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Biomolecules

Biomolecules is an international, peer-reviewed, open access journal on structures and functions of bioactive and biogenic substances, molecular mechanisms with biological and medical implications as well as biomaterials and their applications, published monthly online by MDPI.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q1 (Biochemistry and Molecular Biology) / CiteScore - Q1 (Biochemistry)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 17.9 days after submission; acceptance to publication is undertaken in 2.9 days (median values for papers published in this journal in the second half of 2025).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Sections: published in 15 topical sections.
Testimonials: See what our editors and authors say about Biomolecules.
Companion journal: Receptors.

Impact Factor: 4.8 (2024); 5-Year Impact Factor: 5.6 (2024)

Imprint Information Journal Flyer Open Access ISSN: 2218-273X

Latest Articles

14 pages, 2174 KB

Open AccessArticle

PFAS Compounds Display Distinct Toxicological Effects in Drosophila melanogaster, Reflected by Reduced Viability and Impaired Neuronal Function

by Klara Luedtke, Cristian Blanco Rocha, Magdalena Svensson and Ann-Christin Brorsson

Biomolecules 2026, 16(4), 557; https://doi.org/10.3390/biom16040557 (registering DOI) - 9 Apr 2026

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals associated with a wide range of adverse health effects, yet individual PFAS compounds may exert distinct toxicological mechanisms. In this study, we investigate the toxic effects of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) [...] Read more.

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals associated with a wide range of adverse health effects, yet individual PFAS compounds may exert distinct toxicological mechanisms. In this study, we investigate the toxic effects of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) in Drosophila melanogaster using survival assays and measurements of acetylcholinesterase (AChE) activity as indicators of systematic toxicity and neurotoxicity, respectively. Male flies were exposed to PFOA and PFNA under different feeding conditions, concentrations, and temperatures. Both compounds reduced fly viability and impaired neuronal function, but with markedly different toxicological profiles. PFNA caused a pronounced, concentration-dependent reduction in lifespan under all tested conditions, indicating a strong systemic toxicity. In contrast, PFOA exerted a comparatively weaker effect on survival but induced a more pronounced reduction in AChE activity, consistent with enhanced neurotoxicity. PFOA-induced neurotoxicity in Drosophila may represent early molecular events that predispose neurons to degeneration, contributing to conditions such as dementia. Together, these findings demonstrate that structurally similar PFAS compounds can induce distinct toxicological outcomes and highlight the importance of evaluating individual PFAS using complementary assays. Moreover, this study underscores the utility of Drosophila melanogaster as a sensitive and mechanistically informative model for dissecting compound-specific PFAS toxicity. Full article

(This article belongs to the Special Issue Advances in Drosophila Models for Amyloid and Neurodegenerative Diseases)

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21 pages, 3016 KB

Open AccessArticle

Dose- and Organ-Specific Dual Effects of MitoTempo in Paracetamol-Induced Hepatorenal Toxicity in Mice

by Hilmi Orhan, Kemal Atmaca, Berin Aladağ and Mustafa Kotmakçı

Biomolecules 2026, 16(4), 556; https://doi.org/10.3390/biom16040556 - 9 Apr 2026

Paracetamol (PAR) overdose is a major cause of drug-induced liver injury and is also associated with renal toxicity, both involving mitochondrial dysfunction and oxidative stress. This study investigated the dose- and organ-specific effects of the mitochondria-targeted antioxidant MitoTempo (MT) on PAR-induced hepatorenal toxicity [...] Read more.

Paracetamol (PAR) overdose is a major cause of drug-induced liver injury and is also associated with renal toxicity, both involving mitochondrial dysfunction and oxidative stress. This study investigated the dose- and organ-specific effects of the mitochondria-targeted antioxidant MitoTempo (MT) on PAR-induced hepatorenal toxicity in mice. Male C57BL/6J mice received a single toxic dose of PAR (600 mg/kg), either alone or combined with MT (20 or 40 mg/kg). Twenty-four hours after treatment, serum markers of liver and kidney injury were measured, and mitochondrial function was assessed in both organs. PAR administration caused severe liver injury and moderate renal dysfunction, accompanied by increased mitochondrial oxidative stress, glutathione imbalance, mitochondrial permeability transition pore opening, and disruption of electron transport chain (ETC) integrity. MT co-treatment attenuated several PAR-induced mitochondrial alterations in a dose- and tissue-dependent manner; however, MT did not consistently confer protection and, in some settings, exacerbated oxidative stress and bioenergetic dysfunction, particularly in the kidney. Notably, recovery of ETC protein levels by MT was not consistently associated with restoration of enzymatic activity. Overall, these findings demonstrate that MT exerts dual, dose- and organ-specific effects on PAR-induced mitochondrial dysfunction, highlighting that mitochondria-targeted antioxidants are not universally protective. Full article

(This article belongs to the Special Issue Acute Kidney Injury and Mitochondrial Involvement)

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16 pages, 10760 KB

Open AccessArticle

mTOR Activation Is Required for the Proliferation of Reactive Astrocytes in the Hippocampus During Traumatic Brain Injury

by Lilesh Kumar Pradhan, Xiaoting Wang, Fang Yuan and Xiang Gao

Biomolecules 2026, 16(4), 555; https://doi.org/10.3390/biom16040555 - 9 Apr 2026

Astrocytes undergo pronounced reactivity during traumatic brain injury (TBI); however, the temporal dynamics of this response and the signaling mechanisms regulating astrocyte proliferation remain incompletely defined. In this study, we characterized the spatiotemporal profile of astrocyte reactivity and proliferation in the hippocampus during [...] Read more.

Astrocytes undergo pronounced reactivity during traumatic brain injury (TBI); however, the temporal dynamics of this response and the signaling mechanisms regulating astrocyte proliferation remain incompletely defined. In this study, we characterized the spatiotemporal profile of astrocyte reactivity and proliferation in the hippocampus during TBI and investigated the involvement of mammalian target of rapamycin complex 1 (mTORC1) signaling in these processes. Using a mouse model of TBI, we found that injury triggered a rapid astrocytic response in the hippocampus, characterized by increased glial fibrillary acidic protein (GFAP) expression and morphological hypertrophy as early as 4 h post-injury. Astrocyte proliferation emerged subsequently, peaked during the acute phase (48 and 72 h), and declined to baseline levels at 7 days post-trauma, indicating a transient proliferative response during TBI. Concurrently, mTORC1 signaling was robustly activated in reactive astrocytes in the hippocampus and was specifically associated with proliferative reactive astrocytes during injury. Pharmacological inhibition of mTORC1 signaling with rapamycin significantly reduced reactive astrocyte proliferation during TBI without altering astrocytic hypertrophy. Together, these findings demonstrate that TBI induces a rapid but transient astrocyte activation and proliferation response in the hippocampus and that mTORC1 activation is required for the proliferation, but not the hypertrophic activation, of reactive astrocytes during traumatic brain injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Traumatic Brain Injury)

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20 pages, 4966 KB

Open AccessArticle

An Electrospun Fibrous Eye Mask with Antibacterial and Antioxidant Functions

by Xinhang Duan, Leting Wang, Chuxuan Cheng, Yili Zhang, Bingyue Guo, Hantong Wang, Jinghui Shi and Wenliang Song

Biomolecules 2026, 16(4), 554; https://doi.org/10.3390/biom16040554 - 9 Apr 2026

Ocular infections and inflammation represent a clear risk to eye health, but standard eye masks often lack the necessary therapeutic features. Moreover, most existing studies employ a blended electrospinning approach, which leads to an inhomogeneous spatial distribution of the therapeutic agents. However, using [...] Read more.

Ocular infections and inflammation represent a clear risk to eye health, but standard eye masks often lack the necessary therapeutic features. Moreover, most existing studies employ a blended electrospinning approach, which leads to an inhomogeneous spatial distribution of the therapeutic agents. However, using the coaxial technique can address these limitations. This study develops a coaxial electrospun nanofibrous eye mask with dual antibacterial and antioxidant functions, aiming to provide an innovative ocular treatment tool for eye care. Generally, a core-shell structured bilayer polycaprolactone-polylysine/polyvinyl alcohol-resveratrol (PCL-PLs/PVA-RSV) membrane is successfully prepared by coaxial electrospinning, where the core is resveratrol-loaded PVA and the shell is PLs-loaded PCL. Results show uniform fiber morphology, favorable hydrophilicity, and potential for sustained release due to core-shell design. The membrane significantly inhibits the growth of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli); at the same time, it exhibits excellent free radical scavenging ability and good component biocompatibility, achieving slow release of the two drugs and long-term antioxidant effect. This multifunctional platform offers a synergistic approach to combating microbial infection and oxidative stress, showing great potential for eye care. Full article

(This article belongs to the Section Bio-Engineered Materials)

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21 pages, 918 KB

Open AccessReview

The Role of Neutrophil, Monocyte and Macrophage Calprotectin and S100A12 in the Fibrotic Process

by Nora Elemi Regino-Zamarripa, Ana Sofía Burciaga, Moisés Bocanegra-Mondragón, Alfredo Cruz-Lagunas, Ángel Camarena, Luis Jiménez-Alvarez, Remedios Ramírez, Gustavo Ramírez-Martínez and Joaquín Zúñiga

Biomolecules 2026, 16(4), 553; https://doi.org/10.3390/biom16040553 - 9 Apr 2026

Fibrosis is a progressive and irreversible mechanism affecting any organ. During tissue injury, fibroblast activation is necessary for wound healing but the uncontrolled accumulation of fibrotic tissue leads to local organ damage. The fibrotic process involves the excessive accumulation of extracellular matrix components [...] Read more.

Fibrosis is a progressive and irreversible mechanism affecting any organ. During tissue injury, fibroblast activation is necessary for wound healing but the uncontrolled accumulation of fibrotic tissue leads to local organ damage. The fibrotic process involves the excessive accumulation of extracellular matrix components and inflammatory mediators. Since sustained inflammation precedes fibrosis, the involvement of immune cells, like neutrophils, monocytes and macrophages, is crucial to elucidate its pathogenesis. These immune cells release proinflammatory cytokines and chemokines, and also proteins that act as fibroblast proliferation mediators, such as the S100/calgranulins subgroup, comprising S100A8, S100A9, and S100A12 proteins. Moreover, a homodimer of S100A8 binds to a homodimer of S100A9 forming the heterodimer S100A8/A9, called calprotectin, which is abundant in the cytosol of neutrophils during immune activation. Although calprotectin (S100A8/A9) is the most predominant form, calgranulins S100A8 and S100A9 have independent functions of calprotectin (S100A8/9) complex formation. These calcium-binding proteins have proinflammatory functions and are potential inflammation biomarkers. More evidence in different fibrosis disorders highlights their role as relevant fibroblast proliferation mediators and prognosis markers. Hence, this review focuses on the current understanding of the role of S100A8, S100A9, and S100A12 calgranulins and calprotectin (S100A8/A9) in the fibrotic process of different disorders, and their potential application as disease severity and prognosis biomarkers. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration: From Molecular and Cellular Mechanisms to New Approaches)

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33 pages, 8679 KB

Open AccessArticle

Electrophysiological Characterization of the Venom and Toxins from the Scorpion Tityus championi Targeting Voltage-Gated Sodium Channels and Molecular Modeling of Tch3, a Toxin with Therapeutic Potential for Pain Relief

by Galit Akerman-Sánchez, Steve Peigneur, Kathleen Carleer, Natalia Ortiz, Felipe Navia, Leonardo Fierro, Santiago Castaño, Cecilia Díaz, Jan Tytgat and Oscar Brenes

Biomolecules 2026, 16(4), 552; https://doi.org/10.3390/biom16040552 - 8 Apr 2026

Scorpion neurotoxins are small peptides that target ion channels and offer opportunities for novel therapeutic discovery. This study analyzed the functional effects of the venom and toxins from the Costa Rican endemic scorpion, Tityus championi. Initially, crude venom was tested on different [...] Read more.

Scorpion neurotoxins are small peptides that target ion channels and offer opportunities for novel therapeutic discovery. This study analyzed the functional effects of the venom and toxins from the Costa Rican endemic scorpion, Tityus championi. Initially, crude venom was tested on different isoforms of voltage-gated sodium channels. Our findings revealed that the venom contains toxins that affect mammalian Na_V1.6 and Na_V1.7, as well as the cockroach BgNa_V1 channel. Increased currents through Na_V1.6 and BgNa_V1 channels were associated with bigger window currents and inhibition of inactivation. Decreased Na_V1.7 currents were associated with smaller conductance. Crude venom and TCh3 toxin inhibited action potential generation in invertebrate neurons expressing Na_V1.7-like channels. In these neurons, Tch2 and Tch4 toxins shifted voltage sensitivity to more negative potentials, ultimately widening the window current but decreasing channel availability. Conversely, Tch3 behaved as an inhibitory toxin, closing window currents and decreasing channel availability. Structural modeling showed that Tch3 adopts an αββ fold and binds the S3–S4 loop of Domain II in human Na_V1.7. These data show the diverse effects of scorpion venoms on channels and neurons, characterize its principal toxins, and show that Tch3 has therapeutic potential for pain relief. Full article

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

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24 pages, 3547 KB

Open AccessArticle

DNA Binding, DNA Photocleavage, Molecular Docking Studies and Photo-Induced Effect on Melanoma Cells of 2-Methyl-3-OR Quinazolinone Derivatives

by Chrysoula Mikra, Stella Malichetoudi, Dimitrios Arampatzis, Ioanna Laskari, Maria Koffa, Ewelina Wieczorek-Szweda, Katerina R. Katsani, George Psomas and Konstantina C. Fylaktakidou

Biomolecules 2026, 16(4), 551; https://doi.org/10.3390/biom16040551 - 8 Apr 2026

Thirty 2-methyl-quinazolinone fussed hydroxamic acids (3-OH) and their 3-OEt and 3-OBn derivatives were evaluated for their affinity towards calf-thymus (CT) DNA using UV-vis absorption, viscosity and fluorescence spectroscopy. DNA photocleavage activity was assessed by incubating the compounds with plasmid DNA followed by UV-A [...] Read more.

Thirty 2-methyl-quinazolinone fussed hydroxamic acids (3-OH) and their 3-OEt and 3-OBn derivatives were evaluated for their affinity towards calf-thymus (CT) DNA using UV-vis absorption, viscosity and fluorescence spectroscopy. DNA photocleavage activity was assessed by incubating the compounds with plasmid DNA followed by UV-A and visible light irradiation, which enabled identification of the most potent derivatives active at concentrations of 100 nΜ and 10 μΜ, respectively. Mechanistic studies on the most active compounds indicated the formation of oxygen radical species and a decrease in efficiency under argon. Measurements of singlet oxygen release verified these findings. Molecular docking studies provided further insight into the interactions between the compounds and DNA. UV-A irradiation of the most potent DNA photocleavers in three cell lines, two malignant melanoma lines (A375 and COLO-800) and the immortalized keratinocyte line HaCaT, identified three derivatives that, at a concentration up to 10 μΜ, reduced cell viability by approximately 50%. Taken together, these results indicate that these 2-methylquinazolinone-based hydroxamic acid derivatives are promising candidates for the development of photodynamic therapy agents. Full article

(This article belongs to the Section Chemical Biology)

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17 pages, 2290 KB

Open AccessArticle

French Propolis Caffeic Acid Derivatives Protect Skeletal Muscle from Oxidative Damages

by Luis Portillo-Lemus, Barbara Vernus, Béatrice Chabi, Aurélien Lebrun, Guillaume Cazals, Sylvie Rapior, Françoise Fons, Gilles Carnac and Sylvie Morel

Biomolecules 2026, 16(4), 550; https://doi.org/10.3390/biom16040550 - 8 Apr 2026

Propolis produced by honeybees, Apis mellifera, has been valued since ancient times as a remedy for different ailments for its broad medicinal properties. This wide range of biological activities may arise from the production of distinct propolis types within the hive, each [...] Read more.

Propolis produced by honeybees, Apis mellifera, has been valued since ancient times as a remedy for different ailments for its broad medicinal properties. This wide range of biological activities may arise from the production of distinct propolis types within the hive, each serving specific functions and containing unique molecular compositions. In this study, we investigated the effects of four propolis types—masonry, sealing, brood-protection, and intruder-neutralizing—on hydrogen peroxide (H₂O₂)-induced oxidative injury in human skeletal muscle cells. Among these, only brood-protection propolis significantly prevented the H₂O₂-induced loss of cell viability. Bio-guided fractionation of this active propolis identified five major compounds: benzyl caffeate (BC), caffeic acid phenethyl ester (CAPE), cinnamyl caffeate (CC), prenyl caffeate (PC), and (E)-3-methyl-3-butenyl caffeate (MBC), all displaying stronger cytoprotective effects than their ferulate equivalents. We finally demonstrated that propolis extract and its active compounds reduced lipid peroxidation in post-mortem minced mouse skeletal muscle and compared their efficacy to other natural compounds. Chemical analysis of resins from neighboring flora suggested that black poplar (Populus nigra) buds are the primary botanical source of these caffeate derivatives. Collectively, these results highlight the functional diversity of hive propolis and its potential applications in food preservation as well as in complementary and preventive medicine. Full article

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

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24 pages, 4606 KB

Open AccessArticle

CTCF Regulates Erythroid Differentiation Through Control of Core Erythroid Transcription Factors

by Lorena García-Gaipo, Vanessa Junco, Lucía García-Gutiérrez, Verónica Torrano, Rosa Blanco, Alexandra Wiesinger, Rujula Pradeep, Jose Luis Arroyo, Ana Batlle-López, Javier León, Manuel Rosa-Garrido and M. Dolores Delgado

Biomolecules 2026, 16(4), 549; https://doi.org/10.3390/biom16040549 - 8 Apr 2026

Erythropoiesis is tightly regulated by lineage-specific transcription factors that govern erythroid commitment, proliferation, and differentiation. A core erythroid transcriptional network, together with non-DNA-binding cofactors, occupies regulatory regions of genes essential for erythroid development. This process is further shaped by epigenetic mechanisms, including histone [...] Read more.

Erythropoiesis is tightly regulated by lineage-specific transcription factors that govern erythroid commitment, proliferation, and differentiation. A core erythroid transcriptional network, together with non-DNA-binding cofactors, occupies regulatory regions of genes essential for erythroid development. This process is further shaped by epigenetic mechanisms, including histone post-translational modifications and long-range chromatin interactions. CCCTC-binding factor (CTCF) is a multifunctional regulator with a central role in three-dimensional chromatin organization. Although CTCF has been implicated in hematopoietic differentiation and leukemogenesis, its specific function in erythropoiesis remains poorly defined. Here, we investigated the role of CTCF during erythroid differentiation using two complementary models: pluripotent K562 leukemia cells and primary human CD34⁺ hematopoietic stem/progenitor cells, each induced toward the erythroid lineage by distinct stimuli. In both systems, CTCF silencing impaired erythroid differentiation by repression of key erythroid transcription factor genes, including LMO2, KLF1, MYB, and ETS1. This repression was associated with enrichment of repressive histone marks at CTCF-binding sites within their regulatory regions. Moreover, CTCF cooperated with cohesin to establish and stabilize long-range chromatin interactions at these loci. These results provide new insight into how CTCF-dependent chromatin regulation contributes to normal erythroid development and suggest that perturbation of this regulatory axis may have implications for hematopoietic disorders and malignancies. Full article

(This article belongs to the Special Issue Current and Future Molecular Insights into Hematological Diseases: From Diagnosis to Therapy)

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Graphical abstract

20 pages, 2869 KB

Open AccessArticle

Behavior and Musculoskeletal Effects of Chronic D-Galactose Treatment in Mice: Role of Heme Oxygenase-1

by Sally Wahba, Olufunto O. Badmus, Andrew R. Wasson, Elshymaa A. Abdel-Hakeem, Merhan Mamdouh Ragy, Hanaa Mohamad Ibrahim, Daniela Rüedi-Bettschen and David E. Stec

Biomolecules 2026, 16(4), 548; https://doi.org/10.3390/biom16040548 - 8 Apr 2026

Chronic d-galactose (d-gal) treatment is a model to induce accelerated aging-like phenotypes in rodents. However, the sex differences in behavioral and musculoskeletal manifestations of this model are not well understood. Heme oxygenase-1 (HO-1) is a cytoprotective protein that may have anti-aging properties. The [...] Read more.

Chronic d-galactose (d-gal) treatment is a model to induce accelerated aging-like phenotypes in rodents. However, the sex differences in behavioral and musculoskeletal manifestations of this model are not well understood. Heme oxygenase-1 (HO-1) is a cytoprotective protein that may have anti-aging properties. The goal of this study was to better understand the sex differences in the behavioral and musculoskeletal effects of chronic d-gal treatment in C57BL/6J mice, as well as the role of HO-1 induction or inhibition. Eight-week-old male and female mice received daily saline or d-gal injections (500 mg/kg, s.c.) for 12 weeks. After this time, mice in the d-gal group were randomized into three groups (n = 6/group/sex): d-gal, d-gal + cobalt protoporphyrin (CoPP) (5 mg/kg, s.c. weekly), and d-gal + zinc deutroporphyrin bisglycol (ZnBG) (42 mg/kg, i.p. triweekly) for a period of 4 weeks. Open-field, novel-object recognition, Barnes maze, grip strength, micro-computed tomography (µ-CT), histology, and protein analysis were performed. Chronic d-gal treatment resulted in a sexual dimorphic response, with female mice being more prone to develop deficits in both short- and long-term spatial memory as well as in non-spatial memory. Male mice exhibited deficits only in long-term spatial memory when treated chronically with d-gal. Inhibition of HO-1 was protective in both females and males. Chronic d-gal treatment did not accelerate the development of osteoporosis or sarcopenia in either males or females. Our results demonstrate a sexual dimorphic response to the chronic effects of d-gal treatment on aging, with greater effects in females than in males, which is dependent on HO-1. Full article

(This article belongs to the Special Issue The Heme Oxygenase/Biliverdin Reductase System in Human Health and Disease: New Molecular Insights and Therapeutic Targets)

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Graphical abstract

26 pages, 1979 KB

Open AccessArticle

Adult Zucker Obese fa/fa Rats Present Impaired Immunity and Oxidative-Inflammatory Responses

by Nuria María De Castro, Mónica De la Fuente, Lydia Giménez-Llort, Jaime Ruiz-Tovar, Carmen Vida and María Isabel Baeza

Biomolecules 2026, 16(4), 547; https://doi.org/10.3390/biom16040547 - 8 Apr 2026

Background: Obesity involves an excessive buildup of adipose tissue and is linked to chronic inflammation and oxidative stress, both of which contribute to immunosenescence. Obesity and aging share common features, including immune system impairment and oxidative and inflammatory states, suggesting that obesity may [...] Read more.

Background: Obesity involves an excessive buildup of adipose tissue and is linked to chronic inflammation and oxidative stress, both of which contribute to immunosenescence. Obesity and aging share common features, including immune system impairment and oxidative and inflammatory states, suggesting that obesity may represent a model for accelerated immunosenescence. Objectives/Methods: The aim of this research was to evaluate in Zucker fatty (fa/fa) rats, a well-established genetic model of obesity, multiple immune function parameters (phagocytic activity, natural killer cell function, lymphocyte proliferation in response to mitogens, and cytokine profiles), as well as redox parameters (total antioxidant capacity, glutathione levels, activities of glutathione peroxidase and reductase, and xanthine oxidase activity) in peritoneal leukocytes, spleen, thymus, and liver at adult age (24 weeks). Comparisons were made with Zucker lean controls (fa/+), commonly used as standard controls, and Wistar rats as an independent control group. Results: Zucker fa/fa rats displayed significant physiological disorders, including increased body and organ weights, premature immunosenescence characterized by impaired innate and adaptive immune responses, reduced IL-2 and IL-10 secretion, elevated TNF-α production upon mitogen stimulation, and oxidative stress evidenced by redox imbalance in the spleen, thymus, and liver. Conclusions: These immune dysfunctions and oxidative imbalances are comparable to those observed during the aging process. Given that the immune parameters analyzed are considered indicators of health, aging rate, and longevity, our findings suggest that adult Zucker fa/fa rats could exhibit features of premature aging. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Aging and Cancer: Biological Bases, Therapeutic Strategies and Opportunities)

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28 pages, 7928 KB

Open AccessArticle

Beyond Small Molecules: Orchestrating Cell Fate with Engineered Water-Soluble Membrane Proteins

by Sebastian Valencia-Amores, Israel Davila Aleman, Timothy G. Jenkins and Dario Mizrachi

Biomolecules 2026, 16(4), 546; https://doi.org/10.3390/biom16040546 - 8 Apr 2026

The potential of water-soluble membrane proteins (wsMPs) has not been fully realized. In this article, we exploit the nearly identical functionality of wsMPs with their membrane-bound counterparts and show that we can create water-soluble membrane proteins that incorporate into the plasma membranes of [...] Read more.

The potential of water-soluble membrane proteins (wsMPs) has not been fully realized. In this article, we exploit the nearly identical functionality of wsMPs with their membrane-bound counterparts and show that we can create water-soluble membrane proteins that incorporate into the plasma membranes of cells and alter their fate. As a proof of concept, we demonstrate the functional properties of water-soluble engineered pore-forming proteins, K⁺ ionic channels (MthK), and constitutively active GPCRs—among them frizzled receptors—both in vitro and in vivo. We call this method in vivo deployment of recombinant viable MPs, iDRIVE. Furthermore, we demonstrate that our strategy mediates the unidirectional insertion of MPs into the plasma membrane, and through constitutively active receptors, we present evidence for similar signaling pathway activation between small molecules and our water-soluble proteins using model phenotypes and molecular signaling assays. We present three examples where wsMPs are functional in dictating cellular fate, both in vitro and in vivo. Lastly, we show the induction of similar differential methylation via the activation of the Wnt signaling pathway using the conventional small molecule agonist, CHIR99021, or our wsFrizzled receptors (iDRIVE-FZD) in human embryonic kidney (HEK 293) embryoid spheroids (ESs). Additionally, we show that Wnt activation via wsFrizzled receptors results in even more biologically relevant epigenetic changes than via the small molecule CHIR99021. Future work will employ iDRIVE to differentiate stem cells in the production of research and clinically relevant organoids. Full article

(This article belongs to the Special Issue Recent Molecular Research on Protein Structure and Function)

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12 pages, 873 KB

Open AccessCommunication

Analysis of Circulating and Urinary Levels of hsa-miRNA-770-5p in Diabetic Nephropathy

by Dimitar Nikolov, Georgi Nikolov, Mariela Geneva-Popova, Stanislava Popova-Belova, Mladen Naydenov and Mari Georgieva Karusheva

Biomolecules 2026, 16(4), 545; https://doi.org/10.3390/biom16040545 - 8 Apr 2026

Background: Diabetic nephropathy (DN), also referred to as diabetic kidney disease, represents one of the most common microvascular complications of type 2 diabetes mellitus (T2DM) and remains a leading cause of end-stage renal disease worldwide. Conventional clinical markers, including albuminuria and estimated glomerular [...] Read more.

Background: Diabetic nephropathy (DN), also referred to as diabetic kidney disease, represents one of the most common microvascular complications of type 2 diabetes mellitus (T2DM) and remains a leading cause of end-stage renal disease worldwide. Conventional clinical markers, including albuminuria and estimated glomerular filtration rate (eGFR), are widely used for diagnosis and staging but may have limited sensitivity for detecting early renal injury and predicting disease progression. In recent years, circulating microRNAs (miRNAs) have emerged as promising non-invasive biomarkers that reflect underlying molecular mechanisms of diabetic nephropathy and may complement traditional clinical indicators. Objective: The present study aimed to evaluate serum and urinary levels of hsa-miRNA-770-5p across different stages of diabetic nephropathy and to assess its potential diagnostic value in relation to established indicators of renal function. Methods: A total of 257 participants were included and divided into four groups: healthy controls, patients with T2DM without nephropathy, patients with T2DM and DN in CKD stages I–II, and patients with DN undergoing maintenance hemodialysis (MHD). Serum and urinary levels of miRNA-770-5p were measured using quantitative real-time polymerase chain reaction (qPCR) and analyzed using the 2^−ΔΔCt method. Statistical analyses included comparisons between groups using ANOVA, correlation analyses with renal function parameters such as eGFR and proteinuria/albuminuria, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic performance. Results: Serum levels of miRNA-770-5p were significantly elevated in patients with DN and in patients undergoing maintenance hemodialysis compared with healthy controls and patients with T2DM without nephropathy. In contrast, urinary levels of miRNA-770-5p were markedly reduced in patients with DN. Serum levels in patients with T2DM without nephropathy were slightly lower than those observed in healthy controls. Significant correlations were identified between miRNA-770-5p levels and renal function parameters, including eGFR and proteinuria/albuminuria, supporting the biological relevance of this microRNA in renal injury. ROC curve analysis demonstrated good discriminatory ability for differentiating DN from T2DM without nephropathy (serum AUC = 0.82; urine AUC = 0.79). Conclusions: hsa-miRNA-770-5p demonstrates distinct and opposite patterns in serum and urine that correlate with the severity of diabetic nephropathy. The complementary changes observed in circulating and urinary levels support the potential of miRNA-770-5p as a non-invasive biomarker that may complement conventional clinical markers and provide additional insight into the molecular mechanisms involved in the development and progression of diabetic nephropathy. Full article

(This article belongs to the Special Issue The Biomarkers in Renal Diseases)

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14 pages, 3164 KB

Open AccessArticle

Transcriptomic Assessment of Host Responses in Vaccinia and Venezuelan Equine Encephalitis Virus-Infected Human Dendritic Cells

by Aarti Gautam, Stacy Ann Miller, Burook Misganaw, Nicholas C. Gary, Marti Jett, Sofi Ibrahim and Rasha Hammamieh

Biomolecules 2026, 16(4), 544; https://doi.org/10.3390/biom16040544 - 8 Apr 2026

Understanding host cell response to viral infection could lead to the identification of molecular targets that can be used for the development of diagnostics and therapeutics. In this study, we investigated human dendritic cell (DC) response to infections with Vaccinia (VAC) virus, a [...] Read more.

Understanding host cell response to viral infection could lead to the identification of molecular targets that can be used for the development of diagnostics and therapeutics. In this study, we investigated human dendritic cell (DC) response to infections with Vaccinia (VAC) virus, a highly immunogenic poxvirus, and Venezuelan Equine Encephalitis (VEE) virus, a single-stranded positive-strand RNA alphavirus, using human gene expression microarrays. Comparative changes in DC mRNA expression resulting from infection by the two viruses at 1, 8, and 12 h post-infection (hpi) revealed distinct temporal dynamics. VAC infection triggered early and robust activation of pathways related to chromatin organization, DNA damage, and antigen presentation, while VEE infection exhibited delayed activation of immune signaling pathways, including interferon signaling and cytokine production. Shared pathways, such as interferon signaling and inflammasome activation, highlight universal antiviral responses and potential therapeutic targets. These findings provide a molecular framework affected by VAC and VEE that need to be validated with additional experiments, such as functional assays or in vivo studies. The specific up- or downregulation of these pathways at different time points likely dictates the overall outcome of the viral infection and could potentially lead to better understanding of the temporal regulatory dynamics of virus host response. Full article

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

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24 pages, 1036 KB

Open AccessReview

A New Era of Salvage-Line Treatment for Metastatic Colorectal Cancer: The Role and Clinical Significance of Circulating Tumor DNA

by Eiichiro Toyokawa, Akira Ooki, Eiji Shinozaki, Kaoru Yoshikawa, Keito Suzuki, Manabu Shiozawa, Shin Maeda, Kensei Yamaguchi and Hiroki Osumi

Biomolecules 2026, 16(4), 543; https://doi.org/10.3390/biom16040543 - 7 Apr 2026

The emergence of novel cytotoxic agents, multikinase inhibitors, and various antibody-based therapies has significantly expanded salvage therapy options for metastatic colorectal cancer (mCRC). Consequently, establishing the optimal treatment sequence for patients has become a formidable clinical challenge. Emerging evidence highlights the value of [...] Read more.

The emergence of novel cytotoxic agents, multikinase inhibitors, and various antibody-based therapies has significantly expanded salvage therapy options for metastatic colorectal cancer (mCRC). Consequently, establishing the optimal treatment sequence for patients has become a formidable clinical challenge. Emerging evidence highlights the value of comprehensive biomarker assessment, particularly longitudinal monitoring of circulating tumor DNA (ctDNA), to capture dynamic molecular changes during treatment. Liquid biopsy-based technologies now enable real-time tracking of molecular alterations, supporting truly personalized therapeutic decision-making. Furthermore, prior treatment exposure and residual toxicities must be carefully considered to balance efficacy, safety, and quality of life. This review provides a comprehensive overview of the current salvage-line landscape for mCRC, discusses the clinical utility of ctDNA as a predictive and prognostic tool, and proposes integrated strategies to optimize therapeutic outcomes in the evolving era of precision medicine. Full article

(This article belongs to the Special Issue Tumor Genomics and Liquid Biopsy in Cancer Biology)

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22 pages, 7374 KB

Open AccessArticle

A Cisplatin-Based Prodrug Inhibits Nucleotide Excision Repair Independently of Chromatin Accessibility to Overcome Resistance

by Ya’ara Negev-Korem, Hadar Golan-Berman, Elisheva Heilbrun, Subhendu Karmakar, Yoram Soroka, Marina Frušić-Zlotkin, Ofer Chen, Hiba Hassanain, Esther Stern, Ori Wald, Dan Gibson, Ron Kohen and Sheera Adar

Biomolecules 2026, 16(4), 542; https://doi.org/10.3390/biom16040542 - 7 Apr 2026

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage; however, drug resistance severely limits its efficacy. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), increased detoxification activities, and overexpression [...] Read more.

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage; however, drug resistance severely limits its efficacy. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), increased detoxification activities, and overexpression of lysine deacetylases (KDACs), which reduce chromatin accessibility and alter transcriptional regulation. Combining cisplatin with KDAC inhibitors has shown promise, often attributed to increased drug sensitivity through higher chromatin accessibility; however, this hypothesis has not been validated. Here, we synthesized a novel Pt(IV) derivative, ctc-[Pt(NH₃)₂(VPA)(PhB)Cl₂] (cPVP), which combines cisplatin with two KDAC inhibitors, phenylbutyrate and valproic acid. Compared with cisplatin, cPVP induced significantly greater cytotoxicity, and increased DNA damage formation. High-resolution mapping of genomic cisplatin damage and repair indicated that enhanced sensitivity resulted not from altered chromatin accessibility, but from increased drug uptake and the inhibition of NER. Moreover, cPVP prevented the development of resistance to both cisplatin and itself in cancer cells. Together, these results establish the inhibition of nucleotide excision repair, rather than enhanced damage sensitivity due to chromatin accessibility, as the primary mechanism by which KDAC-targeting cisplatin prodrugs overcome resistance to platinum-based therapies. Full article

(This article belongs to the Special Issue Functional Analysis of Genes Related to DNA Damage)

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14 pages, 463 KB

Open AccessPerspective

Interactys-AI: Toward AI-Driven Structural Mapping of Virus–Host Interfaces for Antiviral Repurposing and Pandemic Preparedness

by Christian Poitras, Ali Harake, Nathalie Grandvaux and Benoit Coulombe

Biomolecules 2026, 16(4), 541; https://doi.org/10.3390/biom16040541 - 5 Apr 2026

Understanding how viruses engage host cell surfaces is fundamental to infection biology and therapeutic development. While vaccines remain central to prevention, recent global crises have emphasized the need for complementary antiviral strategies that can be mobilized rapidly against both known and emerging pathogens. [...] Read more.

Understanding how viruses engage host cell surfaces is fundamental to infection biology and therapeutic development. While vaccines remain central to prevention, recent global crises have emphasized the need for complementary antiviral strategies that can be mobilized rapidly against both known and emerging pathogens. In this context, artificial intelligence (AI) systems for biomolecular structure prediction, culminating in AlphaFold 3, are reshaping what is experimentally and conceptually achievable. Here, we present “Interactys-AI”, a framework designed to exploit AI-based structural modeling to systematically map virus–host protein–protein interactions (PPIs) and connect them to actionable drug repurposing opportunities. Beyond a technical workflow, Interactys-AI reflects a broader transformation toward predictive and anticipatory antiviral discovery. We describe the conceptual foundations of the platform, its implementation, and its application to influenza A H5N1 hemagglutinin. We further discuss how structural AI may redefine preparedness strategies, highlight current limitations, and outline future directions toward real-time therapeutic hypothesis generation. Full article

(This article belongs to the Special Issue Feature Papers in Section "Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates")

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19 pages, 949 KB

Open AccessReview

Optimisation of Micronutrient Supplementation During Pregnancy: Interactions Between Bioactive Compounds, Their Impact on Health, and Regulatory Considerations

by Rebeka Anna Makó and Péter Sipos

Biomolecules 2026, 16(4), 540; https://doi.org/10.3390/biom16040540 - 5 Apr 2026

The intake of vitamins and minerals has a significant impact on the health of both the expectant mother and the newborn. During gestation, the demand for micronutrients increases; therefore, modifying dietary habits and selecting foods that ensure adequate (or sufficient) intake can be [...] Read more.

The intake of vitamins and minerals has a significant impact on the health of both the expectant mother and the newborn. During gestation, the demand for micronutrients increases; therefore, modifying dietary habits and selecting foods that ensure adequate (or sufficient) intake can be challenging. Although food supplements contain substances with beneficial physiological effects and their use can improve micronutrient intake, these products cannot replace proper nutrition. Due to modern nutritional habits, intake of key micronutrients is often inadequate, and their deficiencies are known to correlate with significant clinical outcomes during pregnancy. To reduce these deficiencies, several single- and multi-component dietary supplements have been developed. This review aims to present the health effects of the bioactive compounds found in these products and to discuss interactions (i.e., synergistic, additive, and antagonistic effects) between the micronutrients that may alter their bioefficiency. In addition, with a focus on future directions, this review draws attention to the need for a reassessment of current nutritional guidelines and recommendations, the development of new approaches, and emphasises the importance of establishing harmonised amounts of vitamins and minerals used in dietary supplements for pregnant women. Full article

(This article belongs to the Section Biological Factors)

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25 pages, 919 KB

Open AccessReview

Mast Cells and Substance P: Neuroinflammatory Loops at the Molecular and Translational Clinical Levels

by Ernesto Aitella, Marilena Bruno, Gianluca Azzellino, Massimo De Martinis, Lia Ginaldi and Ciro Romano

Biomolecules 2026, 16(4), 539; https://doi.org/10.3390/biom16040539 - 4 Apr 2026

Mast cells, characterized by a broad repertoire of surface receptors, are increasingly recognized for activation pathways extending beyond the classical IgE/FcεRI axis, particularly in the context of neurogenic inflammation. Substance P (SP), a neuropeptide of the tachykinin family, is a potent activator of [...] Read more.

Mast cells, characterized by a broad repertoire of surface receptors, are increasingly recognized for activation pathways extending beyond the classical IgE/FcεRI axis, particularly in the context of neurogenic inflammation. Substance P (SP), a neuropeptide of the tachykinin family, is a potent activator of mast cells, inducing the release of histamine, cytokines, and other inflammatory mediators. Through complex bidirectional communication, mast cells and SP play a pivotal role in neuro–immune interactions. This narrative review provides an updated overview of mast cell–SP crosstalk, with a focus on underlying molecular mechanisms, receptor-mediated signaling pathways, and their contribution to pathophysiological processes. In addition, we aim to reinterpret established clinical models within the spectrum of pseudoallergic conditions and to explore innovative, etiology-driven therapeutic strategies. Finally, we discuss future perspectives and highlight the need for robust translational models to support clinical and pharmacological research. Full article

(This article belongs to the Special Issue Molecular Basis of Mast Cells Activation and Medical Implications)

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23 pages, 8247 KB

Open AccessArticle

Caloric Restriction Mimetic Hydroxycitrate Mitigates Acute Nephrotoxicity via Autophagy Activation and Oxidative Stress Reduction

by Xinyu Liao, Nadezda V. Andrianova, Ljubava D. Zorova, Anna A. Brezgunova, Kseniia S. Cherkesova, Marina I. Buyan, Dmitry S. Semenovich, Alexandra A. Dalina, Irina B. Pevzner, Juan Jin, Yunguang Wang and Egor Y. Plotnikov

Biomolecules 2026, 16(4), 538; https://doi.org/10.3390/biom16040538 - 4 Apr 2026

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI) and subsequent chronic kidney disease. Nephrotoxicity often develops as a consequence of treatment with commonly prescribed aminoglycoside antibiotics, and remains a significant clinical challenge. One approach to treating AKI and its associated [...] Read more.

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI) and subsequent chronic kidney disease. Nephrotoxicity often develops as a consequence of treatment with commonly prescribed aminoglycoside antibiotics, and remains a significant clinical challenge. One approach to treating AKI and its associated complications is caloric restriction or its pharmacological mimetics. This study aimed to evaluate the effects of caloric restriction mimetic hydroxycitrate (HC) in gentamicin-induced nephrotoxicity, with particular focus on the influence of treatment duration and the underlying molecular mechanisms. In vitro renal tubular epithelial cells models were used to assess HC’s effects on viability, proliferation, and autophagy activation. For in vivo validation, rats with gentamicin-induced AKI received HC treatment via two distinct regimens (3-week and 7-week administration). Experiments on renal tubule cells showed that HC significantly increased cell viability and proliferation and led to the activation of autophagy. In the rat model, only the 7-week administration of HC demonstrated significantly attenuated renal dysfunction in gentamicin-induced AKI. Moreover, it reduced macrophage infiltration, increased renal cell tolerance to apoptosis, activated autophagy, and reduced oxidative stress. Thus, our results indicate that 7-week HC administration could be used as a prophylactic strategy against antibiotic nephrotoxicity, exerting its effects by promoting autophagy, resisting apoptosis, and attenuating oxidative damage. Full article

(This article belongs to the Section Cellular Biochemistry)

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