Biomolecules

22 pages, 1704 KB

Open AccessArticle

Integrated Multi-Omics Analysis Explores the Protective Effects and Potential Mechanisms of Pulsatilla chinensis on Canine Antibiotic-Associated Diarrhea

by Zixuan Zhao, Jianfang Wang, Zhoufeng Wu, Lihua Ye, Jiahan Wang, Yihan Wang, Yuman Zhao, Hua Zhang, Chaochao Luo and Jinjin Tong

Biomolecules 2026, 16(5), 650; https://doi.org/10.3390/biom16050650 (registering DOI) - 27 Apr 2026

Abstract

Diarrhea is a common gastrointestinal disorder in animals, often worsened by antibiotic use. Pulsatilla chinensis (PC) is traditionally used for gastrointestinal issues, but its bioactive constituents and mechanisms remain unclear. This study investigated the preventive effects of PC in a canine model of [...] Read more.

Diarrhea is a common gastrointestinal disorder in animals, often worsened by antibiotic use. Pulsatilla chinensis (PC) is traditionally used for gastrointestinal issues, but its bioactive constituents and mechanisms remain unclear. This study investigated the preventive effects of PC in a canine model of antibiotic-associated diarrhea using an integrated multi-omics approach. LC–MS identified key constituents of PC, including anemoside B4, berberine, stigmasterol, and quercetin. In silico analyses predicted that stigmasterol and quercetin target EGFR and AKT1, modulating inflammation and epithelial repair via PI3K–Akt and IL-17 signaling pathways. In vivo, treatment with PC significantly reduced serum pro-inflammatory cytokines such as TNF-α and IL-6 and elevated immune markers including IgG and IgA compared to the control group. Furthermore, 16S rRNA analysis revealed that PC restored gut microbial diversity, reflected by increased Sobs and Chao1 indices, enriched beneficial Lactobacillus, and decreased the abundance of inflammation-associated taxa such as Proteobacteria, Desulfobacterota, and Escherichia-Shigella. These findings suggest that PC suppresses inflammation and remodels the gut microbiome, providing a mechanistic basis for its use as an herbal alternative to antibiotics. Future studies should include fecal microbiota transplantation and targeted metabolomics to establish causality and optimize therapeutic strategies. Full article

(This article belongs to the Section Molecular Medicine)

24 pages, 4230 KB

Open AccessArticle

Retention and Distribution of Dopamine-Dependent Reward Memory in Regenerating Planaria

by Kenneth Samuel, Abigail K. Hakes, Easter S. Suviseshamuthu and Maria E. Fichera

Biomolecules 2026, 16(5), 649; https://doi.org/10.3390/biom16050649 (registering DOI) - 27 Apr 2026

Abstract

Memory is generally thought to be stored within centralized neural circuits. However, whether learned behaviors can persist in the absence of a brain remains unresolved. Planaria (Girardia spp.) possess a primitive cephalic ganglion and a remarkable capacity for regeneration, providing a unique [...] Read more.

Memory is generally thought to be stored within centralized neural circuits. However, whether learned behaviors can persist in the absence of a brain remains unresolved. Planaria (Girardia spp.) possess a primitive cephalic ganglion and a remarkable capacity for regeneration, providing a unique system to examine non-cephalic memory retention. The primary aim of this study was to determine whether sucrose-induced conditioned place preference (CPP) is retained in posterior, brainless planarian fragments. Planaria were trained using a Pavlovian conditioning paradigm in which an initially unpreferred surface was paired with a 10% sucrose solution, resulting in a robust shift in surface preference. Following amputation, anterior fragments containing the cephalic ganglion as well as posterior fragments lacking the brain preserved the conditioned preference, demonstrating that reward-associated memory is stored even outside the cephalic nervous system. As a secondary objective, we examined the role of dopaminergic reinforcement using a D1 dopamine receptor antagonist during training. While antagonist-treated planaria failed to develop a CPP, posterior fragments from these amputated planaria likewise showed no conditioned preference, indicating that dopamine-dependent signaling is essential for sucrose-associated memory formation across the body. These results provide support for the hypothesis that reward-associated memory in planaria is distributed beyond the brain and can be modulated by dopaminergic pathways, highlighting the utility of this model for exploring fundamental mechanisms of reward, memory, and potential pharmacological interventions. Full article

(This article belongs to the Special Issue The Planarian Model in Pharmacology, Toxicology, and Neuroscience)

17 pages, 1401 KB

Open AccessReview

Allergic Anisakiasis: An Integrated Review of Human, Animal and Cellular Evidence

by Stefania Isola, Emanuela Zumbo, Francesca Dimasi, Paola Lucia Minciullo and Sebastiano Gangemi

Biomolecules 2026, 16(5), 648; https://doi.org/10.3390/biom16050648 (registering DOI) - 27 Apr 2026

Abstract

Allergic anisakiasis (AA), caused by the ingestion of fish contaminated with Anisakis larvae, has emerged as a growing global health concern due to the increasing consumption of raw or undercooked seafood. Anisakis simplex is identified as the primary etiologic species, responsible for gastrointestinal [...] Read more.

Allergic anisakiasis (AA), caused by the ingestion of fish contaminated with Anisakis larvae, has emerged as a growing global health concern due to the increasing consumption of raw or undercooked seafood. Anisakis simplex is identified as the primary etiologic species, responsible for gastrointestinal symptoms, IgE-mediated (Type I) or cell-mediated (Type IV) manifestations, and gastro-allergic anisakiasis (GAA), a unique clinical overlap between parasitic infection and acute IgE-mediated food allergy. In this review, we analyzed the epidemiology of Anisakis simplex allergy, the main diagnostic methods to confirm a diagnosis of food allergy, its clinical manifestations, and how these differ in different countries around the world. This multidisciplinary synthesis provides, for the first time, an integrated understanding of Anisakis-induced disease mechanisms across human, animal, and cellular levels. The persistence of allergenic proteins despite standard food processing underscores the need for improved diagnostic tools, public health surveillance, and preventive strategies—particularly in populations with high seafood consumption or occupational exposure. A comprehensive approach combining clinical, molecular, and immunological perspectives is essential to address the expanding global burden of allergic anisakiasis. Full article

(This article belongs to the Special Issue Immune Response to Allergens)

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16 pages, 510 KB

Open AccessReview

The Role of FOSL1 in Inflammatory Bowel Disease (IBD) Pathogenesis and IBD-Associated Tumorigenesis

by Grace J. Rilee, Senthil K. Radhakrishnan, Guang-Yu Yang and Jiong Li

Biomolecules 2026, 16(5), 647; https://doi.org/10.3390/biom16050647 (registering DOI) - 27 Apr 2026

Abstract

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn’s disease, are chronic inflammatory disorders of the gastrointestinal tract associated with epithelial barrier dysfunction, dysregulated immune responses, and an increased risk of cancer. Persistent inflammation is a key driver of IBD-associated tumorigenesis, yet the [...] Read more.

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn’s disease, are chronic inflammatory disorders of the gastrointestinal tract associated with epithelial barrier dysfunction, dysregulated immune responses, and an increased risk of cancer. Persistent inflammation is a key driver of IBD-associated tumorigenesis, yet the transcriptional regulators linking inflammatory signaling to epithelial transformation remain incompletely defined. FOSL1 (FOS-like antigen 1), a member of the activator protein-1 (AP-1) transcription factor family, has emerged as a critical mediator at the intersection of inflammation, epithelial homeostasis, and cancer progression. FOSL1 is induced by pro-inflammatory pathways commonly activated in IBD, including MAPK/ERK, NF-κB, and cytokine signaling, and regulates gene programs involved in cell proliferation, migration, barrier integrity, immune modulation, and survival. Accumulating evidence demonstrates that FOSL1 expression is elevated in inflamed intestinal mucosa and in IBD-associated malignancies, where it contributes to epithelial dysfunction, chronic inflammation, tumor initiation, metastasis, angiogenesis, and therapeutic resistance. Moreover, FOSL1-driven transcriptional networks show mechanistic overlap between IBD-associated colorectal cancer (CRC) and other inflammation-linked gastrointestinal cancers, such as pancreatic ductal adenocarcinoma (PDAC). In this review, we summarize current knowledge on the regulation and function of FOSL1 in intestinal inflammation and IBD-associated cancers, highlight its context-dependent roles in epithelial and immune compartments, and discuss emerging therapeutic strategies aimed at indirectly targeting FOSL1 signaling pathways. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cancer Induced by Inflammatory Bowel Disease)

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14 pages, 1768 KB

Open AccessArticle

A Campomelic Dysplasia A76E Mutation in Sox9 Destabilizes Protein and DNA Binding Dynamics

by Zeyaul Islam and Prasanna R. Kolatkar

Biomolecules 2026, 16(5), 646; https://doi.org/10.3390/biom16050646 (registering DOI) - 27 Apr 2026

Abstract

Sox9, a pivotal transcription factor belonging to the Sox family, orchestrates critical processes throughout embryonic development, maintenance and differentiation, and exerts a profound influence on organogenesis. Its regulatory versatility stems from precise binding to defined DNA regions, often in collaboration with tissue-specific partners. [...] Read more.

Sox9, a pivotal transcription factor belonging to the Sox family, orchestrates critical processes throughout embryonic development, maintenance and differentiation, and exerts a profound influence on organogenesis. Its regulatory versatility stems from precise binding to defined DNA regions, often in collaboration with tissue-specific partners. The dysregulation of Sox9 during chondrogenesis leads to a skeletal malformation termed campomelic dysplasia and has emerged as a significant factor in various other human diseases, including cancer. A point mutation at position 76 (alanine to glutamic acid, A76E) of Sox9 is recognized as one of the causes of campomelic dysplasia. We have used a combination of biophysical, structural and computational techniques to characterize the Sox9 A76E mutant and compare it with the wild-type (WT) Sox9. WT and A76E Sox9 assemble as homodimers, but form predominantly monomeric complexes in the presence of Sox-specific DNA. A CD analysis shows that the A76E mutant preserves the folding as well as the overall secondary structure of Sox9. Both A76E and WT Sox9 behave similarly in the presence of Sox-specific DNA. Perturbation, with increased temperature, displays a lower melting point for A76E, relative to WT Sox9, indicating decreased stability that may arise due to the long and charged side chain of glutamic acid compared to the small hydrophobic alanine, making unfavorable intra-molecular interactions. The destabilizing effect of the A76E mutant may disturb the formation of a stable higher-order complex that is a prerequisite for normal gene expression. Full article

(This article belongs to the Special Issue Unveiling Protein Functions, Dynamics and Interactions in Health and Disease Using Experimental and Theoretical Approaches, 2nd Edition)

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30 pages, 5029 KB

Open AccessReview

From State, Pathway, to Niche: The Ternary Network of Breast Cancer Stem-like Cells Driving Tumor Progression and Combination Therapy Prospects

by Sitong Man, Lei Zhang and Bo Chen

Biomolecules 2026, 16(5), 645; https://doi.org/10.3390/biom16050645 (registering DOI) - 26 Apr 2026

Abstract

Breast cancer stem-like cells (bCSCs) fundamentally represent a highly dynamic “immune-adaptive functional state” rather than a fixed cellular lineage, serving as the core engine driving tumor recurrence, metastasis, and therapeutic resistance. Despite rapid advances, the heterogeneity of bCSC states and their intricate interactions [...] Read more.

Breast cancer stem-like cells (bCSCs) fundamentally represent a highly dynamic “immune-adaptive functional state” rather than a fixed cellular lineage, serving as the core engine driving tumor recurrence, metastasis, and therapeutic resistance. Despite rapid advances, the heterogeneity of bCSC states and their intricate interactions with the immune microenvironment lack systematic integration. This review centers on the dynamic evolution and niche adaptation of bCSCs. First, we systematically dissect the multilayered regulatory network maintaining stemness, encompassing core transcription factors, epigenetic–metabolic coupling, and the synergistic mechanisms of critical signaling pathways such as Wnt and Notch. Second, we propose a trinary “stemness–immune–spatial” feedback model, elucidating how bCSCs achieve active immune evasion by downregulating antigen presentation, secreting immunosuppressive factors, and embedding within perivascular “immune-cold niches.” Finally, leveraging a multi-omics integration perspective, we reconstruct precision intervention strategies, exploring the synergistic potential of targeting stemness pathways in conjunction with immunotherapies like PD-1/PD-L1 blockade and STING agonists. Furthermore, we highlight the pivotal role of integrating organoids, PDX models, and AI-assisted decision systems in overcoming heterogeneity and enabling personalized treatment. By establishing a closed-loop framework spanning mechanistic insight to spatially precise intervention, this review aims to provide novel theoretical foundations and translational pathways to surmount the bottleneck of therapeutic resistance in breast cancer. Full article

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22 pages, 7580 KB

Open AccessArticle

Zearalenone Promotes Hepatic Stellate Cell Activation and Early Profibrotic Tendency in the Liver

by Lige Bao, Yongze Huang, Jiaxin Bao, Yitong Lu, Chunli Chen, Zhiyong Wu and Jichang Li

Biomolecules 2026, 16(5), 644; https://doi.org/10.3390/biom16050644 (registering DOI) - 26 Apr 2026

Abstract

Zearalenone (ZEA) is a mycotoxin widely present in cereals, feeds, and foods, posing a persistent threat to human and animal health. Hepatic fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition. Chronic liver injury caused by sustained oxidative stress can [...] Read more.

Zearalenone (ZEA) is a mycotoxin widely present in cereals, feeds, and foods, posing a persistent threat to human and animal health. Hepatic fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition. Chronic liver injury caused by sustained oxidative stress can initiate the development of early hepatic fibrosis. However, whether liver injury induced by ZEA can trigger hepatic stellate cell (HSC) activation and promote early profibrotic responses remains unclear. The aim of this study was to assess whether ZEA-induced liver injury promotes HSC activation and early profibrotic responses. To address this, we established a BALB/c mouse exposure model and used the murine HSC line (JS-1) for in vitro validation. The results showed that ZEA exposure caused structural damage in hepatic tissue and produced an incomplete bridging pattern of collagen thickening suggestive of an early profibrotic tendency. ZEA shaped a proinflammatory microenvironment by activating the IκBα/NF-κB axis and induced the TGF-β1/Smad2/3 pathway, accompanied by Smad7 suppression, thereby promoting HSC activation and the expression of fibrosis-related genes. ZEA also altered autophagy-related markers in liver tissue and JS-1 cells. Pharmacological inhibition with chloroquine partially attenuated ZEA-induced upregulation of α-SMA and collagen I/III, suggesting that autophagy-related processes may be involved in ZEA-associated HSC activation and early ECM deposition. In summary, ZEA promotes HSC activation and early profibrotic changes in the liver and is associated with inflammatory activation, TGF-β1/Smad signaling, and altered autophagy-related activity. These findings provide a basis for further investigation into the mechanisms underlying ZEA-induced early profibrotic remodeling in the liver. Full article

(This article belongs to the Topic Recent Advances in Veterinary Pharmacology and Toxicology, 2nd Edition)

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14 pages, 876 KB

Open AccessArticle

Association of the Dedicator of Cytokinesis 2 (DOCK2) Gene Polymorphisms with COVID-19 and Plasma LDH, AST, ALT, and Ferritin Levels

by José Manuel Fragoso, Rosalinda Posadas-Sánchez, Alberto López-Reyes, Laura E. Martínez-Gómez, Julian Ramírez-Bello, Giovanny Fuentevilla-Alvarez and Gilberto Vargas-Alarcón

Biomolecules 2026, 16(5), 643; https://doi.org/10.3390/biom16050643 (registering DOI) - 25 Apr 2026

Abstract

This case-control study investigated the association between polymorphisms in the dedicator of cytokinesis 2 (DOCK2) gene and susceptibility to COVID-19 in a Mexican population. Methods: Genotyping of five single-nucleotide polymorphisms (SNPs) in the DOCK2 gene (rs9307 A/G, rs1045176 G/T, [...] Read more.

This case-control study investigated the association between polymorphisms in the dedicator of cytokinesis 2 (DOCK2) gene and susceptibility to COVID-19 in a Mexican population. Methods: Genotyping of five single-nucleotide polymorphisms (SNPs) in the DOCK2 gene (rs9307 A/G, rs1045176 G/T, rs1045168 C/T, rs2112703 A/C, and rs2287727 A/C) was performed using TaqMan assays in 248 COVID-19 patients and 288 healthy controls. Results: No significant differences were observed in the allelic or genotypic distributions of rs1045176 G/T and rs2287727 A/C between cases and controls. However, under multiple genetic inheritance models (co-dominant, dominant, recessive, heterozygous, and additive), the rs9307 A, rs1045168 C, and rs2112703 A alleles were significantly associated with a reduced risk of COVID-19 (p < 0.05). Furthermore, sub-analyses stratified by genotype in COVID-19 patients revealed that the rs9307 AA, rs1045168 CC, and rs2112703 AA genotypes correlated with altered plasma concentrations of lactic acid dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and ferritin. Conclusions: The DOCK2 SNPs rs9307 A/G, rs1045168 C/T, and rs2112703 A/C are associated with decreased susceptibility to COVID-19 in this population and influence plasma levels of LDH, ALT, AST, and ferritin, suggesting a potential role in disease pathogenesis and severity. Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 5047 KB

Open AccessArticle

AjTEAD1 Targets AjCyclin E to Promote Cell Proliferation During Intestinal Regeneration in Apostichopus japonicus

by Chuili Zeng, Xu Zhan, Ke Xiao and Chenghua Li

Biomolecules 2026, 16(5), 642; https://doi.org/10.3390/biom16050642 (registering DOI) - 25 Apr 2026

Abstract

TEA domain transcription factors are critical regulators of tissue development and regeneration in mammals, yet their roles in aquatic invertebrate regeneration remain poorly understood. Here, a full-length cDNA encoding a putative transcriptional enhanced associate domain protein 1 (TEAD1) ortholog in Apostichopus japonicus ( [...] Read more.

TEA domain transcription factors are critical regulators of tissue development and regeneration in mammals, yet their roles in aquatic invertebrate regeneration remain poorly understood. Here, a full-length cDNA encoding a putative transcriptional enhanced associate domain protein 1 (TEAD1) ortholog in Apostichopus japonicus (AjTEAD1) was cloned and characterized. The open reading frame (ORF) of AjTEAD1 is 1344 bp, encoding a polypeptide of 447 amino acids with a conserved TEA domain (Asp⁴⁰–Leu¹¹¹) and a protein-binding domain (Gly²³¹–Asp⁴⁴⁶). Function analysis demonstrates that AjTEAD1 is essential for intestinal regeneration. AjTEAD1 expression was significantly upregulated during the regeneration process. Functional impairment of AjTEAD1 suppressed intestinal regeneration and attenuated cell proliferation. At the molecular level, we identified the cell cycle gene in A. japonicus (AjCyclin E), whose expression pattern coincided with that of AjTEAD1 and was downregulated following AjTEAD1 knockdown. Dual-luciferase reporter assays further confirmed that AjTEAD1 binds to specific sites in the AjCyclin E promoter and transcriptionally activates its expression. In summary, our study reveals that AjTEAD1 promotes cell proliferation and drives intestinal regeneration in A. japonicus by directly upregulating AjCyclin E transcription. These findings identify the TEAD–Cyclin E axis as a key regulator of echinoderm regeneration, shedding new light on the regenerative processes and cytological mechanisms in economically important species. 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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20 pages, 1336 KB

Open AccessReview

C/EBPδ as a Regulatory Node in Adipocytes: Roles in Differentiation, Metabolism, and Immune Function

by Suining Ma, Meiting Lai, Tongjun Li, Lexun Wang and Xianglu Rong

Biomolecules 2026, 16(5), 641; https://doi.org/10.3390/biom16050641 - 24 Apr 2026

Abstract

CCAAT/enhancer-binding protein δ (C/EBPδ) is a rapidly responsive transcription factor that occupies an important regulatory position in adipocytes. Induced during the early stage of adipocyte differentiation, C/EBPδ integrates hormonal, inflammatory, metabolic, and stress-related cues and contributes to the coordination of downstream transcriptional and [...] Read more.

CCAAT/enhancer-binding protein δ (C/EBPδ) is a rapidly responsive transcription factor that occupies an important regulatory position in adipocytes. Induced during the early stage of adipocyte differentiation, C/EBPδ integrates hormonal, inflammatory, metabolic, and stress-related cues and contributes to the coordination of downstream transcriptional and functional programs. Beyond its role in the initiation of differentiation, C/EBPδ is also involved in adipogenic progression, metabolic regulation, and immune-related functions in adipocytes. Current evidence indicates that C/EBPδ participates in early adipogenic regulatory networks, contributes to lipid metabolic programs, and is associated with immune-regulatory processes linked to lipid antigen presentation. Notably, the biological output of C/EBPδ is strongly shaped by tissue type, developmental stage, and microenvironmental context, ranging from promotion of adipogenic differentiation to regulation of inflammatory, metabolic, and adaptive stress responses under distinct physiological and pathological conditions. This review summarizes the upstream regulatory network, downstream functional framework, and context-dependent roles of C/EBPδ in adipocytes, and further discusses its potential relevance to adipose-related diseases as well as the opportunities and challenges for future precision intervention strategies. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation of Adipogenesis, Adipose Tissue Inflammation and Metabolism)

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19 pages, 4696 KB

Open AccessArticle

PEG-Dependent Tunable Degradation and Curcumin Release from Curcumin-Based Biomedical Polyurethanes

by Man Wang, Hongying Liu, Wei Zhao, Huafen Wang, Yuwei Zhuang, Ran Zhang, Zhaohui Liu, Nengwen Ke and Sichong Chen

Biomolecules 2026, 16(5), 640; https://doi.org/10.3390/biom16050640 - 24 Apr 2026

Abstract

Curcumin, a plant-derived polyphenolic compound, exhibits diverse pharmacological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotective, and cardiovascular protective effects, and is widely used in food, medicine, and other fields. However, its poor water solubility and easy oxidative degradation limit its extensive application in [...] Read more.

Curcumin, a plant-derived polyphenolic compound, exhibits diverse pharmacological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotective, and cardiovascular protective effects, and is widely used in food, medicine, and other fields. However, its poor water solubility and easy oxidative degradation limit its extensive application in biomedicine. To solve these problems, a series of biomedical polyurethanes (Cur-PU) with similar molecular weights but different PEG contents were successfully synthesized using HO-PCL-OH and HO-PEG-OH as soft segments and curcumin as a chain extender. The results indicated that increasing the PEG content reduced the T¹_m, T¹_c, and H¹_c of Cur-PU, along with a slower crystallization rate and lower crystallinity. More importantly, a higher PEG content decreased the water contact angle but increased water solubility and water uptake, which, combined with reduced crystallinity, enhanced hydrophilicity, swelling ratio, curcumin release rate, and degradation rate in an enzymatic solution and pH 8.0 buffer. Thus, precise regulation of Cur-PU’s degradation and curcumin release was achieved by controlling the PEG content. Biocompatibility tests confirmed that Cur-PU exhibited excellent antioxidant and antibacterial activities, making it a highly promising biomedical material. Full article

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

22 pages, 11126 KB

Open AccessArticle

Cell Type-Specific Downregulation of Dnmt3a in Nucleus Accumbens Oligodendrocytes Prevents Myelin Damage and Reduces Susceptibility to Social Stress in Male Mice

by Yifan Niu, Kaiwei Li, Kaiyuan Zhan, Mingshan Pi, Qi Xiong, Ji Wang, Xiaochuan Wang, Xiji Shu, Yiyuan Xia and Mengbing Huang

Biomolecules 2026, 16(5), 639; https://doi.org/10.3390/biom16050639 - 24 Apr 2026

Abstract

Background: Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in [...] Read more.

Background: Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in stress-related neurobiological adaptations. In this study, we employed a well-established mouse model of chronic social defeat stress (CSDS) to investigate the functional role of Dnmt3a in modulating individual susceptibility to social stress. Methods: Male C57BL/6J mice were exposed to chronic/submaximal social defeat stress (CSDS/SSDS). AAV vectors were used to achieve Dnmt3a overexpression or global and oligodendrocyte-specific knockdown in the nucleus accumbens (NAc). Behavioral tests, including social interaction, open field, and elevated zero maze, were conducted alongside Western blotting and immunofluorescence assays. Results: CSDS selectively increased Dnmt3a expression in NAc oligodendrocytes of stress-susceptible mice. Overexpression of Dnmt3a in the NAc enhanced susceptibility to stress, whereas its knockdown conferred resilience, without affecting baseline behaviors. Dnmt3a negatively regulated myelin basic protein (MBP) and dopamine D1 receptor expression. Stress-susceptible mice exhibited shortened myelinated segments and reduced D1 receptor levels, while D2 receptor expression remained unchanged. Conclusions: Dnmt3a in NAc oligodendrocytes modulates susceptibility to social stress through a Dnmt3a-MBP/D1 receptor-NAc pathway, highlighting a critical glia-neuron interaction. This mechanism extends our understanding of the neurobiological basis of stress-related disorders and positions Dnmt3a as a promising therapeutic target for developing precision interventions or biomarkers. Full article

(This article belongs to the Section Molecular Medicine)

15 pages, 728 KB

Open AccessArticle

Picropodophyllotoxin Mitigates Severe Inflammation Through HMGB1 Inhibition

by Gyuri Han, Ga Eun Kim and Jong-Sup Bae

Biomolecules 2026, 16(5), 638; https://doi.org/10.3390/biom16050638 - 24 Apr 2026

Abstract

Background/Objectives: Plant-derived phytochemicals are being increasingly explored for their ability to treat various illnesses, especially those affecting the vasculature. High mobility group box 1 (HMGB1) acts as a crucial mediator during the late phase of sepsis, promoting the secretion of pro-inflammatory cytokines and [...] Read more.

Background/Objectives: Plant-derived phytochemicals are being increasingly explored for their ability to treat various illnesses, especially those affecting the vasculature. High mobility group box 1 (HMGB1) acts as a crucial mediator during the late phase of sepsis, promoting the secretion of pro-inflammatory cytokines and thereby fueling inflammation and systemic complications. Higher plasma HMGB1 levels not only hinder accurate diagnosis and prognosis but also worsen disease outcomes in inflammatory states. Picropodophyllotoxin (PPT), a key bioactive ingredient isolated from the root of Podophyllum hexandrum, has shown a range of beneficial effects, including anti-cancer and anti-proliferative actions, across several tumor types. Nevertheless, its possible involvement in HMGB1-driven severe vascular inflammation remains unexplored. The current work aimed to investigate whether PPT could influence lipopolysaccharide (LPS)-induced HMGB1 activity and its related inflammatory signaling in human umbilical vein endothelial cells (HUVECs). Methods: A combination of in vitro and in vivo approaches was used to assess the anti-inflammatory action of PPT. These included measurements of endothelial barrier function, cell survival, leukocyte attachment and migration, levels of cell adhesion molecules, and the release of pro-inflammatory factors. Both cultured human endothelial cells and mouse disease models were used to thoroughly evaluate how PPT affects HMGB1-triggered inflammatory reactions. Results: The findings showed that PPT markedly reduced HMGB1 movement from inside HUVECs to the outside, thereby limiting its release into the environment. Moreover, PPT effectively decreased neutrophil sticking and migration, lowered the appearance of HMGB1 receptors, and prevented the activation of nuclear factor-κB (NF-κB), a master switch in inflammatory signaling. At the same time, PPT treatment strongly lowered tumor necrosis factor-α (TNF-α) production, adding to its anti-inflammatory profile. Conclusions: Taken together, these results indicate that PPT potently inhibits HMGB1-driven inflammatory processes by acting at several levels of the inflammatory cascade, such as HMGB1 movement, receptor binding, NF-κB activation, and subsequent cytokine release. Therefore, PPT stands out as a hopeful therapeutic option for HMGB1-related inflammatory diseases and deserves further exploration in preclinical and clinical studies. Full article

(This article belongs to the Section Cellular Biochemistry)

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19 pages, 819 KB

Open AccessArticle

Soluble E-Cadherin as a New Prognostic Biomarker Able to Predict Survival in Newly Diagnosed Diffuse Large B-Cell Lymphoma

by Paola Carolina Rabesquini Marcelino da Silva, Igor Cerejo Tavares da Silva de Almeida, Joaquim Gasparini dos Santos, Leonardo Jun Otuyama, Cadiele Oliana Reichert, Hebert Fabrício Culler, Nélio Cézar de Aquino, Lilian de Souza França, Sheila Aparecida Coelho da Siqueira, Renata de Oliveira Costa, Vanderson Rocha, Sérgio Paulo Bydlowski, Débora Levy, Juliana Pereira and Luís Alberto de Pádua Covas Lage

Biomolecules 2026, 16(5), 637; https://doi.org/10.3390/biom16050637 - 24 Apr 2026

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, constituting an important public health problem. Although curable, it presents a widely variable prognosis. The main tool used for prognostic stratification in DLBCL is the International Prognostic Index (IPI), [...] Read more.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, constituting an important public health problem. Although curable, it presents a widely variable prognosis. The main tool used for prognostic stratification in DLBCL is the International Prognostic Index (IPI), which does not consider crucial biological variables for understanding its prognostic heterogeneity. Cell adhesion molecules (CAMs) play a central role in cancer biology and can be evaluated in affected tissues or in plasma, in soluble forms (sCAMs). CAMs promote proliferation, survival, and dissemination of malignant cells. Although extensively studied in solid tumors, their role remains unclear in hematological malignancies, particularly in DLBCL. Methods: This is a prospective and longitudinal study involving 87 newly diagnosed DLBCL (ND-DLBCL) patients aiming to quantify plasma levels of sCAMs (sICAM-1, sVCAM-1, sP-selectin, and sE-cadherin) at diagnosis and assessing its potential prognostic impact, as well as establishing clinical-biological associations. Results: Plasma quantification of sICAM-1, sVCAM-1, and sP-selectin did not present prognostic impact in DLBCL. However, continuous increases in sE-cadherin levels, as well as sE-cadherin ≥ 126.55 ng/mL were associated with lower response rates to R-CHOP regimen, higher frequency of recurrence following first-line therapy, and shortened survival. Additionally, sE-cadherin concentration ≥ 126.55 ng/mL was an independent predictor related to decreased overall survival. Conclusion: sE-cadherin measured at diagnosis has emerged as a new prognostic biomarker able to predict response, relapse and survival in ND-DLBCL. Full article

(This article belongs to the Special Issue Novel Diagnostic Tools and Biomarkers in Hematology)

21 pages, 930 KB

Open AccessReview

MicroRNAs in Pediatric Primary Hypertension: Promising Biomarkers or Context-Dependent Regulators?—A Narrative Review

by Michał Szyszka and Piotr Skrzypczyk

Biomolecules 2026, 16(5), 636; https://doi.org/10.3390/biom16050636 - 24 Apr 2026

Abstract

Hypertension affects approximately 1.4 billion people worldwide. It is worth noting that it is also found in approximately 4% of children, with about half of pediatric patients having primary hypertension. Despite its widespread prevalence, the pathogenesis of primary hypertension remains poorly understood. Among [...] Read more.

Hypertension affects approximately 1.4 billion people worldwide. It is worth noting that it is also found in approximately 4% of children, with about half of pediatric patients having primary hypertension. Despite its widespread prevalence, the pathogenesis of primary hypertension remains poorly understood. Among the many hypotheses, research into epigenetic factors, primarily microRNA, has gained momentum in recent years. The role of microRNA is to bind to mRNA and thus influence protein translation. It is postulated that the main sites where microRNA influences blood pressure are the vascular wall, vascular smooth muscle cells, and the kidney. Many microRNAs have been identified whose importance in primary hypertension development has been demonstrated in experimental and human studies. This article discusses in detail the significance of microRNA-16, -21, -27a, -27b, -133a, and -145. It presents the current state of knowledge, as well as the challenges, limitations, and uncertainties regarding the use of these fascinating molecules as biomarkers and in potential therapy. MicroRNAs are an extremely promising area of research into the pathogenesis of primary hypertension. However, we still do not know whether they will prove to be a promising biomarker of primary hypertension. Full article

(This article belongs to the Section Molecular Biomarkers)

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21 pages, 5097 KB

Open AccessReview

Prominin-1 and Retinal Degenerative Disorders: Expanding the Biology from Photoreceptors to the Retinal Pigment Epithelium

by Sujoy Bhattacharya, Caitlin Ang, Megan Soucy, Stephen H. Tsang and Edward Chaum

Biomolecules 2026, 16(5), 635; https://doi.org/10.3390/biom16050635 - 24 Apr 2026

Abstract

Prominin-1 (Prom1/CD133) has long been recognized as a structural determinant of photoreceptor outer segment (OS) morphogenesis, yet rapidly accumulating evidence extends its role to retinal pigment epithelium (RPE) homeostasis, encompassing autophagy–lysosomal flux, outer segment phagocytosis, mitochondrial function, and regulation of inflammatory [...] Read more.

Prominin-1 (Prom1/CD133) has long been recognized as a structural determinant of photoreceptor outer segment (OS) morphogenesis, yet rapidly accumulating evidence extends its role to retinal pigment epithelium (RPE) homeostasis, encompassing autophagy–lysosomal flux, outer segment phagocytosis, mitochondrial function, and regulation of inflammatory stress. This review synthesizes mechanistic and transcriptomic insights that position PROM1 as a central regulator of photoreceptor and RPE integrity, reframing Prom1 disease as a multi-compartment retinal disorder relevant to both inherited retinal dystrophies (IRDs) and atrophic age-related macular degeneration (aAMD). We develop a dual-axis conceptual model in which Prom1 dysfunction can initiate pathology in either the photoreceptors (OS morphogenesis failure) or the RPE, including impaired autophagic flux, lysosomal activity, defective phagocytosis, and Epithelial-Mesenchymal Transition (EMT)-like de-differentiation, with secondary cross-compartmental degeneration. Clinically, autosomal-dominant missense variants associate with macular or cone-rod dystrophy, whereas biallelic truncating/splice-site mutations drive early-onset rod–cone disease and panretinal/RPE atrophy, illustrating genotype–phenotype diversity. By integrating recent high-resolution transcriptomic data from Prom1-deficient RPE cells with long-standing insights into photoreceptor biology, we highlight converging pathways of degeneration that challenge a photoreceptor-centric view and unify disparate phenotypes within a single molecular framework. These insights broaden the therapeutic landscape, advancing gene augmentation and pathway-targeted strategies to preserve RPE integrity, sustain photoreceptor function, and modify disease course in PROM1-associated IRDs and atrophic AMD. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration: From Pathogenesis to Therapeutic Strategies)

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14 pages, 1884 KB

Open AccessArticle

Headspace Volatile Organic Compound (VOC) Profiling of Infected and Non-Infected Wound Swabs—A Pilot Study

by Shane Fitzgerald, Linda Holland, Melissa Finnegan, Kellie Fortune, Brid Cooney, Eoghan O’Neill, John H. McDermott, Seamus Sreenan, Tommy Kyaw-Tun and Aoife Morrin

Biomolecules 2026, 16(5), 634; https://doi.org/10.3390/biom16050634 - 24 Apr 2026

Abstract

Infections of chronic wounds are a major healthcare burden worldwide and can lead to poor health outcomes such as amputations of limbs and death. Detecting infections early significantly increases the effectiveness of therapeutic interventions. Screening of volatile organic compounds (VOCs) emitted from wound [...] Read more.

Infections of chronic wounds are a major healthcare burden worldwide and can lead to poor health outcomes such as amputations of limbs and death. Detecting infections early significantly increases the effectiveness of therapeutic interventions. Screening of volatile organic compounds (VOCs) emitted from wound swab samples can potentially serve as a highly specific indicator of infection. Profiling of VOCs from infected and non-infected wounds was carried out. Swab samples were collected from 26 wounds from 23 patients (n = 20 diabetic patients; n = 3 non-diabetic patients). There were 16 wounds sampled that were clinically determined as infected, and 10 as non-infected. Headspace-solid phase microextraction gas chromatography-mass spectrometry (HS-GC-MS) was used to rapidly sample and detect VOCs from the swabs following a short incubation period. A total of 42 compounds were identified and included for analysis. Infected wounds emitted more diverse VOCs compared to non-infected wounds. Higher numbers of compounds with significantly higher abundances were detected from severely infected wounds compared to less severely infected wounds. Abundances of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) were found to be the strongest discriminators of infected from non-infected wounds. Further validation is needed, but the results of this pilot study highlight the potential of detecting these compounds as a highly specific and targeted route to predicting or detecting wound infections in the future. Full article

(This article belongs to the Section Molecular Biomarkers)

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26 pages, 6041 KB

Open AccessReview

Computational Approaches to Cancer Cell Dormancy: From Detection to Dynamic Modelling

by Lucas G. N. Spink, Shi Pan, Minyoung Kim, Belis Yener, Borbála Bánfalvi and Maria Secrier

Biomolecules 2026, 16(5), 633; https://doi.org/10.3390/biom16050633 - 24 Apr 2026

Abstract

Cancer cell dormancy is a clinically consequential yet computationally under-defined phenomenon characterised by reversible growth arrest and delayed disease recurrence. Although advances in single-cell and multi-omic profiling have improved detection of dormant and persister populations, their molecular identity and dynamical behaviour remain difficult [...] Read more.

Cancer cell dormancy is a clinically consequential yet computationally under-defined phenomenon characterised by reversible growth arrest and delayed disease recurrence. Although advances in single-cell and multi-omic profiling have improved detection of dormant and persister populations, their molecular identity and dynamical behaviour remain difficult to resolve. In this review, we examine how computational methods have been applied to infer dormant cell identity, heterogeneity, microenvironmental regulation, state transitions, and reactivation dynamics. We highlight how single-cell transcriptomics, lineage tracing, spatial profiling, and integrative multi-omic analyses reveal substantial context-dependent variability, undermining the notion of a universal dormancy signature. We further discuss emerging mathematical and statistical frameworks to model the awakening from dormancy, alongside approaches linking dormancy-associated features to clinical outcomes. Recurring challenges include fragmented operational definitions, rare-state detection, cross-study incompatibility, and the use of snapshot data to interrogate inherently temporal processes. We argue that progress will depend on computational frameworks that treat dormancy as a dynamic, multi-scale systems problem rather than a static cell-type classification task. Full article

(This article belongs to the Special Issue Cellular Quiescence and Dormancy)

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18 pages, 7134 KB

Open AccessArticle

Tyrosine 48 Phosphorylation of Cytochrome c Alters Mitochondrial Respiration, ROS Production, and Apoptosis

by Paul T. Morse, Susanna Vuljaj, Nabil Yazdi, Matthew P. Zurek, Junmei Wan, Icksoo Lee, Asmita Vaishnav, Brian F.P. Edwards, Tasnim Arroum and Maik Hüttemann

Biomolecules 2026, 16(5), 632; https://doi.org/10.3390/biom16050632 (registering DOI) - 24 Apr 2026

Abstract

Cytochrome c (Cytc) tyrosine 48 (Y48) has been previously shown to be phosphorylated in bovine liver, and phosphomimetic substitution (Y48E) inhibits key functions of Cytc in vitro, including respiration and apoptosis. In this study, we investigated the effect of Y48 [...] Read more.

Cytochrome c (Cytc) tyrosine 48 (Y48) has been previously shown to be phosphorylated in bovine liver, and phosphomimetic substitution (Y48E) inhibits key functions of Cytc in vitro, including respiration and apoptosis. In this study, we investigated the effect of Y48 modification in a double-knockout cell culture model that stably expressed either unphosphorylated wild-type (WT) Cytc, control Y48F Cytc, or phosphomimetic Y48E Cytc. Our findings revealed that Y48E Cytc caused partial inhibition of mitochondrial respiration in intact cells, which corresponded with lower mitochondrial membrane potentials (ΔΨ_m) and reduced reactive oxygen species (ROS) production. When subjected to an oxygen–glucose deprivation/reoxygenation (OGD/R) model, which simulates ischemia/reperfusion injury, the Y48E phosphomimetic cell line showed lower ROS production compared to the unphosphorylated WT and Y48F Cytc cell lines, the latter of which generated higher levels of ROS upon reoxygenation. As a result, the Y48E Cytc cell line had significantly lower cell death rates when exposed to OGD/R, confirming the cytoprotective role of Y48 phosphorylation of Cytc. In summary, our research indicates that the loss of Y48 phosphorylation in Cytc during ischemia leads to reperfusion injury by driving maximum electron transport chain flow, hyperpolarization of ΔΨ_m, bursts of ROS, and death of cells through apoptosis. Full article

(This article belongs to the Section Cellular Biochemistry)

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