inhibitor complexes suggested that both At-I2 and TdRL1 bind to TdPP1 by wrapping their flexible C-terminal tails around it, blocking access to the active site. Remarkably, the model showed that TdRL1 differs from At-I2 in its interaction with TdPP1 by trapping the phosphatase with its N-terminal tail. These findings provide important insights into the regulatory mechanisms governing the activity of PP1s in plants and highlight the potential for targeted inhibition to modulate plant stress responses. Full article

(This article belongs to the Section Molecular Biology)

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21 pages, 6710 KiB

Open AccessArticle

HNF4α-Mediated LINC02560 Promotes Papillary Thyroid Carcinoma Progression by Targeting the miR-505-5p/PDE4C Axis

by Yongcheng Su, Beibei Xu, Chunyi Gao, Wenbin Pei, Miaomiao Ma, Wenqing Zhang, Tianhui Hu, Fuxing Zhang and Shaoliang Zhang

Biomolecules 2025, 15(5), 630; https://doi.org/10.3390/biom15050630 (registering DOI) - 28 Apr 2025

Viewed by 47

Abstract

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid malignancy, and its progression is closely associated with patient outcomes. This study investigated the role of the long non-coding RNA LINC02560 in the pathogenesis and aggressiveness of PTC through cell culture, transfection, [...] Read more.

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid malignancy, and its progression is closely associated with patient outcomes. This study investigated the role of the long non-coding RNA LINC02560 in the pathogenesis and aggressiveness of PTC through cell culture, transfection, RT-qPCR, Western blot analysis, and various functional assays, such as MTT, EdU, colony formation, wound healing, and Transwell migration assays. Our results revealed a significant upregulation of LINC02560 in PTC tissues, correlating with poor prognosis in affected patients. Functional analyses demonstrated that silencing of LINC02560 markedly inhibited the proliferation, migration, and invasion of the PTC cell lines, KTC-1, and BCPAP, whereas overexpression promoted these aggressive traits. Mechanistically, LINC02560 acted as a competitive endogenous RNA, sponging miR-505-5p and alleviating its suppression on PDE4C degradation, thereby activating the P-AKT and epithelial–mesenchymal transition (EMT) signaling pathways. Additionally, HNF4α was identified as a transcription factor capable of enhancing the expression of LINC02560. In conclusion, our findings elucidate the critical HNF4α/LINC02560/miR-505-5p/PDE4C axis in PTC pathology, presenting this regulatory network as a promising biomarker combination and potential therapeutic target to improve patient outcomes and survival rates, warranting further clinical investigation to validate these insights and support the development of targeted therapies in PTC management. Full article

(This article belongs to the Section Molecular Biomarkers)

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59 pages, 2886 KiB

Open AccessReview

Updated Review on Natural Polyphenols: Molecular Mechanisms, Biological Effects, and Clinical Applications for Cancer Management

by Zainab Sabry Othman Ahmed, Elyas Khan, Nathan Elias, Alhussein Elshebiny and Qingping Dou

Biomolecules 2025, 15(5), 629; https://doi.org/10.3390/biom15050629 (registering DOI) - 28 Apr 2025

Viewed by 65

Abstract

Polyphenols, naturally occurring compounds found exclusively in plants, have gained significant attention for their potential in cancer prevention and treatment. These compounds are known for their antioxidant properties and are abundant in various plant-based foods, such as vegetables, fruits, grains, and beverages. Recent [...] Read more.

Polyphenols, naturally occurring compounds found exclusively in plants, have gained significant attention for their potential in cancer prevention and treatment. These compounds are known for their antioxidant properties and are abundant in various plant-based foods, such as vegetables, fruits, grains, and beverages. Recent studies have highlighted the broad spectrum of health benefits of polyphenols, including their antiviral, anti-inflammatory, and anticancer properties. In addition, these naturally derived compounds are increasingly important for drug discovery due to their high molecular diversity and novel biofunctionalities. This review provides an in-depth analysis of the current research and knowledge on the potential use of dietary polyphenols as bioactive compounds for the prevention and treatment of various cancers. This review aims to provide valuable insights into the mechanisms underlying the anticancer properties of phenolic compounds in both laboratory and clinical settings. Furthermore, this review highlights the positive clinical outcomes associated with the use of polyphenols as anticancer agents and offers guidance for future research to advance this promising field. 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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18 pages, 2885 KiB

Open AccessArticle

A Study of the Effects of Oleuropein and Polydatin Association on Muscle and Bone Metabolism

by Maria Beatrice Morelli, Cristina Aguzzi, Riccardo Rascioni and Fiorenzo Mignini

Biomolecules 2025, 15(5), 628; https://doi.org/10.3390/biom15050628 (registering DOI) - 28 Apr 2025

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Abstract

Sarcopenia and osteoporosis are age-related musculoskeletal pathologies that often develop in parallel, and numerous studies support the concept of a bone–muscle unit, where deep interaction between the two tissues takes place. In Mediterranean areas, the lowest incidence of osteoporosis within Europe is observed, [...] Read more.

Sarcopenia and osteoporosis are age-related musculoskeletal pathologies that often develop in parallel, and numerous studies support the concept of a bone–muscle unit, where deep interaction between the two tissues takes place. In Mediterranean areas, the lowest incidence of osteoporosis within Europe is observed, so the Mediterranean diet was suggested to play an important role. Consequently, in this study, oleuropein, a phenolic compound found in olive oil, and polydatin, another natural polyphenol found in the Mediterranean diet, were evaluated to determine their beneficial effects on bone and muscle metabolism. In human osteoblasts and skeletal muscle myoblasts, the effects were examined, and, after analyzing the cytotoxic effect to find non-toxic doses, the modulation of bone and muscle differentiation markers was evaluated at the gene and protein levels using PCR, Western blot, and immunohistochemistry. Interestingly, the compounds increased markers involved in osteoblast differentiation, such as osteocalcin, type I collagen, and dentin-sialo-phosphoprotein, as well as markers involved in myoblast differentiation, such as myogenic regulatory factors and creatine kinase. These effects were most noticeable when the compounds were administered together. These results suggest a beneficial role for oleuropein–polydatin association on bone and muscle tissue pathologies simultaneously. Full article

(This article belongs to the Special Issue The Value of Natural Compounds as Therapeutic Agents: 2nd Edition)

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24 pages, 3628 KiB

Open AccessArticle

Dissecting the Emerging Regulatory and Mechanistic Paradigms of Transcribed Conserved Non-Coding Elements in Breast Cancer

by Wenyong Zhu, Hao Huang, Qiong Li, Yu Gu, Rongxin Zhang, Huiling Shu, Yunqi Zhao, Hongde Liu and Xiao Sun

Biomolecules 2025, 15(5), 627; https://doi.org/10.3390/biom15050627 (registering DOI) - 27 Apr 2025

Viewed by 110

Abstract

Transcribed conserved non-coding elements (TCNEs), which are non-coding genomic elements that can regulate vital gene expression, play an unclear role in the development of severe diseases mainly associated with carcinogenesis. Currently, there are no mature tools for the identification of TCNEs. To compensate [...] Read more.

Transcribed conserved non-coding elements (TCNEs), which are non-coding genomic elements that can regulate vital gene expression, play an unclear role in the development of severe diseases mainly associated with carcinogenesis. Currently, there are no mature tools for the identification of TCNEs. To compensate for the lack of a systematic interpretation of the functional characterization and regulatory mechanisms of TCNE spatiotemporal activities, we developed a flexible pipeline, called captureTCNE, to depict the landscape of TCNEs and applied it to our breast cancer cohort (SEU-BRCA). Meanwhile, we investigated the genome-wide characteristics of TCNEs and unraveled that TCNEs harbor enhancer-like chromatin signatures as well as participate in the transcriptional machinery to regulate essential genes or architect biological regulatory networks of breast cancer. Specifically, the TCNE transcripts could recruit RBPs, such as ENOX1 and PTBP1, which are involved in gene expression regulation, to participate in the formation of regulatory networks and the association with altered splicing patterns. In particular, the presence of a non-classical secondary structure, called RNA G-quadruplex, on TCNE transcripts contributed to the recruitment of RBPs associated with subtype-specific transcriptional processes related to the estrogen response in breast cancer. Ultimately, we also analyzed the mutational signatures of variant-containing TCNEs and discerned twenty-one genes as essential components of the regulatory mechanism of TCNEs in breast cancer. Our study provides an effective TCNE identification pipeline and insights into the regulatory mechanisms of TCNEs in breast cancer, contributing to further knowledge of TCNEs and the emergence of innovative therapeutic strategies for breast cancer. Full article

(This article belongs to the Special Issue Application of Bioinformatics in Medicine)

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15 pages, 2182 KiB

Open AccessArticle

A Lipidomic Approach to Studying the Downregulation of Free Fatty Acids by Cytosolic Phospholipase A₂ Inhibitors

by Asimina Bourboula, Christiana Mantzourani, Ioanna Chalatsa, Christina Machalia, Evangelia Emmanouilidou, Maroula G. Kokotou and George Kokotos

Biomolecules 2025, 15(5), 626; https://doi.org/10.3390/biom15050626 (registering DOI) - 27 Apr 2025

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Abstract

Inhibitors of cytosolic phospholipase A₂ (GIVA cPLA₂) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA₂ inhibitors in cells have [...] Read more.

Inhibitors of cytosolic phospholipase A₂ (GIVA cPLA₂) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA₂ inhibitors in cells have been studied by determining the inhibition of arachidonic acid release. However, although to a lesser extent, GIVA cPLA₂ may also hydrolyze glycerophospholipids, releasing other free fatty acids (FFAs), such as linoleic acid or oleic acid. In the present work, we applied a liquid chromatography–high-resolution mass spectrometry method to study the levels of intracellular FFAs, after treating cells with selected GIVA cPLA₂ inhibitors. Six inhibitors belonging to different chemical classes were studied, using SH-SY5Y neuroblastoma cells as a model. This lipidomic approach revealed that treatment with each inhibitor created a distinct intracellular FFA profile, suggesting not only inhibitory potency against GIVA cPLA₂, but also other parameters affecting the outcome. Potent inhibitors were found to reduce not only arachidonic acid, but also other long-chain FAs, such as adrenic or linoleic acid, even medium-chain FAs, such as caproic or caprylic acid, suggesting that GIVA cPLA₂ inhibitors may affect FA metabolic pathways in general. The downregulation of intracellular FFAs may have implications in reprogramming FA metabolism in neurodegenerative diseases and cancer. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Members)

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42 pages, 3927 KiB

Open AccessReview

Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers

by Whi-An Kwon and Jae Young Joung

Biomolecules 2025, 15(5), 625; https://doi.org/10.3390/biom15050625 (registering DOI) - 27 Apr 2025

Viewed by 172

Abstract

Metastatic prostate cancer (mPCa) remains a significant cause of cancer-related mortality in men. Advances in molecular profiling have demonstrated that the androgen receptor (AR) axis, DNA damage repair pathways, and the PI3K/AKT/mTOR pathway are critical drivers of disease progression and therapeutic resistance. Despite [...] Read more.

Metastatic prostate cancer (mPCa) remains a significant cause of cancer-related mortality in men. Advances in molecular profiling have demonstrated that the androgen receptor (AR) axis, DNA damage repair pathways, and the PI3K/AKT/mTOR pathway are critical drivers of disease progression and therapeutic resistance. Despite the established benefits of hormone therapy, chemotherapy, and bone-targeting agents, mPCa commonly becomes treatment-resistant. Recent breakthroughs have highlighted the importance of identifying actionable genetic alterations, such as BRCA2 or ATM defects, that render tumors sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Parallel efforts have refined imaging—particularly prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography—to detect and localize metastatic lesions with high sensitivity, thereby guiding patient selection for PSMA-targeted radioligand therapies. Multi-omics innovations, including liquid biopsy technologies, enable the real-time tracking of emergent AR splice variants or reversion mutations, supporting adaptive therapy paradigms. Nonetheless, the complexity of mPCa necessitates combination strategies, such as pairing AR inhibition with PI3K/AKT blockade or PARP inhibitors, to inhibit tumor plasticity. Immuno-oncological approaches remain challenging for unselected patients; however, subsets with mismatch repair deficiency or neuroendocrine phenotypes may benefit from immune checkpoint blockade or targeted epigenetic interventions. We present these pivotal advances, and discuss how biomarker-guided integrative treatments can improve mPCa management. Full article

(This article belongs to the Special Issue Prostate Cancer Biomarkers and Therapeutics)

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16 pages, 671 KiB

Open AccessReview

The Role of Klotho in Oral and Maxillofacial Diseases: Mechanisms and Research Progress

by Shiqi Lin, Bozhao Wang and Jian Li

Biomolecules 2025, 15(5), 624; https://doi.org/10.3390/biom15050624 (registering DOI) - 27 Apr 2025

Viewed by 95

Abstract

Klotho, an anti-aging protein, has been extensively studied in systemic conditions such as chronic kidney disease and cardiovascular disorders. In recent years, its pivotal protective role and clinical significance in various oral and maxillofacial diseases have been increasingly demonstrated. It has been demonstrated [...] Read more.

Klotho, an anti-aging protein, has been extensively studied in systemic conditions such as chronic kidney disease and cardiovascular disorders. In recent years, its pivotal protective role and clinical significance in various oral and maxillofacial diseases have been increasingly demonstrated. It has been demonstrated that Klotho regulates oxidative stress, apoptosis, inflammation, and fibrosis via multiple molecular signaling pathways, including Nrf2, NF-κB, PI3K/Akt/FoxO1, insulin/IGF-1, FGF/FGFR, and Wnt/β-catenin. Consequently, these regulatory effects have been observed in conditions such as periodontitis, oral squamous cell carcinoma, malignant salivary gland tumors, oral submucous fibrosis, etc. Moreover, the decreased expression or dysfunctional activity of Klotho is frequently associated with the onset and progression of these diseases. This study provides a comprehensive review of the underlying mechanisms and recent advances in Klotho research within the realm of oral and maxillofacial diseases, offering novel perspectives for future basic and clinical investigations. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 2179 KiB

Open AccessArticle

FAM46C Expression Sensitizes Multiple Myeloma Cells to PF-543-Induced Cytotoxicity

by Annarita Miluzio, Federica De Grossi, Marilena Mancino, Stefano Biffo and Nicola Manfrini

Biomolecules 2025, 15(5), 623; https://doi.org/10.3390/biom15050623 (registering DOI) - 26 Apr 2025

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Abstract

FAM46C is a tumor suppressor initially identified in multiple myeloma (MM) but increasingly recognized for its role also in other cancers. Despite its significance, studies exploring the therapeutic potential of FAM46C in combination with targeted treatments remain limited. Sphingosine kinases (SphK1 and SphK2) [...] Read more.

FAM46C is a tumor suppressor initially identified in multiple myeloma (MM) but increasingly recognized for its role also in other cancers. Despite its significance, studies exploring the therapeutic potential of FAM46C in combination with targeted treatments remain limited. Sphingosine kinases (SphK1 and SphK2) are key regulators of sphingolipid signaling, a pathway essential for maintaining cell structure and function but frequently deregulated in tumors, making them promising targets for cancer therapy. Preliminary work from our laboratory showed that FAM46C expression synergizes with administration of SKI-I, a pan-inhibitor of sphingosine kinases. In this study, we focused specifically on SphK1, the sphingosine kinase predominantly implicated in cancer and investigated the combinatorial effect of forced FAM46C expression and treatment with PF-543, a selective SphK1 inhibitor. We found that FAM46C overexpression enhances, whereas its downregulation reduces, the cytotoxic efficacy of PF-543 in MM cell lines. Using an in vivo xenograft model, we further validated these findings, showing that FAM46C-expressing MM tumors are indeed sensitive to PF-543 while tumors harboring the D90G loss-of-function variant of FAM46C are not. Overall, our results uncover a novel synergistic interaction between FAM46C expression and SphK1 inhibition, highlighting a promising therapeutic strategy for MM treatment. Full article

(This article belongs to the Section Molecular Biology)

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17 pages, 650 KiB

Open AccessReview

Therapeutic Effects of GLP-1 Receptor Agonists and DPP-4 Inhibitors in Neuropathic Pain: Mechanisms and Clinical Implications

by Yaswanth Kuthati, Venkata Naga Goutham Davuluri and Chih-Shung Wong

Biomolecules 2025, 15(5), 622; https://doi.org/10.3390/biom15050622 (registering DOI) - 26 Apr 2025

Viewed by 191

Abstract

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the small intestine upon food intake. GLP-1 enhances insulin secretion, suppresses glucagon release, and promotes satiety, resulting in reduced food consumption and subsequent weight loss. Endogenous GLP-1 has a very short half-life and is [...] Read more.

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the small intestine upon food intake. GLP-1 enhances insulin secretion, suppresses glucagon release, and promotes satiety, resulting in reduced food consumption and subsequent weight loss. Endogenous GLP-1 has a very short half-life and is rapidly degraded by the enzyme dipeptidyl-peptidase-IV (DPP-4). To address this limitation, GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors (DPP-4is) were developed and have demonstrated potency in clinical practice. In recent years, GLP-1RA and DPP4-i therapies are known to have pleiotropic effects, such as a reduction in oxidative stress, autophagy regulation, metabolic reprogramming, enhancement of anti-inflammatory signaling, regulation of gene expression, and being neuroprotective. These effects imply a therapeutic perspective for GLP-1RA and DPP-4i therapies in neuropathic pain treatment. Preclinical and clinical studies increasingly support the hypothesis that these therapies may alleviate neuropathic pain by targeting multiple mechanisms that induce neuropathic pain, such as inflammation, oxidative stress, and mitochondrial dysfunction. This review explores the mechanisms by which GLP-1RAs and DPP-4is alleviate neuropathic pain. It also highlights current advancements in incretin research, focusing on the therapeutic effects of GLP-1RAs and DPP-4-is for neuropathic pain. Full article

(This article belongs to the Section Biological Factors)

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31 pages, 2634 KiB

Open AccessReview

Molecular Mechanisms in the Carcinogenesis of Oral Squamous Cell Carcinoma: A Literature Review

by Laertty Garcia de Sousa Cabral, Isabela Mancini Martins, Ellen Paim de Abreu Paulo, Karina Torres Pomini, Jean-Luc Poyet and Durvanei Augusto Maria

Biomolecules 2025, 15(5), 621; https://doi.org/10.3390/biom15050621 (registering DOI) - 25 Apr 2025

Viewed by 98

Abstract

The tumor microenvironment (TME) plays a crucial role in the development, progression, and metastasis of oral squamous cell carcinoma (OSCC). The TME comprises various cellular and acellular components, including immune cells, stromal cells, cytokines, extracellular matrix, and the oral microbiome, all of which [...] Read more.

The tumor microenvironment (TME) plays a crucial role in the development, progression, and metastasis of oral squamous cell carcinoma (OSCC). The TME comprises various cellular and acellular components, including immune cells, stromal cells, cytokines, extracellular matrix, and the oral microbiome, all of which dynamically interact with tumor cells to influence their behavior. Immunosuppression is a key feature of the OSCC TME, with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) contributing to an environment that allows tumor cells to evade immune surveillance and supports angiogenesis. The oral microbiome also plays a pivotal role in OSCC pathogenesis, as dysbiosis, or imbalances in the microbiota, can lead to chronic inflammation, which promotes carcinogenesis through the production of pro-inflammatory cytokines and reactive oxygen species (ROS). Pathogens like Porphyromonas gingivalis and Fusobacterium nucleatum have, hence, been implicated in OSCC-driven tumor progression, as they induce inflammation, activate oncogenic pathways, and modulate immune responses. In this review, we discuss how the interplay between immunosuppression and microbiome-driven inflammation creates a tumor-promoting environment in OSCC, leading to treatment resistance and poor patient outcomes, and explore the potential therapeutic implication of a better understanding of OSCC etiology and molecular changes. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Members)

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22 pages, 3152 KiB

Open AccessReview

Natural Compounds in Cancer Therapy: Revealing the Role of Flavonoids in Renal Cell Carcinoma Treatment

by Zixuan Chen and Min Liu

Biomolecules 2025, 15(5), 620; https://doi.org/10.3390/biom15050620 - 25 Apr 2025

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Abstract

Renal cell carcinoma (RCC) is the most lethal malignancy of the urinary system, with limited treatment options due to drug resistance and the adverse effects associated with current therapies. This review aims to systematically examine the therapeutic potential of flavonoids, which are natural [...] Read more.

Renal cell carcinoma (RCC) is the most lethal malignancy of the urinary system, with limited treatment options due to drug resistance and the adverse effects associated with current therapies. This review aims to systematically examine the therapeutic potential of flavonoids, which are natural polyphenolic compounds possessing anti-inflammatory, antioxidant, and anticancer properties, in the context of RCC treatment. We summarize the anticancer activities of 26 natural flavonoids, classified into six subclasses, and explore their mechanisms of action, including the inhibition of tumor cell proliferation, migration, and invasion, as well as the induction of apoptosis, autophagy, and ferroptosis. Particular attention is paid to their modulation of key signaling pathways such as the JAK/STAT3, PI3K/Akt/mTOR, and miRNA-related axes, including miR-21/YAP1 and miR-324-3p/GPX4, providing a molecular basis for their anti-RCC activity. We also address several pharmacological challenges that limit the clinical application of flavonoids, including poor bioavailability, metabolic instability, and potential toxicity. Emerging solutions such as novel flavonoid derivatives, advanced drug delivery systems, and rational combination therapy strategies are also discussed. Current clinical evidence, including a phase II trial of flavopiridol in advanced RCC, highlights the potential but also the need for further validation. In conclusion, flavonoids offer a promising approach to improving RCC treatment. Future research should focus on optimizing their therapeutic efficacy and ensuring their safe clinical translation, with the goal of achieving personalized and minimally invasive cancer therapies. Full article

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

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15 pages, 2903 KiB

Open AccessArticle

Field-Effect Transistor Based on Nanocrystalline Graphite for DNA Immobilization

by Bianca Adiaconita, Eugen Chiriac, Tiberiu Burinaru, Catalin Marculescu, Cristina Pachiu, Oana Brincoveanu, Octavian Simionescu and Marioara Avram

Biomolecules 2025, 15(5), 619; https://doi.org/10.3390/biom15050619 - 25 Apr 2025

Viewed by 172

Abstract

In recent years, field-effect transistors (FETs) based on graphene have attracted significant interest due to their unique electrical properties and their potential for biosensing and molecular detection applications. This study uses FETs with a nanocrystalline graphite (NCG) channel to detect DNA nucleobases. The [...] Read more.

In recent years, field-effect transistors (FETs) based on graphene have attracted significant interest due to their unique electrical properties and their potential for biosensing and molecular detection applications. This study uses FETs with a nanocrystalline graphite (NCG) channel to detect DNA nucleobases. The exceptional electronic properties of NCG, and its high surface area, enable strong π–π stacking interactions with DNA nucleobases, promoting efficient adsorption and stabilization of the biomolecules. The direct attachment of nucleobases to the NCG channel leads to substantial changes in the device’s electrical characteristics, which can be measured in real time to assess DNA binding and sequence recognition. This method enables highly sensitive, label-free DNA detection, opening up new possibilities for rapid genetic analysis and diagnostics. Understanding the interactions between DNA nucleobases and graphene-based materials is crucial for advancing genetic research and biotechnology, paving the way for more accurate and efficient diagnostic tools. Full article

(This article belongs to the Special Issue Biomolecules and Materials Based Approaches in Biomedical Field: 2nd Edition)

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22 pages, 13635 KiB

Open AccessArticle

Pericarpium Trichosanthis Injection Protects Isoproterenol-Induced Acute Myocardial Ischemia via Suppressing Inflammatory Damage and Apoptosis Pathways

by Zizheng Wu, Xing Chen, Jiahao Ye, Xiaoyi Wang and Zhixi Hu

Biomolecules 2025, 15(5), 618; https://doi.org/10.3390/biom15050618 - 24 Apr 2025

Viewed by 207

Abstract

This research proposes to systematically investigate the cardioprotective mechanisms of Pericarpium Trichosanthis injection (PTI) against acute myocardial ischemia through an integrated approach combining ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) constituent profiling, UNIFI database-assisted component identification, network pharmacology-guided target prediction, molecular docking [...] Read more.

This research proposes to systematically investigate the cardioprotective mechanisms of Pericarpium Trichosanthis injection (PTI) against acute myocardial ischemia through an integrated approach combining ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) constituent profiling, UNIFI database-assisted component identification, network pharmacology-guided target prediction, molecular docking verification, and in vivo experimental validation. The multimodal methodology is designed to comprehensively uncover the therapeutic benefits and molecular pathways underlying this traditional Chinese medicine formulation. Methods: UPLC-Q-TOF/MS and the UNIFI database were used in conjunction with a literature review to screen and validate the absorbed components of PTI. Using network pharmacology, we constructed protein-protein interaction (PPI) networks for pinpointing prospective therapeutic targets. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify potential signaling pathways. In vivo experiments were conducted to investigate the mechanisms by which PTI ameliorated isoproterenol-induced myocardial injury in rats. All animal experiments have adhered to ARRIVE guidelines. Results: UPLC-Q-TOF/MS revealed 11 core active components in PTI. Network pharmacology prioritization identified pseudoaspidin, ciryneol C, cynanoside M, daurinol, and n-butyl-β-D-fructopyranoside as central bioactive constituents within the compound-target interaction network. Topological analysis of the protein interactome highlighted AKT1, EGFR, MMP9, SRC, PTGS2, STAT3, BCL2, CASP3, and MAPK3 as the most interconnected nodes with the highest betweenness centrality. Pathway enrichment analysis established the PI3K/Akt signaling cascade as the principal mechanistic route for PTI’s cardioprotective effects. Molecular docking simulations demonstrated high-affinity interactions between characteristic components (e.g., cynanoside M, darutigenol) and pivotal targets including PTGS2, MAPK3, CASP3, and BCL2. In vivo investigations showed PTI treatment markedly attenuated myocardial tissue degeneration and collagen deposition (p < 0.05), normalized electrocardiographic ST-segment deviations, and suppressed pro-inflammatory cytokine production (IL-6, TNF-α). The formulation concurrently reduced circulating levels of cardiac injury indicators (LDH, cTnI) and oxidative stress parameters (ROS, MDA), Regarding apoptosis regulation, PTI reduced Bax, caspase-3, and caspase-9, while elevating Bcl-2 (p < 0.05), effectively inhibiting myocardial cell apoptosis with all therapeutic outcomes reaching statistical significance. These findings highlight PTI’s protective effects against myocardial injury through multi-target modulation of inflammation, oxidation, and apoptosis. Conclusions: PTI exerts its therapeutic effects in treating acute myocardial ischemia by regulating and suppressing inflammatory responses, and inhibiting cardiomyocyte apoptosis. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 1714 KiB

Open AccessReview

The Role of N6-Methyladenosine (m6A) RNA Modification in the Pathogenesis of Parkinson’s Disease

by Yulu Wang, Tianyuan Zhao, Chunsen Yuan and Xuechai Chen

Biomolecules 2025, 15(5), 617; https://doi.org/10.3390/biom15050617 - 23 Apr 2025

Viewed by 133

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease with a high prevalence among the middle-aged and elderly population. The pathogenesis of PD is closely linked to the misfolding and aggregation of α-synuclein, which contributes to the formation of Lewy bodies. These processes are associated [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disease with a high prevalence among the middle-aged and elderly population. The pathogenesis of PD is closely linked to the misfolding and aggregation of α-synuclein, which contributes to the formation of Lewy bodies. These processes are associated with the degeneration of dopaminergic neurons, a key neuropathological change that underlies the motor symptoms of PD. In addition, genetic susceptibility, mitochondrial dysfunction, oxidative stress and neuroinflammation are involved in the progress of the disease. Previous studies indicated that the dysregulation of epigenetic modifications, including DNA methylation and histone acetylation, may be the key pathophysiological factors in PD. N6-methyladenosine (m6A) is a dynamically reversible modification in eukaryotes RNA, and could regulate mRNA degradation, stability, maturation, and translation. Recently, clinical research has shown that the global m6A level is significantly reduced in PD patients as well as the expression changes in m6A-associated proteins. Moreover, the dysregulation of m6A modification was shown to impact dopamine metabolism and damage dopaminergic neurons, indicating that m6A RNA modification may play a critical role in the pathogenesis of PD. In this review, we summarize recent clinical studies on m6A RNA modification in PD patients and discuss the regulatory role of m6A modification in dopamine metabolism and dopaminergic neurons death. Furthermore, based on the different m6A modification databases and prediction websites, we analyzed the potential m6A modification sites on the mRNA of key PD pathogenic genes (SNCA, PRKN, PINK1, and LRRK2) for the first time, aiming to offer new gene targets and perspectives understanding the pathogenesis of PD. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 1219 KiB

Open AccessArticle

Pancreatic MicroRNAs in Ictidomys tridecemlineatus Associated with Metabolic Diseases: Nature’s Insights into Important Biomarkers

by Olawale O. Taiwo, Saif Rehman and Kenneth B. Storey

Biomolecules 2025, 15(5), 616; https://doi.org/10.3390/biom15050616 - 23 Apr 2025

Viewed by 91

Abstract

Hibernation involves a profound metabolic rate depression (MRD) that enables certain species to survive prolonged periods of low energy availability. The thirteen-lined ground squirrel uses MRD to arrange cellular and biochemical pathways which suppress nonvital genetic and cellular pathways to conserve internal energy [...] Read more.

Hibernation involves a profound metabolic rate depression (MRD) that enables certain species to survive prolonged periods of low energy availability. The thirteen-lined ground squirrel uses MRD to arrange cellular and biochemical pathways which suppress nonvital genetic and cellular pathways to conserve internal energy while preserving all essential processes. This study investigates the role of microRNAs (miRNAs) in controlling key signaling pathways and cellular processes in pancreatic tissue during hibernation. Using next-generation sequencing and broad genomic analysis, we analyzed and identified seven differentially expressed miRNAs (miR-29a-3p, miR-22-3p, miR-125-5p, miR-200a-3p, miR-328-3p, miR-21-5p, and miR-148-3p) in the pancreas of hibernating 13-lined ground squirrels (Ictidomys tridecemlineatus). Our findings reveal that these miRNAs regulate pathways involved in glucose homeostasis, including insulin secretion and metabolic regulation, contributing to the unique adaptations of hibernation. These insights advance our understanding of the molecular adaptations underlying hibernation and may have implications for therapeutic strategies targeting metabolic disorders such as diabetes. Full article

(This article belongs to the Section Molecular Biology)

39 pages, 1641 KiB

Open AccessReview

The Role of Astrocytes in the Molecular Pathophysiology of Schizophrenia: Between Neurodevelopment and Neurodegeneration

by Licia Vellucci, Benedetta Mazza, Annarita Barone, Anita Nasti, Giuseppe De Simone, Felice Iasevoli and Andrea de Bartolomeis

Biomolecules 2025, 15(5), 615; https://doi.org/10.3390/biom15050615 - 23 Apr 2025

Viewed by 113

Abstract

Schizophrenia is a chronic and severe psychiatric disorder affecting approximately 1% of the global population, characterized by disrupted synaptic plasticity and brain connectivity. While substantial evidence supports its classification as a neurodevelopmental disorder, non-canonical neurodegenerative features have also been reported, with increasing attention [...] Read more.

Schizophrenia is a chronic and severe psychiatric disorder affecting approximately 1% of the global population, characterized by disrupted synaptic plasticity and brain connectivity. While substantial evidence supports its classification as a neurodevelopmental disorder, non-canonical neurodegenerative features have also been reported, with increasing attention given to astrocytic dysfunction. Overall, in this study, we explore the role of astrocytes as a structural and functional link between neurodevelopment and neurodegeneration in schizophrenia. Specifically, we examine how astrocytes contribute to forming an aberrant substrate during early neurodevelopment, potentially predisposing individuals to later neurodegeneration. Astrocytes regulate neurotransmitter homeostasis and synaptic plasticity, influencing early vulnerability and disease progression through their involvement in Ca²⁺ signaling and dopamine–glutamate interaction—key pathways implicated in schizophrenia pathophysiology. Astrocytes differentiate via nuclear factor I-A, Sox9, and Notch pathways, occurring within a neuronal environment that may already be compromised in the early stages due to the genetic factors associated with the ‘two-hits’ model of schizophrenia. As a result, astrocytes may contribute to the development of an altered neural matrix, disrupting neuronal signaling, exacerbating the dopamine–glutamate imbalance, and causing excessive synaptic pruning and demyelination. These processes may underlie both the core symptoms of schizophrenia and the increased susceptibility to cognitive decline—clinically resembling neurodegeneration but driven by a distinct, poorly understood molecular substrate. Finally, astrocytes are emerging as potential pharmacological targets for antipsychotics such as clozapine, which may modulate their function by regulating glutamate clearance, redox balance, and synaptic remodeling. Full article

(This article belongs to the Special Issue The Role of Astrocytes in Neurodegenerative Diseases)

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35 pages, 3801 KiB

Open AccessReview

Targeting the Electron Transport System for Enhanced Longevity

by Marko Radovic, Lucas P. Gartzke, Simon E. Wink, Joris A. van der Kleij, Frouwkje A. Politiek and Guido Krenning

Biomolecules 2025, 15(5), 614; https://doi.org/10.3390/biom15050614 - 23 Apr 2025

Viewed by 173

Abstract

Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. [...] Read more.

Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. Rapamycin and metformin are the most extensively studied longevity drugs. Rapamycin inhibits mTORC1, promoting mitophagy, enhancing mitochondrial biogenesis, and reducing inflammation. Metformin partially inhibits Complex I, lowering reverse electron transfer (RET)-induced ROS formation and activating AMPK to stimulate autophagy and mitochondrial turnover. Both compounds mimic caloric restriction, shift metabolism toward a catabolic state, and confer preclinical—and, in the case of metformin, clinical—longevity benefits. More recently, small molecules directly targeting mitochondrial membranes and ETS components have emerged. Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress. 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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24 pages, 3732 KiB

Open AccessArticle

Acute Neurovascular Inflammatory Profile in Patients with Aneurysmal Subarachnoid Hemorrhage

by Ruby R. Taylor, Robert W. Keane, Begoña Guardiola, Raul Martí, Daniel Alegre, W. Dalton Dietrich, Jon Perez-Barcena and Juan Pablo de Rivero Vaccari

Biomolecules 2025, 15(5), 613; https://doi.org/10.3390/biom15050613 - 23 Apr 2025

Viewed by 124

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition that results from intracranial aneurysm rupture, leading to the accumulation of blood between the arachnoid and pia mater. The blood breakdown products and damage-associated molecule patterns (DAMPs), which are released as a result of vascular [...] Read more.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition that results from intracranial aneurysm rupture, leading to the accumulation of blood between the arachnoid and pia mater. The blood breakdown products and damage-associated molecule patterns (DAMPs), which are released as a result of vascular and cellular compromise following aneurysm rupture, elicit local endothelial reactions leading to the narrowing of cerebral arteries and ischemia. In addition, vascular inflammation, characterized by activated endothelial cells, perpetuates disruption of the neurovascular unit and the blood–brain barrier. The uncertain prognosis of aSAH patients contributes to the necessity of a fluid biomarker that can serve as a valuable adjunct to radiological and clinical evaluation. Limited studies have investigated vascular inflammation and angiogenic protein expression following aSAH. Reliable markers of the vascular inflammatory and angiogenic response associated with aSAH may allow for the earlier detection of patients at risk for complications and aid in the identification of novel pharmacologic targets. We investigated whether vascular inflammatory and angiogenesis signaling proteins may serve as potential biomarkers of aSAH. Serum and cerebrospinal fluid (CSF) from fifteen aSAH subjects and healthy age-matched controls as well as hydrocephalus (CSF) no-aneurysm controls were evaluated for levels of vascular inflammatory and angiogenesis proteins. Protein measurement was carried out using electrochemiluminescence. The area under the curve (AUC) was calculated using receiver operating characteristics (ROC) to obtain information on biomarker reliability, specificity, sensitivity, cut-off points, and likelihood ratio. In addition, patients were grouped by Glasgow Outcome Score—Extended at 3 months post-injury to determine the correlation between vascular inflammatory protein levels and clinical outcome measures. aSAH subjects demonstrated elevated vascular inflammatory protein levels in serum and CSF when compared to controls. Certain vascular injury and angiogenic proteins were found to be promising biomarkers of inflammatory response in aSAH in the CSF and serum. In particular, elevated levels of serum amyloid-alpha (SAA) were found to be correlated with unfavorable outcomes following aSAH. Determination of these protein levels in CSF and serum in aSAH may be utilized as reliable biomarkers of inflammation in aSAH and used clinically to monitor patient outcomes. Full article

(This article belongs to the Special Issue Biomarkers of Cardiovascular and Cerebrovascular Diseases, 2nd Edition)

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38 pages, 2476 KiB

Open AccessReview

Understanding the Role of Adipokines in Cardiometabolic Dysfunction: A Review of Current Knowledge

by Sayantap Datta, Saisudha Koka and Krishna M. Boini

Biomolecules 2025, 15(5), 612; https://doi.org/10.3390/biom15050612 - 23 Apr 2025

Viewed by 142

Abstract

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and [...] Read more.

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and progression of cardiometabolic disorders remain poorly understood. Adipokines are adipocyte-specific cytokines that are central to deleterious cardiometabolic alterations. They exhibit both pro-inflammatory and anti-inflammatory effects, complicating their association with cardiometabolic disturbances. Thus, understanding the cardiometabolic association of adipokines from a molecular and signaling perspective assumes great importance. This review presents a comprehensive outline of the most prominent adipokines exhibiting pro-inflammatory and/or anti-inflammatory functions in cardiometabolic dysfunction. The review also presents an insight into the pathophysiological implications of such adipokines in different cardiometabolic dysfunction conditions, the status of adipokine druggability, and future studies that can be undertaken to address the existing scientific gap. A clear understanding of the functional and mechanistic role of adipokines can potentially improve our understanding of cardiovascular disease pathophysiology and enhance our current therapeutic regimen in the years to come. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Members)

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15 pages, 2356 KiB

Open AccessArticle

New Lead Schiff Bases Predominantly Mediate Vasorelaxant Activity Through α₁ Receptor Blocking Activity

by Zakia Subhan, Niaz Ali, Abid Ullah, Wajid Ali, Muhammad Nabi and Syed Wadood Ali Shah

Biomolecules 2025, 15(5), 611; https://doi.org/10.3390/biom15050611 - 23 Apr 2025

Viewed by 181

Abstract

Schiff bases synthesized in our laboratory have demonstrated pain-relieving effects through both peripheral and central nervous system pathways. Considering that centrally acting analgesics often affect the muscle tone of the gastrointestinal tract (GIT) and related deep internal organs, this study was conducted to [...] Read more.

Schiff bases synthesized in our laboratory have demonstrated pain-relieving effects through both peripheral and central nervous system pathways. Considering that centrally acting analgesics often affect the muscle tone of the gastrointestinal tract (GIT) and related deep internal organs, this study was conducted to examine potential relaxant effects on blood vessels and GIT smooth muscles. The possible relaxant effects of Schiff bases (SB1 and SB2) on isolated rabbit aortic strips were evaluated. The experiments involved assessing their impact on contractions induced by 80 mM potassium chloride (KCL) and 1 µM norepinephrine (NE). Norepinephrine concentration response curves (N. ECRCs) were constructed in the absence and presence of three different concentrations of SB1 and SB2, using N. ECRCs as a negative control. Terazosin served as a standard α1 receptor blocker. Docking studies were employed to validate the mechanism of action for SB1 and SB2. The study outcomes suggest that SB1 is more potent than SB2, demonstrating lower EC₅₀ values for NE-induced contractions in intact (5.50 × 10⁻⁵ ± 2.23 M) and denuded (5.81 × 10⁻⁵ ± 3.80 M) aortae. For NE-induced contractions, SB1 showed percent relaxation values of 48% and 41% in intact and denuded aortae, respectively. In comparison, SB2 exhibited values of 82.5% and 74%, showing that SB1 is more efficacious than SB2. The rightward shift of N. ECRCs for both SB1 and SB2 confirms their inhibition of α1 receptors. Additive effects of SB1 and SB2 were seen in the presence of verapamil (p < 0.0001). Docking analysis revealed that the compounds can properly bind to the target receptor Gq 1D (P25100). Findings show that both Schiff base SB1 and SB2 produce significant (p < 0.05) vasorelaxation via the α1 receptor blocking mechanism. Full article

(This article belongs to the Section Chemical Biology)

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