Biomolecules

20 pages, 3980 KiB

Open AccessArticle

A Single-Chain Variable Fragment Antibody Alleviates Inflammation and Apoptosis of Neurons by Inhibiting Tau Aggregation

by Zongbao Wang, Jingye Lin, Peipei Chang, Mingzhu Sun and Sen Li

Biomolecules 2025, 15(6), 872; https://doi.org/10.3390/biom15060872 (registering DOI) - 15 Jun 2025

Abstract

Tau pathology is one of the main pathological features of Alzheimer’s disease (AD). Intracellular Tau may be released to the extracellular space upon neuron degeneration, where it has the potential to be toxic to other neurons. The propagation of Tau pathology, mediated by [...] Read more.

Tau pathology is one of the main pathological features of Alzheimer’s disease (AD). Intracellular Tau may be released to the extracellular space upon neuron degeneration, where it has the potential to be toxic to other neurons. The propagation of Tau pathology, mediated by extracellular Tau aggregates, may underlie the pathogenesis of AD. Antibody therapies targeting Tau proteins are, therefore, considered highly promising. In this study, the cytotoxicity of extracellular Tau aggregates on SH-SY5Y cells was examined. The effect of extracellular Tau aggregates on intracellular Tau aggregation was also studied using a FRET-based assay. The extracellular Tau aggregates were found to cause intracellular Tau aggregation after entering the cells; meanwhile, ROS (reactive oxygen species) induced by Tau aggregates facilitated this process. A single-chain variable fragment antibody (scFv T1) inhibits Tau aggregation both extracellularly and intracellularly. ScFv T1 also inhibited the accumulation of ROS and alleviated the inflammation and apoptosis induced by Tau aggregates. These findings could provide experimental support for the study of neurotoxicity and related mechanisms of extracellular Tau aggregates, in addition to providing insights into the development of novel therapeutic agents to treat AD. Full article

(This article belongs to the Section Chemical Biology)

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16 pages, 7578 KiB

Open AccessArticle

Brianolide from Briareum stechei Attenuates Atopic Dermatitis-like Skin Lesions by Regulating the NFκB and MAPK Pathways

by Chia-Chen Wang, Kang-Ling Wang, Yu-Jou Hsu, Chao-Hsien Sung, Mei-Jung Chen, Meng-Fang Huang, Ping-Jyun Sung and Chi-Feng Hung

Biomolecules 2025, 15(6), 871; https://doi.org/10.3390/biom15060871 (registering DOI) - 14 Jun 2025

Abstract

Atopic dermatitis (AD) is a common chronic skin disease affecting both children and adults. Currently lacking a clinical cure, AD presents significant physical and emotional challenges for patients and their families, substantially impacting their quality of life. This underscores significant unmet needs in [...] Read more.

Atopic dermatitis (AD) is a common chronic skin disease affecting both children and adults. Currently lacking a clinical cure, AD presents significant physical and emotional challenges for patients and their families, substantially impacting their quality of life. This underscores significant unmet needs in AD management and highlights the necessity for developing effective therapeutic applications. Recently, several chlorine-containing active substances with promising pharmacological activity have been discovered in soft corals cultivated through coral farming. Among these, brianolide, isolated from the soft coral Briareum stechei, has shown promising potential. This study investigated brianolide’s regulatory effects on the inflammatory response in atopic dermatitis and its underlying mechanisms. Using an in vitro human keratinocyte cell line (HaCaT) stimulated with tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ) to mimic AD inflammation, brianolide was found to inhibit cytokine and chemokine expression via the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB)-signaling pathways. In an in vivo animal model of 2,4-Dinitrochlorobenzene (DNCB)-induced AD, brianolide demonstrated anti-inflammatory effects, reducing transepidermal water loss (TEWL), ear thickness, erythema, and epidermal blood flow. These findings provide new insights into brianolide’s activity against AD-related inflammation, elucidate potential mechanisms, and contribute to understanding the pharmacological potential of natural coral products for AD treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Autoimmune Diseases)

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27 pages, 1993 KiB

Open AccessReview

Relationship Between Thyroid Dysfunction and Ovarian Cancer

by Justyna Gogola-Mruk, Aleksandra Sirek, Izabela Kumor, Gabriela Wojtaszek, Klaudia Roszak, Karolina Kulig and Anna Ptak

Biomolecules 2025, 15(6), 870; https://doi.org/10.3390/biom15060870 (registering DOI) - 14 Jun 2025

Abstract

This review looks at the causes of the association between thyroid dysfunction (hyperthyroidism and hypothyroidism) and ovarian cancer (OC) risk. Epidemiological data have revealed that thyroid dysfunction, particularly hyperthyroidism, is associated with increased risk, progression, and mortality in patients with OC. In addition, [...] Read more.

This review looks at the causes of the association between thyroid dysfunction (hyperthyroidism and hypothyroidism) and ovarian cancer (OC) risk. Epidemiological data have revealed that thyroid dysfunction, particularly hyperthyroidism, is associated with increased risk, progression, and mortality in patients with OC. In addition, research studies and databases have demonstrated that both the expression and localization of thyroid hormone receptors alpha (TRα) and beta (TRβ) and membrane thyroid hormone receptor integrin alpha V beta 3 (αvβ3) affect OC progression and survival in OC patients. Furthermore, this review described the levels of the thyroid hormones (THs) thyroxine (T₄) and 3,5,3′-triiodo-L-thyronine (T₃) in the blood of OC patients and their role in OC progression. Moreover, we present studies that reported the relationship between hyperthyroidism and hypothyroidism and the levels of metabolic hormones in the blood and the possible effects on metabolic reprogramming in OC cells. We also report data indicating the relationship between the treatment of thyroid dysfunction and OC progression. Finally, the cited case studies described the essential case of struma ovarii, which is OC, including thyroid tissue. This review describes the link between thyroid dysfunction and OC risk and progression, which may be important in treating OC patients with thyroid dysfunction. Full article

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

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14 pages, 2244 KiB

Open AccessArticle

Positive Effects of (+)-Epicatechin on Traumatic Spinal Cord Injury Recovery

by Cristian Gonzalez-Ruiz, Rodrigo Mondragón-Lozano, Hermelinda Salgado-Ceballos, Francisco Villarreal, Yuridia Martínez-Meza, Eduardo Meaney, Nayelli Nájera and Guillermo Ceballos

Biomolecules 2025, 15(6), 869; https://doi.org/10.3390/biom15060869 (registering DOI) - 14 Jun 2025

Abstract

Neurological damage from traumatic spinal cord injury (SCI) results in a grade of disability ranging from mild to severe motor and sensory dysfunction. It occurs more frequently in men of productive age. Treatment essentially consists of anti-inflammatories and rehabilitation. Other treatments are only [...] Read more.

Neurological damage from traumatic spinal cord injury (SCI) results in a grade of disability ranging from mild to severe motor and sensory dysfunction. It occurs more frequently in men of productive age. Treatment essentially consists of anti-inflammatories and rehabilitation. Other treatments are only partially effective, and inadequate treatment and secondary conditions often cause premature mortality. The search for pharmacological approaches is a continuous effort. This study aimed to assess the effects of a natural compound on spinal cord injury (SCI) as an alternative damage prevention maneuver. We evaluated the protective effects of the flavanol (+)-epicatechin (EC) in a rat model of moderate trauma-induced SCI on protein markers of damage events. The results showed that EC induced significant protection against SCI. No changes were found in angiopoietin-1, beclin-1, myelin basic protein, glial fibrillary acidic protein, neurofilament heavy polypeptide, and neuronal nuclear antigen after the injury, suggesting that damage progression was impeded. The reduction in damage translates into better movement. The results suggest that (+)-epicatechin may be a suitable alternative for treating SCI. Full article

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

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15 pages, 27538 KiB

Open AccessArticle

A Near-Infrared Fluorescent Probe for Specific Imaging of Lymph Node Metastases in Ovarian Cancer via Active Targeting of the Gonadotropin-Releasing Hormone Receptor

by Qiyu Liu, Jiaan Sun, Xiaobo Zhou, Mingxing Zhang, Tao Pu, Xiaolan Gao, Meng Zhang, Congjian Xu and Xiaoyan Zhang

Biomolecules 2025, 15(6), 868; https://doi.org/10.3390/biom15060868 (registering DOI) - 14 Jun 2025

Abstract

Lymph node metastases are common in advanced ovarian cancer and are associated with poor prognosis. Accurate intraoperative identification of lymph node metastases remains a challenge in ovarian cancer surgery due to the lack of tumor-specific intraoperative imaging tools. Here, we developed a gonadotropin-releasing [...] Read more.

Lymph node metastases are common in advanced ovarian cancer and are associated with poor prognosis. Accurate intraoperative identification of lymph node metastases remains a challenge in ovarian cancer surgery due to the lack of tumor-specific intraoperative imaging tools. Here, we developed a gonadotropin-releasing hormone receptor (GnRHR)-targeted near-infrared (NIR) fluorescent probe, GnRHa-PEG-Rh760, through conjugation of a GnRH analog peptide with the Rh760 fluorophore and polyethylene glycol (PEG). A non-targeted probe (PEG-Rh760) served as control. In mouse models of subcutaneous xenografts, peritoneal and lymph node metastases derived from ovarian cancer cells, GnRHa-PEG-Rh760 showed superior tumor-specific accumulation. NIR fluorescence imaging revealed strong fluorescence signals localized to primary tumors, peritoneal lesions, and metastatic lymph nodes with no off-target signals in normal lymph nodes. The spatial co-localization between the NIR fluorescence of GnRHa-PEG-Rh760 and tumor-derived bioluminescence clearly confirmed the probe’s target specificity. GnRHa-PEG-Rh760 mainly accumulated in the tumor and liver and was gradually cleared at 96 h post-injection. The retention of fluorescence signals in normal ovary tissue further validated GnRHR-mediated binding of the probe. Notably, GnRHa-PEG-Rh760 exhibited excellent biocompatibility with no observed systemic toxicity as evidenced by hematologic and histopathologic analyses. These data demonstrate the potential of GnRHa-PEG-Rh760 as an intraoperative imaging agent, providing real-time fluorescence imaging guidance to optimize surgical precision. This study highlights the value of receptor-targeted molecular imaging probes in precision cancer surgery. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 871 KiB

Open AccessSystematic Review

Current Efficacy of Multiepitope Vaccines Against Helminths: A Systematic Review

by Ignacio Trujillo-Rodríguez, Julio López-Abán, Montserrat Alonso-Sardón, Belén Vicente-Santiago, Antonio Muro-Álvarez and Raúl Manzano-Román

Biomolecules 2025, 15(6), 867; https://doi.org/10.3390/biom15060867 (registering DOI) - 13 Jun 2025

Abstract

Background: Vaccination represents an efficient way to control communicable diseases. Reliable vaccines would reduce the use of anthelmintics drugs and fight against the concern of anthelmintics resistances. Unfortunately, anthelmintic vaccines face many difficulties in their development. One of the most innovative vaccine [...] Read more.

Background: Vaccination represents an efficient way to control communicable diseases. Reliable vaccines would reduce the use of anthelmintics drugs and fight against the concern of anthelmintics resistances. Unfortunately, anthelmintic vaccines face many difficulties in their development. One of the most innovative vaccine models in this field is multiepitope vaccines since, based on advances in immunoinformatics, they facilitate immunization against parasites at different stages of their cycles. Objective: In this study, we evaluate the published efficacy of multiepitope vaccines against helminths. Methods: Independent reviewers conducted a comprehensive search of multiple databases until 20 September 2024, following PRISMA 2020 guidelines. The review included original in vivo protection studies using chimeric vaccines with antigenic epitopes in experimental models. Key information was summarized, tabulated, and analyzed, and risk of bias was assessed using the SYRCLE risk tool. Results: A total of 15 preclinical studies were included. In those immunization experiments, parasite load reductions varied from 12.4% to 100%. Conclusions: Overall, this study shows protections in parasite load or lesion in 50–80% and significant survival rates using experimental vaccines including B- and T-cell epitopes in a wide range of helminthic infections. Given the variability of the experiments and the limited available data, there was not a clear correlation between protections and immune responses. Confirmation trials are needed to corroborate the protection and immunological mechanisms reached not only in this initial valuable study but also with other multiepitope candidates. Full article

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

47 pages, 1398 KiB

Open AccessReview

The Role of LAIR1 as a Regulatory Receptor of Antitumor Immune Cell Responses and Tumor Cell Growth and Expansion

by Alessandro Poggi, Serena Matis, Chiara Rosa Maria Uras, Lizzia Raffaghello, Roberto Benelli and Maria Raffaella Zocchi

Biomolecules 2025, 15(6), 866; https://doi.org/10.3390/biom15060866 (registering DOI) - 13 Jun 2025

Abstract

It is becoming evident that the therapeutic effect of reawakening the immune response is to limit tumor cell growth and expansion. The use of immune checkpoint inhibitors, like blocking antibodies against programmed cell death receptor (PD) 1 and/or cytotoxic T lymphocyte antigen (CTLA) [...] Read more.

It is becoming evident that the therapeutic effect of reawakening the immune response is to limit tumor cell growth and expansion. The use of immune checkpoint inhibitors, like blocking antibodies against programmed cell death receptor (PD) 1 and/or cytotoxic T lymphocyte antigen (CTLA) 4 alone or in combination with other drugs, has led to unexpected positive results in some tumors but not all. Several other molecules inhibiting lymphocyte antitumor effector subsets have been discovered in the last 30 years. Herein, we focus on the leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1/CD305). LAIR1 represents a typical immunoregulatory molecule expressed on almost all leukocytes, unlike other regulatory receptors expressed on discrete leukocyte subsets. It bears two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the intracytoplasmic protein domain involved in the downregulation of signals mediated by activating receptors. LAIR1 binds to several ligands, such as collagen I and III, complement component 1Q, surfactant protein D, adiponectin, and repetitive interspersed families of polypeptides expressed by erythrocytes infected with Plasmodium malariae. This would suggest LAIR1 involvement in several cell-to-cell interactions and possibly in metabolic regulation. The presence of both cellular and soluble forms of LAIR would indicate a fine regulation of the immunoregulatory activity, as happens for the soluble/exosome-associated forms of PD1 and CTLA4 molecules. As a consequence, LAIR1 appears to play a role in some autoimmune diseases and the immune response against tumor cells. The finding of LAIR1 expression on hematological malignancies, but also on some solid tumors, could open a rationale for the targeting of this molecule to treat neoplasia, either alone or in combination with other therapeutic options. Full article

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

15 pages, 3433 KiB

Open AccessArticle

A 3D Composite Model Using Electrospinning Technology to Study Endothelial Damage

by Carmen Ciavarella, Luana Di Lisa, Gianandrea Pasquinelli, Maria Letizia Focarete and Sabrina Valente

Biomolecules 2025, 15(6), 865; https://doi.org/10.3390/biom15060865 (registering DOI) - 13 Jun 2025

Abstract

Background: Endothelial dysfunction triggers atherosclerosis pathogenesis. This study aimed at developing a 3D scaffold model able to reproduce in vitro the human vascular intima and study the endothelial damage induced by oxidative low-density lipoproteins (ox-LDLs) and shear stress. (2) Methods: Three-dimensional sandwich-like scaffolds [...] Read more.

Background: Endothelial dysfunction triggers atherosclerosis pathogenesis. This study aimed at developing a 3D scaffold model able to reproduce in vitro the human vascular intima and study the endothelial damage induced by oxidative low-density lipoproteins (ox-LDLs) and shear stress. (2) Methods: Three-dimensional sandwich-like scaffolds were fabricated using electrospinning technology, functionalized with type I collagen and laminin, and subsequently coated with methacrylated gelatin hydrogel (GelMa) to achieve the final composite structure. Human umbilical vein endothelial cells (HUVECs) were used as the cell model for testing the suitability of 3D supports for cell culture exposed to ox-LDL both under static and shear stress conditions. Cell viability, ultrastructural morphology, and nitric oxide (NO) levels were analyzed. (3) Results: Electrospun mats and their functionalization were optimized to reproduce the chemical and physical properties of the vascular intima tunica. The 3D supports were suitable for the cell culture. Ox-LDL did not affect the HUVEC behavior in the 3D models under a static environment. Conversely, high shear stress (500 µL/min, HSS) significantly decreased the cell viability, also under the ox-LDL treatment. (4) Conclusions: Endothelial cell cultures on electrospun supports exposed to HSS provide a candidate in vitro model for investigating the endothelial dysfunction in atherosclerosis research. Technical improvements to the experimental setting are necessary for validating and standardizing the suggested 3D model. Full article

(This article belongs to the Special Issue Biomolecules and Biomaterials for Tissue Engineering, 2nd Edition)

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17 pages, 1389 KiB

Open AccessFeature PaperReview

Drug Transporters and Metabolizing Enzymes in Antimicrobial Drug Pharmacokinetics: Mechanisms, Drug–Drug Interactions, and Clinical Implications

by Kaili Lin, Ruoqing Wang, Tong Li, Yawen Zuo, Shilei Yang, Deshi Dong and Yanna Zhu

Biomolecules 2025, 15(6), 864; https://doi.org/10.3390/biom15060864 - 13 Jun 2025

Abstract

Drug transporters and metabolizing enzymes are integral components of drug disposition, governing the absorption, distribution, metabolism, and excretion (ADME) of pharmaceuticals. Their activities critically determine therapeutic efficacy and toxicity profiles, particularly for antimicrobial agents, one of the most widely prescribed drug classes frequently [...] Read more.

Drug transporters and metabolizing enzymes are integral components of drug disposition, governing the absorption, distribution, metabolism, and excretion (ADME) of pharmaceuticals. Their activities critically determine therapeutic efficacy and toxicity profiles, particularly for antimicrobial agents, one of the most widely prescribed drug classes frequently co-administered with other medications. Emerging evidence highlights the clinical significance of the drug–drug interactions (DDIs) mediated by these systems, which may alter antimicrobial pharmacokinetics, compromise treatment outcomes, or precipitate adverse events. With the continuous introduction of novel antimicrobial agents into clinical practice, the role of drug transporters and metabolizing enzymes in the pharmacokinetics of antibiotics and the DDIs between antibiotics and other drugs mediated by these transporters and enzymes are important to determine in order to provide a theoretical basis for the safe and effective use of antimicrobial drugs in clinical use. Full article

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

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16 pages, 5646 KiB

Open AccessArticle

Retinoic-Acid-Related Orphan Receptor Alpha Is Involved in the Regulation of the Cytoskeleton of Hair Follicle Stem Cells

by Yu Zhang, Xuefei Zhao, Shuqi Li, Suying Bai and Wei Zhang

Biomolecules 2025, 15(6), 863; https://doi.org/10.3390/biom15060863 - 13 Jun 2025

Abstract

The development and replacement of hair play a significant role in the life history of animals. In recent years, retinoic-acid-related orphan receptor alpha (Rorα) has been found to participate in the regulation of hair follicle development, yet the underlying mechanisms remain [...] Read more.

The development and replacement of hair play a significant role in the life history of animals. In recent years, retinoic-acid-related orphan receptor alpha (Rorα) has been found to participate in the regulation of hair follicle development, yet the underlying mechanisms remain incompletely understood. This study aims to analyze the regulatory role of Rorα on the cytoskeleton of hair follicle stem cells (HFSCs). We treated HFSCs with a RORA agonist and subsequently analyzed differential gene expression using qPCR, Western blotting, and immunofluorescence, finding that agonist-induced activation of RORA suppressed the expression levels of cytoskeleton-related genes. Additionally, F-actin staining with phalloidin, followed by migration assays and wound healing tests for cell migration detection, revealed that this process affected the cytoskeletal state of HFSCs and inhibited their migration and adhesion capabilities. We further conducted interaction analyses using CUT&RUN combined with ddPCR and EMSA, demonstrating that RORA can bind to the promoter regions of the Actg1 gene and regulate their transcription. This study contributes to a comprehensive understanding of the regulatory processes involved in hair follicle development and may provide broader insights into the treatment of diseases such as alopecia. Full article

(This article belongs to the Section Cellular Biochemistry)

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19 pages, 5427 KiB

Open AccessArticle

Long-Term Exercise Mitigates Energy Expenditure and Inflammatory Responses Induced by Sleep Deprivation in Mice

by Tian-Shu Zheng, Xin-Ran Gao, Chen Gu, Yu-Ning Ru, Rui-Ping Xu, Yu-Hang Yang and De-Hua Wang

Biomolecules 2025, 15(6), 862; https://doi.org/10.3390/biom15060862 - 13 Jun 2025

Abstract

Background: Sleep deprivation (SD), defined as the disruption or loss of normal sleep, negatively affects energy metabolism, immune function, and gut microbiota in both humans and animals. Although SD has detrimental effects, it is often unavoidable due to work or study demands. [...] Read more.

Background: Sleep deprivation (SD), defined as the disruption or loss of normal sleep, negatively affects energy metabolism, immune function, and gut microbiota in both humans and animals. Although SD has detrimental effects, it is often unavoidable due to work or study demands. Exercise has been shown to improve sleep quality, regulate metabolism, and enhance immune function. However, whether exercise can mitigate the adverse effects of unavoidable SD remains unclear. Methods: To explore the protective effects of exercise against SD-induced gut microbiota and metabolic dysfunction, mice were randomly assigned to four groups: control (CTR), exercise (EXE), SD, and exercise + SD (EXE + SD). Inflammatory markers and gut microbiota composition were analyzed to assess the impacts of SD and exercise interventions. Results: The inflammatory levels and energy metabolism in SD mice were significantly increased compared to those in CTR mice. Compared with SD mice, EXE + SD mice had a more stable gut microbiota structure and higher butyrate levels. Meanwhile, the inflammatory response caused by SD was also inhibited by exercise preconditioning. Both lipopolysaccharide inhibitors injection and butyrate supplementation can partially alleviate the elevation of inflammatory response and energy metabolism caused by SD. Conclusion: The inflammation and energy metabolism disorders in mice caused by SD can be inhibited by exercise preconditioning through stabilizing the structure of gut microbiota. This protective effect is highly likely related to the increase in butyric acid levels caused by exercise. Full article

(This article belongs to the Section Cellular Biochemistry)

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Graphical abstract

36 pages, 6162 KiB

Open AccessReview

Biomolecule-Based Coacervation: Mechanisms, Applications, and Future Perspectives in Biomedical and Biotechnological Fields

by Dong Hyun Kim, Mi-Ran Ki, Da Yeon Chung and Seung Pil Pack

Biomolecules 2025, 15(6), 861; https://doi.org/10.3390/biom15060861 - 13 Jun 2025

Abstract

Coacervate is a form of liquid–liquid phase separation (LLPS) in which a solution containing one or more charged components spontaneously separates into two immiscible liquid phases. Due to their ability to mimic membraneless cellular environments and their high biocompatibility, coacervates have found broad [...] Read more.

Coacervate is a form of liquid–liquid phase separation (LLPS) in which a solution containing one or more charged components spontaneously separates into two immiscible liquid phases. Due to their ability to mimic membraneless cellular environments and their high biocompatibility, coacervates have found broad applications across various fields of life sciences. This review provides a comprehensive overview of recent advances in biomolecule-based coacervation for biotechnological and biomedical applications. Encapsulation via biomolecule-based coacervation enables high encapsulation efficiency, enhanced stability, and the sustained release of cargos. In the field of tissue engineering, coacervates not only support cell adhesion and proliferation but also serve as printable bioinks with tunable rheological properties for 3D bioprinting. Moreover, biomolecule-based coacervates have been utilized to mimic membraneless organelles, serving as experimental models to understand the origin of life or investigate the mechanisms of biochemical compartmentalization. This review discusses the mechanisms of coacervation induced by various types of biomolecules, evaluates their respective advantages and limitations in applied contexts, and outlines future research directions. Given their modularity and biocompatibility, biomolecule-based coacervates are expected to play a pivotal role in next-generation therapeutic development and the construction of controlled tissue microenvironments, especially when integrated with emerging technologies. Full article

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

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19 pages, 1191 KiB

Open AccessReview

Targeting Senescence: A Review of Senolytics and Senomorphics in Anti-Aging Interventions

by Timur Saliev and Prim B. Singh

Biomolecules 2025, 15(6), 860; https://doi.org/10.3390/biom15060860 - 13 Jun 2025

Abstract

Cellular senescence is a fundamental mechanism in aging, marked by irreversible growth arrest and diverse functional changes, including, but not limited to, the development of a senescence-associated secretory phenotype (SASP). While transient senescence contributes to beneficial processes such as tissue repair and tumor [...] Read more.

Cellular senescence is a fundamental mechanism in aging, marked by irreversible growth arrest and diverse functional changes, including, but not limited to, the development of a senescence-associated secretory phenotype (SASP). While transient senescence contributes to beneficial processes such as tissue repair and tumor suppression, the persistent accumulation of senescent cells is implicated in tissue dysfunction, chronic inflammation, and age-related diseases. Notably, the SASP can exert both pro-inflammatory and immunosuppressive effects, depending on cell type, tissue context, and temporal dynamics, particularly in early stages where it may be profibrotic and immunomodulatory. Recent advances in senotherapeutics have led to two principal strategies for targeting senescent cells: senolytics, which selectively induce their apoptosis, and senomorphics, which modulate deleterious aspects of the senescence phenotype, including the SASP, without removing the cells. This review critically examines the molecular mechanisms, therapeutic agents, and clinical potential of both approaches in the context of anti-aging interventions. We discuss major classes of senolytics, such as tyrosine kinase inhibitors, BCL-2 family inhibitors, and natural polyphenols, alongside senomorphics including mTOR and JAK inhibitors, rapalogs, and epigenetic modulators. Additionally, we explore the biological heterogeneity of senescent cells, challenges in developing specific biomarkers, and the dualistic role of senescence in physiological versus pathological states. The review also highlights emerging tools, such as targeted delivery systems, multi-omics integration, and AI-assisted drug discovery, which are advancing precision geroscience and shaping future anti-aging strategies. Full article

(This article belongs to the Special Issue Molecular Advances in Mechanism and Regulation of Lifespan and Aging)

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23 pages, 15181 KiB

Open AccessArticle

Physiological Mechanisms and Core Genes in Response to Saline-Alkali Stress in Foxtail Millet (Setaria italica L.)

by Huimin Wang, Yun Li, Yanan Yang, Yanrui Xu, Xiaoying Fan, Zhenqing Guo, Yucui Han and Xiaohu Lin

Biomolecules 2025, 15(6), 859; https://doi.org/10.3390/biom15060859 - 12 Jun 2025

Abstract

Soil salinization and alkalization are becoming increasingly severe in recent decades, which poses serious threats to crop production and food security in the world. Foxtail millet (Setaria italica L.) is an important cereal crop in China, and it is important to elucidate [...] Read more.

Soil salinization and alkalization are becoming increasingly severe in recent decades, which poses serious threats to crop production and food security in the world. Foxtail millet (Setaria italica L.) is an important cereal crop in China, and it is important to elucidate its saline-alkali tolerance mechanisms for the breeding of new saline-alkali tolerant varieties. In this study, we used 75% seawater to treat two foxtail millet varieties with different saline-alkali tolerances (JK3, saline-alkali tolerant; B175, saline-alkali sensitive) during the seedling stage, and conducted morphological, cellular ultrastructure, physiological, and transcriptomic analyses on the two varieties. The morphological analysis of the saline-alkali response indicated that JK3 exhibited stronger saline-alkali tolerance than B175. The results of the cellular ultrastructure showed that under saline-alkali stress, JK3 had a more intact leaf cell structure than B175, indicating that saline-alkali stress causes less damage to its cells. The physiological analysis of saline-alkali response indicated that JK3 had consistently higher activities of catalase and polyphenol oxidase, as well as higher contents of soluble sugars and soluble proteins at 48–120 h than B175. Transcriptomic analysis revealed that JK3 enhanced its saline-alkali tolerance by positively regulating pathways such as tryptophan/fatty acid metabolism, the MAPK signaling pathway, and peroxisome pathways. Further, WGCNA combining morphological and physiological indicators identified four key modules and five functional pathways (MAPK signaling, glycerolipid metabolism, phosphate and phosphonate metabolism, galactose metabolism, and endoplasmic reticulum protein processing) in response to saline-alkali stress, and identified a total of 24 core genes. Functional annotation indicated that these genes may be involved in the response to saline-alkali stress. These findings lay a foundation for in-depth studies of the molecular mechanisms for saline-alkali tolerance in foxtail millet. Full article

(This article belongs to the Section Biological Factors)

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41 pages, 10349 KiB

Open AccessReview

Recent Advances in Monitoring Technologies for Cardiac Troponin I: A Pivotal Biomarker in Cardiovascular Diseases

by Ning Zhang, Yusong Wang, Fachuang Li, Yuxin Zhu, Zheng Fu, Mengda Jia, Xiaoran Zhan and Wanqing Zhang

Biomolecules 2025, 15(6), 858; https://doi.org/10.3390/biom15060858 - 12 Jun 2025

Abstract

Cardiovascular diseases (CVDs) are among the leading causes of morbidity and mortality rates globally, presenting a severe threat to human health and life. Acute myocardial infarction (AMI) is one of the most common and extremely severe disorders within CVDs, causing an estimated 17.5 [...] Read more.

Cardiovascular diseases (CVDs) are among the leading causes of morbidity and mortality rates globally, presenting a severe threat to human health and life. Acute myocardial infarction (AMI) is one of the most common and extremely severe disorders within CVDs, causing an estimated 17.5 million deaths each year. Cardiac troponin I (cTnI) is considered a biomarker for myocardial infarction and a “gold standard” method for diagnosing AMI due to its high specificity and sensitivity. The ability to rapidly detect cTnI with high sensitivity is critical throughout the diagnosis and treatment process of AMI. It is a necessary precursor for doctors to quickly assess the disease and initiate subsequent therapies. This work comprehensively explores various techniques for the analysis and detection of cTnI. We systematically review current cutting-edge technologies used for cTnI detection. According to optical, electrical, and intelligent technology dimensions, this study meticulously classifies and elaborates on the research progress of related sensors. Based on current research findings and technological development trends, we further project the future research directions and application prospects of cTnI sensors. This is geared towards providing valuable references for the further development of this field. Full article

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19 pages, 7559 KiB

Open AccessArticle

The SlymiR394-ZDS Module Enhances the Antioxidant Capacity of Tomato by Promoting Lycopene Synthesis

by Qiuyu Zhao, Li Zhao, Jiuzhi Shi, Xiaoxiao Chen, Zhenchao Yang and Yongjun Wu

Biomolecules 2025, 15(6), 857; https://doi.org/10.3390/biom15060857 - 12 Jun 2025

Abstract

Lycopene, a natural pigment, is valuable for human health because of its strong antioxidant capacity. However, studies on the involvement of tomato miR394 in the regulation of lycopene have not been reported. The aim of this study was to reveal the molecular mechanism [...] Read more.

Lycopene, a natural pigment, is valuable for human health because of its strong antioxidant capacity. However, studies on the involvement of tomato miR394 in the regulation of lycopene have not been reported. The aim of this study was to reveal the molecular mechanism by which miR394 regulates lycopene synthesis by targeting ζ-carotene dehydrogenase (ZDS). The miR394-silenced transgenic tomato plants were constructed by short tandem target mimicry (STTM) technology, and the association between lycopene content and antioxidant capacity was analyzed by combining qRT-PCR, UV spectrophotometry, and a free radical scavenging assay. The targeting relationship between miR394 and ZDS was verified using a subcellular localization assay. The results showed that the silencing of miR394 significantly upregulated the expression of the ZDS gene and promoted lycopene accumulation. The antioxidant enzyme activities of STTM394 transgenic plants were significantly enhanced, and the free radical scavenging ability was obviously improved. Subcellular localization experiments confirmed that miR394 directly inhibited the chloroplast expression of ZDS. In conclusion, this study reveals for the first time that the miR394-ZDS module enhances the antioxidant capacity by regulating lycopene metabolism, which provides a new target for themolecular breeding of highly nutritious tomatoes. Full article

(This article belongs to the Section Biological Factors)

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12 pages, 1208 KiB

Open AccessReview

Role of SOST in Response to Mechanical Stimulation in Bone and Extraosseous Organs

by Minyou Chen, Wenjing Li, Le Lei and Lingli Zhang

Biomolecules 2025, 15(6), 856; https://doi.org/10.3390/biom15060856 - 11 Jun 2025

Abstract

Sclerostin (SOST) is a specific osteocyte protein. During the differentiation and proliferation of osteoblasts and osteoclasts, the high expression of SOST can inhibit bone formation and contribute to osteoporosis and the bone metastasis of malignant tumors. Most of the research on SOST has [...] Read more.

Sclerostin (SOST) is a specific osteocyte protein. During the differentiation and proliferation of osteoblasts and osteoclasts, the high expression of SOST can inhibit bone formation and contribute to osteoporosis and the bone metastasis of malignant tumors. Most of the research on SOST has focused on bone cells, but studies have found that SOST is not a specific product of bone cells but that it is also expressed by articular chondrocytes. SOST can regulate the progression of osteoarthritis in bone and cartilage, promote subchondral bone sclerosis, and inhibit cartilage degeneration. A review of the literature found that SOST can not only regulate bone metabolism, but it is also expressed in cardiovascular, kidney, liver, and other tissues, influencing the occurrence and development of diseases in these organs and tissues. Studies have found that diseases of extra-bone organs, such as atherosclerosis, aneurysm, chronic kidney disease, and cirrhosis, may be related to the expression of SOST. Simultaneously, long-term exercise can reduce SOST levels, especially in areas of high bone strain. Prolonged exercise induces bone adaptation to mechanical stress, resulting in diminished responsiveness of bone cells to exercise and a reduction in serum SOST levels. Short-term acute exercise can elevate serum SOST levels, but these results are often limited by age, gender, and energy status. In general, serum SOST rises immediately after short-term acute exercise, returning to baseline or even decreasing after exercise. Full article

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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34 pages, 7701 KiB

Open AccessArticle

Docking Simulations of G-Protein Coupled Receptors Uncover Crossover Binding Patterns of Diverse Ligands to Angiotensin, Alpha-Adrenergic and Opioid Receptors: Implications for Cardiovascular Disease and Addiction

by Harry Ridgway, Graham J. Moore, Laura Kate Gadanec and John M. Matsoukas

Biomolecules 2025, 15(6), 855; https://doi.org/10.3390/biom15060855 - 11 Jun 2025

Abstract

Recent bioassay studies have unexpectedly supported the high (computationally predicted) binding affinities of angiotensin receptor blockers (ARBs) at α-adrenergic receptors (αARs) in isolated smooth muscle. Computational predictions from ligand docking studies are consistent with very low concentrations of ARBs (e.g., sartans or bisartans) [...] Read more.

Recent bioassay studies have unexpectedly supported the high (computationally predicted) binding affinities of angiotensin receptor blockers (ARBs) at α-adrenergic receptors (αARs) in isolated smooth muscle. Computational predictions from ligand docking studies are consistent with very low concentrations of ARBs (e.g., sartans or bisartans) that partially reduce (20–50%) the contractile response to phenylephrine, suggesting that some ARBs may function as partial inverse agonists at αARs. Virtual ligand screening (docking) and molecular dynamics (MD) simulations were carried out to explore the binding affinities and stabilities of selected non-peptide ligands (e.g., ARBs and small-molecule opioids) for several G-protein coupled receptor (GPCR) types, including angiotensin II (AngII) type 1 receptor (AT₁R), α1AR, α2AR, and μ-(µOR) and ժ-opioid receptors (ժOR). Results: All ligands docked preferentially to the binding pocket on the cell surface domain of the GPCR types investigated. Drug binding was characterized by weak interactions (hydrophobic, hydrogen bonding, pi-pi) and stronger ionic and salt-bridge interactions (cation-pi and cation-anion interactions). Ligands specific to each GPCR category showed considerable cross-binding with alternative GPCRs, with small-molecule medications appearing less selective than their peptide or ARB functional equivalents. ARBs that exhibit higher affinities for AT₁R also demonstrate higher affinities for µORs and ժORs than opiate ligands, such as fentanyl and naltrexone. Moreover, ARBs had a higher affinity for αARs than either alpha agonists (epinephrine and phenylephrine) or inhibitors (prazosin and doxazosin). MD simulations of membrane-embedded ARB-GPCR complexes proved stable over nanosecond time scales and suggested that some ARBs may behave as agonists or antagonists depending on the GPCR type. Based on the results presented in this and related investigations, we propose that agonists bind to the resting A-site of GPCRs, while inverse agonists occupy the desensitizing D-site, which partial agonists like morphine and fentanyl share, contributing to addiction. ARBs block both AngII and alpha receptors, suggesting that they are more potent antihypertensive drugs than ACE inhibitors. ARBs have the potential to inhibit morphine tolerance and appear to disrupt receptor desensitization processes, potentially by competing at the D-site. Our results suggest the possible therapeutic potential of ARBs in treating methamphetamine and opiate addictions. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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34 pages, 2009 KiB

Open AccessReview

The Multifaceted Role of Calcium Signaling in Regulated Necrosis

by Eric Perez-Rivera, Claudia Plasencia and Uris Ros

Biomolecules 2025, 15(6), 854; https://doi.org/10.3390/biom15060854 - 11 Jun 2025

Abstract

Calcium is a versatile ion that regulates diverse intracellular processes, including cell death and survival, cytokine and chemokine production, lipid scrambling, and immune cell activation. In regulated necrosis, an early increase in cytosolic calcium is a hallmark of pathways such as pyroptosis, necroptosis, [...] Read more.

Calcium is a versatile ion that regulates diverse intracellular processes, including cell death and survival, cytokine and chemokine production, lipid scrambling, and immune cell activation. In regulated necrosis, an early increase in cytosolic calcium is a hallmark of pathways such as pyroptosis, necroptosis, and ferroptosis, and resembles the calcium surge triggered by pore-forming toxins. The complexity of calcium signaling is orchestrated by specialized channels in various cellular compartments and calcium-binding proteins that respond to localized calcium concentrations. However, the coordination of this intricate code during regulated necrosis and its connections to other calcium-driven processes remains poorly understood. This review provides an overview of the molecular mechanisms of calcium signaling in regulated necrosis, analyzing parallels with pore-forming toxin-mediated membrane damage to uncover nodes that are shared by these seemingly independent pathways. We also discuss advanced techniques for studying calcium dynamics, with high precision, that can be applied to study regulated necrosis. Calcium signaling emerges as a central hub where necrotic cell death pathways converge, shaping the unique signatures of dying cells and influencing their communication with the immune system. This integrated perspective highlights the complex and multifaceted role of calcium in cells and its implications for fundamental cellular processes. Full article

(This article belongs to the Special Issue Necrotic Cell Death Mechanisms and Therapies)

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