Biomolecules

17 pages, 3352 KB

Open AccessArticle

Functional Evaluation of Computationally Designed IL-10 in IL-10 KO Mice

by Jordan Stokes, Iram Hyder, Zhihang Shen, Peter Ramdhan, Allison Bayer, Clive Wasserfall, Chenglong Li and Sihong Song

Biomolecules 2026, 16(3), 482; https://doi.org/10.3390/biom16030482 - 23 Mar 2026

Viewed by 1478

Abstract

Studies have shown that IL-10 has therapeutic potential for inflammatory diseases. However, it is challenging to use IL-10 as a therapeutic drug because it also possesses pro-inflammatory functions. To reduce these pro-inflammatory effects of IL-10, we have designed three IL-10 mutants using structure-based [...] Read more.

Studies have shown that IL-10 has therapeutic potential for inflammatory diseases. However, it is challenging to use IL-10 as a therapeutic drug because it also possesses pro-inflammatory functions. To reduce these pro-inflammatory effects of IL-10, we have designed three IL-10 mutants using structure-based computational design technology. We demonstrated that these mutants exhibited significantly lower activity in IL-10-responsive cell lines than wild-type IL-10. Using recombinant adeno-associated virus (rAAV8) vectors expressing wild-type or mutant IL-10 molecules, we performed gene therapy experiments in IL-10 KO mice. The results showed that our vectors mediated high levels of transgene expression. Importantly, IL-10 gene therapy increased body weight gain, reduced colon injury, and prevented the development of inflammatory bowel disease (IBD). Moreover, IL-10 mutant gene therapy elicited significantly lower stimulation of CD8 T and NK cells compared with the wild-type IL-10 group. In summary, our IL-10 mutants provide a protective effect comparable to wild-type IL-10 in the IL-10 KO mouse model, suggesting that they may potentially have reduced pro-inflammatory function. While rigorous investigations of safety and efficacy in different disease models will be required, these results indicate the therapeutic potential of IL-10 mutant gene therapy for inflammatory diseases such as IBD. Full article

(This article belongs to the Special Issue Advancing Innovations in Biomedical Research for Translational Applications)

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14 pages, 3962 KB

Open AccessArticle

Targeting LIPA with ERX-41 Induces ER Stress and Inhibits Tumor Progression in Inflammatory Breast Cancer

by Zenaida Fuentes, Gaurav Sharma, Bianca A. Romo, Rahul Gopalam, Khaled Mohamed Nassar, Paulina Ramirez, Nicole Mejia, Chia-Yuan Chen, Scott Elmore, Henry Neal, Harika Nagandla, Panneerdoss Subbarayalu, Uday P. Pratap, Christoforos Thomas, Jung-Mo Ahn, Ganesh V. Raj, Suryavathi Viswanadhapalli and Ratna K. Vadlamudi

Biomolecules 2026, 16(3), 481; https://doi.org/10.3390/biom16030481 - 23 Mar 2026

Viewed by 1506

Abstract

Approximately 2–4% of all breast cancer cases are inflammatory breast cancer (IBC), an extremely rare and severe subtype of the disease. Current therapies, including chemotherapy, surgery, and radiotherapy, remain insufficient, underscoring the need for novel therapeutic approaches. IBC exhibits elevated basal endoplasmic reticulum [...] Read more.

Approximately 2–4% of all breast cancer cases are inflammatory breast cancer (IBC), an extremely rare and severe subtype of the disease. Current therapies, including chemotherapy, surgery, and radiotherapy, remain insufficient, underscoring the need for novel therapeutic approaches. IBC exhibits elevated basal endoplasmic reticulum (ER) stress, suggesting a potential vulnerability. We recently developed ERX-41, a small molecule that exacerbates ER stress in cancer cells by inhibiting the endoplasmic reticulum-localized function of Lysosomal acid lipase A (LIPA). Here, we evaluated the therapeutic potential of ERX-41 in IBC models. ERX-41 markedly reduced the viability of IBC cells and significantly impaired clonogenic survival while promoting apoptosis. The specificity of ERX-41 was confirmed using LIPA-knockdown and LIPA-knockout cells. RT-PCR-based assays revealed rapid induction of XBP1 splicing within 6 h of treatment, and Western blot analyses demonstrated activation of ER stress markers including CHOP, PERK, and ATF4. In KPL4 xenografts, ERX-41 treatment significantly decreased tumor volume, accompanied by reduced proliferation and increased ER stress marker expression by IHC. Collectively, these findings identify LIPA as a therapeutically actionable vulnerability in IBC and establish ERX-41 as a potential drug for IBC. Full article

(This article belongs to the Section Molecular Medicine)

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35 pages, 1310 KB

Open AccessReview

Effects of Naringenin in Preclinical Models of Breast Cancer

by Emily C. Irwin, Newman Siu Kwan Sze and Evangelia Tsiani

Biomolecules 2026, 16(3), 480; https://doi.org/10.3390/biom16030480 - 23 Mar 2026

Cited by 1 | Viewed by 1146

Abstract

Breast cancer is the most commonly diagnosed cancer among women, with approximately one in eight women developing the disease during their lifetime. Despite advancements in current treatment options, breast cancer was responsible for an estimated 670,000 deaths worldwide in 2022. This highlights the [...] Read more.

Breast cancer is the most commonly diagnosed cancer among women, with approximately one in eight women developing the disease during their lifetime. Despite advancements in current treatment options, breast cancer was responsible for an estimated 670,000 deaths worldwide in 2022. This highlights the urgent need for the development of novel therapeutic strategies. Historically, plant-derived compounds have played a significant role in cancer therapy, exemplified by widely used chemotherapeutic agents such as paclitaxel and docetaxel. In recent years, increasing attention has been directed toward novel plant-derived compounds as potential anti-cancer agents. Among these, Naringenin, a flavonoid predominantly found in citrus fruits, has shown promising antioxidant, anti-inflammatory, and anti-cancer properties. This review highlights recent studies investigating the effects of Naringenin and its derivatives on breast cancer. Evidence from both in vitro and in vivo animal models suggests that Naringenin may exert anti-tumor activity by inhibiting cell proliferation, promoting apoptosis, modulating key cell signaling pathways, and enhancing radio-sensitivity in breast cancer cells. Although preclinical evidence strongly supports the anticancer potential of Naringenin in breast cancer, comprehensive clinical studies are urgently needed to validate its efficacy and safety in humans. Full article

(This article belongs to the Special Issue Novel Molecules for Cancer Treatment (3rd Edition))

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13 pages, 500 KB

Open AccessHypothesis

The Osteoimmune Axis: Immune–Mechanical Crosstalk in Periodontal Bone Remodeling

by Anna Ewa Kuc, Grzegorz Hajduk, Paulina Kuc, Joanna Lis, Beata Kawala and Michał Sarul

Biomolecules 2026, 16(3), 479; https://doi.org/10.3390/biom16030479 - 23 Mar 2026

Cited by 1 | Viewed by 1132

Abstract

Background: Orthodontic tooth movement is traditionally explained through mechanical deformation of the periodontal ligament (PDL); however, increasing evidence indicates that immune mechanisms critically shape bone remodeling outcomes. Mechanical stimuli influence immune cell recruitment, cytokine release, and phenotypic polarization, but these components are rarely [...] Read more.

Background: Orthodontic tooth movement is traditionally explained through mechanical deformation of the periodontal ligament (PDL); however, increasing evidence indicates that immune mechanisms critically shape bone remodeling outcomes. Mechanical stimuli influence immune cell recruitment, cytokine release, and phenotypic polarization, but these components are rarely integrated into a unified framework. Conceptual framework: We propose the Osteoimmune Axis Model, a conceptual framework describing how mechanical loading may bias immune polarity and thereby gate periodontal remodeling. Compressive loading appears to favor an M1 macrophage/Th17-dominant program associated with pro-inflammatory cytokines and enhanced RANKL-mediated osteoclastogenesis. In contrast, tensile or physiological strains may favor M2 macrophages and regulatory T cells (Treg), supporting IL-10, TGF-β, angiogenesis, extracellular-matrix repair, and osteoblastic activity. Stromal cells are proposed to act as mechanosensors and immune amplifiers that shape cytokine gradients and feedback loops. Predictions: The model predicts that identical forces may produce divergent outcomes depending on immune baseline; load duration may be more destructive than peak magnitude; tensile strain may stabilize M2/Treg pathways; thin periodontal phenotypes may shift toward the catabolic pole at lower mechanical loads; ROS may amplify immune-mediated bone loss; and immunomodulation may raise the threshold for pathological remodeling. Conclusion: The Osteoimmune Axis integrates mechanobiology and immunology into a testable framework for explaining variability in orthodontic periodontal remodeling and for generating hypothesis-driven, immune-aware risk assessment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Microenvironmental Regulation in Bone-Related Diseases and Muscle Atrophy)

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16 pages, 4767 KB

Open AccessArticle

Synthesis of BSA-Coated Iron Oxide Nanoparticles with Size Control for High-Performance T₁ Contrast Agents in Magnetic Resonance Imaging

by Bosede Kolawole, Jie Zheng, Dongmei Cao and Yongfeng Zhao

Biomolecules 2026, 16(3), 478; https://doi.org/10.3390/biom16030478 - 23 Mar 2026

Viewed by 1066

Abstract

The excellent biocompatibility and favorable physicochemical properties of iron oxide nanoparticles have made them attractive candidates for magnetic resonance imaging. However, it remains challenging to synthesize high-performance T₁ contrast agents with controlled sizes and biocompatible coating materials. In this study, we demonstrate [...] Read more.

The excellent biocompatibility and favorable physicochemical properties of iron oxide nanoparticles have made them attractive candidates for magnetic resonance imaging. However, it remains challenging to synthesize high-performance T₁ contrast agents with controlled sizes and biocompatible coating materials. In this study, we demonstrate a simple and environmentally friendly approach for synthesizing ultra-small iron oxide nanoparticles using bovine serum albumin (BSA) as a template. Following synthesis, the iron oxide nanoparticles (Fe₃O₄) were oxidized to Fe₂O₃ via the addition of hydrogen peroxide, which resulted in enhanced T₁-weighted magnetic resonance contrast. The use of BSA not only stabilized the nanoparticles but also enabled precise control over nanoparticle size by adjusting the Fe-to-BSA molar ratio. This method yielded highly uniform and crystalline ultra-small nanoparticles ranging from approximately 3.7 to 7.9 nm in diameter. The T₁ contrast performance of the Fe₂O₃@BSA nanoparticles was evaluated at 3 T magnetic field. Among the synthesized samples, nanoparticles with sizes of 4.6 nm exhibited the strongest T₁ contrast enhancement along with low r₂/r₁ ratios. These features highlight their potential as promising alternatives to gadolinium-based contrast agents. In addition to their superior performance, this synthesis method is low-cost and non-toxic, making it suitable for scalable biomedical applications. Full article

(This article belongs to the Special Issue Advances in Nano-Based Drug Delivery: Unveiling the Next Frontier)

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17 pages, 912 KB

Open AccessReview

Decoding the Regulatory Mechanism of Astaxanthin on Autophagy: Insights for Anti-Inflammatory Intervention

by Li Feng, Ming Yu, Xiao Ma, Peixi Qin and Yi Zhang

Biomolecules 2026, 16(3), 477; https://doi.org/10.3390/biom16030477 - 23 Mar 2026

Cited by 1 | Viewed by 1641

Abstract

Autophagy is a crucial process for cellular self-regulation and renewal. Upon exposure to stress, membrane structures—primarily derived from the endoplasmic reticulum and mitochondria, with contributions from the plasma membrane—drive autophagosome biogenesis. This process begins with the formation of a cup-shaped phagophore, which elongates [...] Read more.

Autophagy is a crucial process for cellular self-regulation and renewal. Upon exposure to stress, membrane structures—primarily derived from the endoplasmic reticulum and mitochondria, with contributions from the plasma membrane—drive autophagosome biogenesis. This process begins with the formation of a cup-shaped phagophore, which elongates to sequester cytoplasmic cargo, closes to form an autophagosome, and ultimately fuses with lysosomes to create an autolysosome where degradation and recycling occur. This regulated process plays a vital role in maintaining cellular homeostasis, the pathogenesis of various diseases, and modulation of inflammation. Astaxanthin (AST), a carotenoid produced by microalgae, various microorganisms and marine organisms, possesses a unique chemical structure that endows it with significant biological activities, including potent antioxidant and anti-inflammatory properties. Emerging evidence, primarily from preclinical studies, suggests that AST modulates autophagy by regulating signaling pathways such as Reactive Oxygen Species (ROS)/Mitogen-activated Protein Kinase (MAPK) and interacting with nuclear factor erythroid 2-related factor 2(Nrf2)-mediated antioxidant responses, thereby influencing inflammatory balance. This review systematically elucidates how AST acts as a key “molecular modulator” in animal or cellular models, dynamically regulating autophagy to restore cellular homeostasis and thereby influencing the course and outcome of inflammation. Furthermore, we explore the autophagy-mediated anti-inflammatory effects of AST across different organ systems and discuss its preliminary clinical translational potential and future challenges, aiming to provide a concise and forward-looking roadmap for this promising research field. Full article

(This article belongs to the Section Molecular Medicine)

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27 pages, 4674 KB

Open AccessArticle

A Novel Drug Delivery System for the Treatment of Lupus Nephritis: From Delivery System Design and Optimization to Treatment

by Xumeng Xiong, Jin Tao, Zequn Jin and Ying Hu

Biomolecules 2026, 16(3), 476; https://doi.org/10.3390/biom16030476 - 23 Mar 2026

Viewed by 2133

Abstract

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), characterized by immune system disorders and multiple organ damage. Current clinical treatment of LN requires a complex multi-drug combination, which is often associated with severe side effects and low patient compliance. [...] Read more.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), characterized by immune system disorders and multiple organ damage. Current clinical treatment of LN requires a complex multi-drug combination, which is often associated with severe side effects and low patient compliance. The aim of this study was to design a self-nanoemulsifying drug delivery system (SNEDDS) co-loading total glucosides of Paeonia (TGP) and dihydroartemisinin (DHA) to increase the solubility of the drug as well as achieve synergistic anti-inflammatory and immunomodulatory effects for LN therapy. Network pharmacology, molecular docking and molecular dynamics simulations were employed to predict the core therapeutic targets and related signaling pathways. The SNEDDS co-loaded with TGP and DHA was optimized via central composite design response surface methodology (CCD-RSM). Its physicochemical properties, particle size and the polydispersity index (PDI) of the optimized formulation were characterized. In vivo therapeutic efficacy was evaluated in MRL/lpr mice by measuring disease-related indicators (urinary protein, serum ANA, and anti-ds-DNA) and inflammatory cytokines (TNF-α, IL-6, and IL-1β). Renal tissue pathology was also examined. All data were analyzed by one-way analysis of variance (ANOVA) with p < 0.05 considered statistically significant. The core therapeutic targets predicted with high relevance were AKT1, MAPK1, MAPK3, and RELA. The optimized SNEDDS achieved a high loading capacity of 16.11 ± 0.43 mg/g for TGP and 12.79 ± 1.33 mg/g for DHA, with a particle size of (25.84 ± 0.30) nm and PDI of (0.07 ± 0.02). In MRL/lpr mice, SNEDDS treatment significantly reduced urinary protein levels (p < 0.01), serum ANA (p < 0.01) and anti-ds-DNA titers (p < 0.01) compared with the model group. Additionally, the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) were markedly decreased (p < 0.05), and renal tissue damage was alleviated. Conclusions: The SNEDDS co-loaded TGP and DHA is a promising oral nanotherapeutic strategy for LN, offering synergistic anti-inflammatory and immunomodulatory effects. Full article

(This article belongs to the Section Molecular Medicine)

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26 pages, 1953 KB

Open AccessArticle

Peripheral Oxidation-Inflammation and Immunosenescence in Triple-Transgenic Mice for Alzheimer’s Disease (3xTg-AD) at Early Neuropathological Stages of Disease and Decrease of Immune Impairment by Voluntary Exercise

by Mónica De la Fuente, Antonio Garrido, Carmen Vida, Rashed Manassra and Lydia Gimenez-Llort

Biomolecules 2026, 16(3), 475; https://doi.org/10.3390/biom16030475 - 22 Mar 2026

Cited by 1 | Viewed by 940

Abstract

Inflammatory-oxidative stress generated by immune cells plays an important role in aging and in age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Triple-transgenic mice for AD (3xTg-AD) are a suitable model for mimicking this disease in an age-dependent manner. We previously showed that [...] Read more.

Inflammatory-oxidative stress generated by immune cells plays an important role in aging and in age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Triple-transgenic mice for AD (3xTg-AD) are a suitable model for mimicking this disease in an age-dependent manner. We previously showed that peritoneal leukocyte functions and their redox-inflammatory state are altered early in female 3xTg-AD mice, which exhibit premature aging compared to non-transgenic (NTg) animals. However, their characteristics at 9 months of age, when they present an early neuropathological state, and the sex differences are not known. Here, we analyzed several spleen and thymus leukocyte functions (chemotaxis, natural killer activity, and lymphoproliferation in response to mitogens), pro-inflammatory (IL-1B, TNF-alpha) and anti-inflammatory (IL-10) released cytokine concentrations, and redox parameters (glutathione concentrations and glutathione peroxidase, glutathione reductase, and xanthine oxidase activities) in male and female 3xTg-AD mice compared to age-matched controls. We also analyzed the effects of voluntary physical exercise on immune functions. Our results show that 9-month-old male and female 3xTg-AD mice have worse immune functions, redox state, and inflammation than NTg counterparts. Physical exercise improves immune function. Thus, accelerated aging reflected by peripheral immunosenescence and oxidation-inflammation in 3xTg-AD mice precedes hallmark neuropathology, and exercise can slow down AD progression. Full article

(This article belongs to the Special Issue Inflammatory Mechanisms and Molecular Targets in Neurological Disorders: Effects of Neuroprotective Drugs)

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22 pages, 8535 KB

Open AccessArticle

Endogenous and Exogenous Small RNA Signatures as Novel Tools for Postmortem Interval Determination

by Yafei Wang, Botao Li, Yue Wang, Qinmin Chen, Zhonghua Wang, Guangping Fu, Shujin Li, Chenyu Zhang, Zhen Zhou and Bin Cong

Biomolecules 2026, 16(3), 474; https://doi.org/10.3390/biom16030474 - 22 Mar 2026

Viewed by 1153

Abstract

Background: Accurate estimation of the postmortem interval (PMI), the time elapsed between death and body discovery, is a critical challenge in forensic science due to the complex interplay of factors affecting decomposition. Traditional methods based on macroscopic changes often lack precision, especially in [...] Read more.

Background: Accurate estimation of the postmortem interval (PMI), the time elapsed between death and body discovery, is a critical challenge in forensic science due to the complex interplay of factors affecting decomposition. Traditional methods based on macroscopic changes often lack precision, especially in later postmortem stages. Methods: This study aimed to develop a novel PMI estimation framework by integrating the dynamics of endogenous small non-coding RNAs (sncRNAs) and exogenous bacterial-derived small RNAs (sRNAs) using sRNA transcriptomics and machine learning. Results: Cardiac RNA degradation strongly correlated with PMI, with a random forest (RF) model achieving high accuracy (coefficient of determination (R²) = 0.939, mean absolute error (MAE) = 2.987 h). Employing PANDORA-seq, we profiled temporal changes in sncRNAs (miRNAs, tsRNAs and piRNAs) in postmortem cardiac tissue within 30 h in a mouse model, while simultaneously assessing RNA integrity (RIN) across eight organs. PANDORA-seq revealed stable sncRNA landscapes with specific dynamic shifts, leading to the identification of seven novel biomarkers (four tsRNAs, three piRNAs) for PMI prediction (R² = 0.760, MAE = 158.990 min). Bacterial-derived sRNAs, predominantly from Staphylococcus aureus, were upregulated at 30 h postmortem, suggesting complementary biomarker potential. Bioinformatics analysis indicated that host miRNAs may target bacterial mRNAs, hinting at cross-kingdom interactions. Conclusion: These findings highlight the potential of integrated endogenous and exogenous sRNA analysis in PMI estimation, providing a high-precision, rapid diagnostic tool and revealing complex postmortem molecular processes. Full article

(This article belongs to the Collection Feature Papers in Molecular Biomarkers)

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26 pages, 2736 KB

Open AccessReview

Palmitoylation in Renal Physiology and Pathology

by Jingru Ma, Zhen Zhang, Jiaqi Guo, Hu Cai, Jian Yao, Dahai Yang, Huiyuan Zhu, Haijing Liu, Changhe Wang and Hongbo Xu

Biomolecules 2026, 16(3), 473; https://doi.org/10.3390/biom16030473 - 22 Mar 2026

Viewed by 1161

Abstract

Palmitoylation is a critical post-translational modification that involves the covalent binding of palmitic acid to cysteine residues within proteins. It is widely recognized that palmitoylation plays a significant role in regulating protein membrane localization, stability, and interactions. The kidney plays a key role [...] Read more.

Palmitoylation is a critical post-translational modification that involves the covalent binding of palmitic acid to cysteine residues within proteins. It is widely recognized that palmitoylation plays a significant role in regulating protein membrane localization, stability, and interactions. The kidney plays a key role in maintaining fluid homeostasis and excreting metabolic waste, and its normal function relies on the precise regulation of protein function. Emerging evidence reveals the crucial role of palmitoylation in renal physiological and pathological processes. However, the intricate pathways and molecular regulators in the kidney that are involved in palmitoylation remain insufficiently elucidated. This review summarizes the role and possible underlying physiological and pathological mechanism of palmitoylation in the kidney, including enzymes and inhibitors that regulate palmitoylation, the signaling pathways involved, target proteins involved in palmitoylation, and specific modification sites. Moreover, we focus on detection techniques and corresponding research strategies for palmitoylation. This review can also serve as a practical reference to improve the understanding of palmitoylation and the treatment of kidney-related diseases. Full article

(This article belongs to the Section Molecular Biology)

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19 pages, 3015 KB

Open AccessArticle

The Role of Cholesterol at the CHOL2 Site and the Dimeric Interface in the Regulation of Serotonin Transporter Function and Dimerization

by Jian Yang, Chan Li, Xingyu Huang and Yuan-Wei Zhang

Biomolecules 2026, 16(3), 472; https://doi.org/10.3390/biom16030472 - 21 Mar 2026

Viewed by 780

Abstract

Serotonin transporter (SERT) precisely regulates serotonin (5–HT) signaling in the central nervous system and is a major target of antidepressants for the treatment of major depressive disorder. Despite significant progress in characterizing its structure and transport mechanism, the regulation of SERT function by [...] Read more.

Serotonin transporter (SERT) precisely regulates serotonin (5–HT) signaling in the central nervous system and is a major target of antidepressants for the treatment of major depressive disorder. Despite significant progress in characterizing its structure and transport mechanism, the regulation of SERT function by various modulators remains to be fully understood. In the present study, we focused on two potential cholesterol sites in human SERT to investigate cholesterol occupation at these sites and its functional relevance by biochemical approaches. Mutations of an intramolecular site (CHOL2) significantly decreased both specific transport activity and K_m for 5–HT and stabilized the transporter in an inward-facing conformation. In addition, our NanoBiT luminescent assay for protein–protein proximity demonstrated that cholesterol mediated the protomer–protomer interactions by residing in a site at the dimeric interface. Mutations of the interfacial site remarkably reduced the interactions between SERT protomers and substantially impaired their transport activity. The structural analysis indicated that the residues participating in cholesterol residing in the interfacial site were conformationally sensitive. Thus, we have proposed that cholesterol at these sites could play a vital role in the regulation of SERT function by a conformational mechanism. Our study has provided new insights into the molecular mechanism by which cholesterol can regulate SERT function and dimerization. Full article

(This article belongs to the Special Issue The Structure and Function of Neurotransmitter Receptors and Transporters: From Molecular Biology to Translational Research)

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32 pages, 14438 KB

Open AccessArticle

Divergent Amplification of Y-Linked Dosage-Sensitive Genes Triggers Regulatory Mismatch Underlying Cattle–Yak Male Sterility

by Yu Wang, Yulin Chen, Zhenlin Zhu, Xiaofei Zeng, Wei Ha, Longwei Su, Lian Hu, Yili Liu, Biao Li, Juan Loor and Mingfeng Jiang

Biomolecules 2026, 16(3), 471; https://doi.org/10.3390/biom16030471 - 21 Mar 2026

Cited by 1 | Viewed by 857

Abstract

As the hybrid offspring of cattle and yak, cattle–yaks suffer from male sterility, manifesting as cascading spermatogenic failure. Despite the Y chromosome’s pivotal role in spermatogenesis, the absence of a high-quality yak Y assembly has long impeded mechanistic understandings from this perspective. Here, [...] Read more.

As the hybrid offspring of cattle and yak, cattle–yaks suffer from male sterility, manifesting as cascading spermatogenic failure. Despite the Y chromosome’s pivotal role in spermatogenesis, the absence of a high-quality yak Y assembly has long impeded mechanistic understandings from this perspective. Here, a near-complete 42.4 Mb yak Y chromosome is constructed through a multi-stage assembly strategy that integrates de novo assembly with pangenome graph construction and Hi-C guided refinement. By developing a rigorously standardized gene annotation pipeline for precise cross-species comparison, we find that yaks have undergone a greater expansion of Y-linked ampliconic genes than cattle. Integrating this ampliconic landscape with short-read and full-length transcriptomics further demonstrates that yaks exhibit a drastic 2-to-4-fold increase in transcriptionally active copies of spermatogenesis-related ampliconic genes (including TSPY1, ZNF280BY, HSFY and PRAMEY) relative to cattle. Given negligible homology outside the pseudoautosomal region and conservation of key meiotic proteins, we propose a ‘cis-trans regulatory mismatch’ model driven by divergent Y-linked amplification as a working hypothesis to explain the primary genetic mechanism of cattle–yak male sterility. Together, these findings offer critical insights for addressing cattle–yak male sterility and establish the Y chromosome as an active driver of reproductive isolation beyond its traditional degenerate characterization. Full article

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

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26 pages, 995 KB

Open AccessReview

Oxidative Stress in Diabetic Cardiomyopathy: Molecular Mechanisms and Emerging Therapeutic Targets

by Umberto Capece, Davide Nilo, Cassandra Morciano, Roberto Nilo, Serenella Spiezia, Marta Chiara Sircana, Vincenzo Russo, Marco Alfonso Perrone, Leonilde Bonfrate, Carlo Acierno, Ferdinando Carlo Sasso and Alfredo Caturano

Biomolecules 2026, 16(3), 470; https://doi.org/10.3390/biom16030470 - 20 Mar 2026

Cited by 4 | Viewed by 2408

Abstract

Diabetic cardiomyopathy (DCM) is a distinct myocardial disorder that develops independently of coronary artery disease and hypertension and represents a major contributor to heart failure in patients with diabetes. Beyond hemodynamic alterations, DCM is driven by complex molecular mechanisms involving metabolic dysregulation, mitochondrial [...] Read more.

Diabetic cardiomyopathy (DCM) is a distinct myocardial disorder that develops independently of coronary artery disease and hypertension and represents a major contributor to heart failure in patients with diabetes. Beyond hemodynamic alterations, DCM is driven by complex molecular mechanisms involving metabolic dysregulation, mitochondrial dysfunction, inflammation, and fibrotic remodeling. Increasing evidence identifies oxidative stress as a central integrative process linking these pathogenic pathways in the diabetic heart. Chronic hyperglycemia, insulin resistance, and altered substrate utilization promote excessive generation of reactive oxygen species, overwhelming endogenous antioxidant defenses and disrupting myocardial redox homeostasis. Oxidative stress induces direct damage to lipids, proteins, and DNA while simultaneously activating redox-sensitive signaling pathways that amplify inflammation, endothelial dysfunction, cardiomyocyte apoptosis, and fibrosis. In addition, epicardial and visceral adipose tissue have emerged as active contributors to myocardial oxidative stress through paracrine and systemic mechanisms, reinforcing inflammatory and fibrotic crosstalk. This review provides a comprehensive overview of the molecular sources and targets of oxidative damage in DCM, examines the impairment of antioxidant defense systems, and discusses emerging therapeutic strategies aimed at restoring redox balance. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Cardiopathy and Therapeutic Strategies)

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23 pages, 1693 KB

Open AccessReview

The Mast Cell–PAR2–TRP Axis: A Convergent Mechanism for Visceral Hypersensitivity Independent of Divergent Motility in IBS

by Kaiyue Deng, Jiazhen Cao, Zitong Wang, Jing He, Jialin Jia, Ru Nie, Xingbang Wang, Zhiqiang Dou, Zijian Liu, Yongzhi Deng and Tie Li

Biomolecules 2026, 16(3), 469; https://doi.org/10.3390/biom16030469 - 20 Mar 2026

Cited by 1 | Viewed by 1508

Abstract

Most patients with irritable bowel syndrome have diarrhea or constipation, two opposite bowel habits. Although defecation habits represent opposing phenotypes, patients across all subtypes exhibit visceral hypersensitivity. This review explores the common pathway that causes visceral hypersensitivity: the mast cell–PAR2–TRP axis. The mechanism [...] Read more.

Most patients with irritable bowel syndrome have diarrhea or constipation, two opposite bowel habits. Although defecation habits represent opposing phenotypes, patients across all subtypes exhibit visceral hypersensitivity. This review explores the common pathway that causes visceral hypersensitivity: the mast cell–PAR2–TRP axis. The mechanism involves tryptase released by mast cells. Furthermore, tryptase activates PAR2, which sensitizes downstream TRP ion channels that conduct pain signals. The review also examines the factors leading to the formation of different fecal characteristics. In terms of treatment, this review also summarizes therapeutic agents targeting different components of this axis. Future pharmaceutical research should focus more on the mast cell–PAR2–TRP axis. Full article

(This article belongs to the Special Issue TRP Channels in Cardiovascular and Inflammatory Disease, 2nd Edition)

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27 pages, 10408 KB

Open AccessArticle

Integrative Multi-Analysis Identifies METTL3-Regulated FGF19 and H6PD as Candidate Targets in Diabetic Cognitive Impairment

by Jun Fu, Huarui Wang, Junjie Yan, Weiyuan Chen, Ruguang Wang, Hongchang Gao and Chen Li

Biomolecules 2026, 16(3), 468; https://doi.org/10.3390/biom16030468 - 20 Mar 2026

Viewed by 1034

Abstract

Diabetic cognitive impairment (DCI) is a serious and growing public health concern. The role of N6-methyladenosine (m⁶A), the predominant mRNA modification in the mammalian brain, in DCI pathogenesis remains not fully elucidated. Here, GEO-derived diabetes datasets were combined with in vivo [...] Read more.

Diabetic cognitive impairment (DCI) is a serious and growing public health concern. The role of N6-methyladenosine (m⁶A), the predominant mRNA modification in the mammalian brain, in DCI pathogenesis remains not fully elucidated. Here, GEO-derived diabetes datasets were combined with in vivo and in vitro models to reveal aberrant expression of m⁶A-related genes. The results showed that the overall level of m⁶A RNA methylation in both the diabetic group and the high-glucose group was significantly decreased compared to the normal group. In addition, the expression of methyltransferase METTL3, which is involved in the regulation of m⁶A RNA methylation, was downregulated in both diabetic and hyperglycemic groups, and was positively correlated with the downregulation of the overall m⁶A level. Neuronal models with stable METTL3 knockdown were generated using lentiviral transduction. Subsequent ¹H-NMR metabolomic and MeRIP-qPCR analyses demonstrated that METTL3 deficiency disrupts key metabolic pathways, including phosphatidylethanolamine and phosphatidylcholine biosynthesis and glucose–alanine metabolism, and identified Fgf15 (the mouse ortholog of human FGF19) and H6PD as candidate downstream targets. Collectively, these data suggest that METTL3-dependent m⁶A RNA methylation alterations may contribute to DCI through metabolic dysregulation, positioning METTL3 as a promising therapeutic target for DCI. Full article

(This article belongs to the Section Molecular Genetics)

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26 pages, 976 KB

Open AccessReview

Next-Generation Metabolic Reprogramming in iPSC-Derived Cardiomyocytes: CRISPR-EV Synergy for Precision Cardiac Regeneration

by Dhienda C. Shahannaz and Tadahisa Sugiura

Biomolecules 2026, 16(3), 467; https://doi.org/10.3390/biom16030467 - 20 Mar 2026

Cited by 2 | Viewed by 1559

Abstract

Cardiovascular disease remains the leading global cause of mortality, largely due to the limited regenerative capacity of adult human myocardium. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a scalable platform for cardiac repair and disease modeling; however, their persistent metabolic immaturity—characterized by reliance [...] Read more.

Cardiovascular disease remains the leading global cause of mortality, largely due to the limited regenerative capacity of adult human myocardium. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a scalable platform for cardiac repair and disease modeling; however, their persistent metabolic immaturity—characterized by reliance on glycolysis, reduced oxidative phosphorylation (OXPHOS), and structurally underdeveloped mitochondria—limits functional integration and long-term therapeutic efficacy. Recent advances indicate that targeted metabolic reprogramming can enhance mitochondrial biogenesis, increase ATP production, and improve stress resilience in iPSC-CMs. This review examines the complementary integration of CRISPR-based metabolic engineering and extracellular vesicle (EV)-mediated metabolic modulation as a systems-level strategy for cardiac maturation. We discuss CRISPR activation, interference, and epigenome-editing approaches targeting regulators such as PGC-1α, TFAM, and PPARs to promote stable enhancement of mitochondrial networks and respiratory capacity. In parallel, engineered EVs delivering miRNAs, metabolic enzymes, and redox modulators provide non-genomic mechanisms to optimize bioenergetic function and mitigate oxidative stress. By synthesizing mechanistic insights, quantitative bioenergetic metrics, and translational considerations, we propose CRISPR-EV synergy as a precision framework for durable metabolic maturation of iPSC-CMs, with implications for regenerative therapy, pharmacologic screening, and myocardial repair. Full article

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

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22 pages, 2051 KB

Open AccessReview

Dynamic Coordination: How ERF Transcription Factors Coordinate Plant Development and Adaptive Stress Responses

by Mingcheng Wang, Panyue Du, Liyang Xi, Haifeng Lin and Shuqiao Zhang

Biomolecules 2026, 16(3), 466; https://doi.org/10.3390/biom16030466 - 19 Mar 2026

Cited by 27 | Viewed by 1436

Abstract

As sessile organisms, plants must dynamically allocate resources between growth and stress resilience. This review focuses on Ethylene Response Factor (ERF) transcription factors as central regulators of this fundamental balance. We evaluate the molecular basis of ERF function, highlighting their modular structure, dynamic [...] Read more.

As sessile organisms, plants must dynamically allocate resources between growth and stress resilience. This review focuses on Ethylene Response Factor (ERF) transcription factors as central regulators of this fundamental balance. We evaluate the molecular basis of ERF function, highlighting their modular structure, dynamic post-translational regulation, and ability to form context-specific protein complexes that integrate diverse signals. While ERF family members show functional redundancy, certain ERF subgroups, such as the ERF-VIIs, exhibit clearer evidence of dual roles in coordinating both developmental programs and adaptive responses to stress. We further elucidate the mechanisms underlying ERF-mediated trade-offs, explaining how these factors direct spatial resource allocation and enable temporal switching between growth and defense states. Finally, we explore how emerging technologies, such as CRISPR-based genome editing and various synthetic biology tools, can harness ERF regulatory networks. These approaches offer promising strategies for engineering crops with precisely tuned adaptive capacity, supporting sustainable agriculture even in changing climate conditions. This synthesis highlights specific ERF subgroups as pivotal integrators and future targets for crop improvement. Full article

(This article belongs to the Special Issue Molecular Regulation of Transcription Factors in Plant Growth and Stress Responses)

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26 pages, 727 KB

Open AccessReview

Gintonin as a Lysophosphatidic Acid-Enriched GPCR Ligand System: Molecular Architecture and Receptor Pharmacology in Panax ginseng

by Kyung-Hee Kim and Byong Chul Yoo

Biomolecules 2026, 16(3), 465; https://doi.org/10.3390/biom16030465 - 19 Mar 2026

Cited by 1 | Viewed by 864 | Correction

Abstract

For decades, the pharmacological identity of Panax ginseng has been primarily attributed to triterpenoid saponins known as ginsenosides. However, accumulating evidence indicates that ginseng also contains a structurally distinct lipid–protein complex, termed gintonin, enriched in lysophosphatidic acid (LPA) species. Unlike ginsenosides, which predominantly [...] Read more.

For decades, the pharmacological identity of Panax ginseng has been primarily attributed to triterpenoid saponins known as ginsenosides. However, accumulating evidence indicates that ginseng also contains a structurally distinct lipid–protein complex, termed gintonin, enriched in lysophosphatidic acid (LPA) species. Unlike ginsenosides, which predominantly exert modulatory effects on membrane dynamics and intracellular kinase pathways, gintonin directly activates LPA G protein-coupled receptors (GPCRs), thereby inducing rapid phospholipase C (PLC) activation and intracellular Ca²⁺ mobilization. Biochemical analyses have identified major LPA species within the gintonin fraction, including C16:0, C18:1, and other unsaturated LPA species such as C18:2 stabilized within a proteinaceous matrix that may influence receptor engagement kinetics. Pharmacological studies demonstrate that gintonin preferentially activates LPA₁ and LPA₃ receptor subtypes, triggering downstream signaling cascades involving MAPK, PI3K/Akt, and Rho pathways. These receptor-mediated effects occur on a rapid temporal scale, distinguishing gintonin from the slower transcriptional and kinase-modulating actions of ginsenosides. In this review, we synthesize current evidence regarding the chemical architecture, receptor pharmacology, and signaling dynamics of gintonin and propose a dual signaling framework in which steroid-like saponins and lipid GPCR ligands represent complementary molecular axes within P. ginseng. Recognition of this layered signaling organization refines the molecular understanding of ginseng biology and highlights gintonin as a unique plant-derived GPCR ligand system.
Full article

(This article belongs to the Section Lipids)

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19 pages, 2012 KB

Open AccessReview

Ganglioside GM3 in the Tumor Microenvironment: Mechanisms of Signaling Regulation and Strategies for Angiogenesis Inhibition

by Min Zeng, Hongda Zhuang, Siyuan Zhao, Roger Chammas and Yong Chen

Biomolecules 2026, 16(3), 464; https://doi.org/10.3390/biom16030464 - 19 Mar 2026

Cited by 4 | Viewed by 1133

Abstract

Ganglioside GM3, a fundamental glycosphingolipid on the mammalian cell surface, is a key regulator of transmembrane signaling and cellular recognition. In oncology, GM3 acts as a tumor suppressor by modulating the activity of various receptor tyrosine kinases (RTKs) and their downstream pathways. Recent [...] Read more.

Ganglioside GM3, a fundamental glycosphingolipid on the mammalian cell surface, is a key regulator of transmembrane signaling and cellular recognition. In oncology, GM3 acts as a tumor suppressor by modulating the activity of various receptor tyrosine kinases (RTKs) and their downstream pathways. Recent studies highlight its function in the tumor microenvironment (TME), specifically its ability to impede pathological angiogenesis. This review summarizes the molecular mechanisms by which GM3 interferes with pro-angiogenic signaling, such as the VEGF/VEGFR axis, and discusses how this inhibition can be used for therapy. We explore the clinical potential of GM3-based strategies, including monoclonal antibodies and cancer vaccines, discussing the potential of targeting GM3 to reshape the TME and suppress tumor-associated vascularization. Full article

(This article belongs to the Special Issue Novel Molecules for Cancer Treatment (3rd Edition))

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19 pages, 344 KB

Open AccessReview

Nicotine-Mediated Alterations in Exosome Content: Implications for Stroke and Neurological Dysfunction

by Christopher Grahe, Richard D. Egleton, Nalini Santanam and Ji Chen Bihl

Biomolecules 2026, 16(3), 463; https://doi.org/10.3390/biom16030463 - 19 Mar 2026

Cited by 1 | Viewed by 1098

Abstract

Nicotine damages the cardiovascular system in a variety of ways, from promoting inflammation to causing oxidative stress to prompting unnecessary autophagy. The alteration to the nervous system that yields nicotine dependence further exacerbates the negative impact that nicotine use has on public health. [...] Read more.

Nicotine damages the cardiovascular system in a variety of ways, from promoting inflammation to causing oxidative stress to prompting unnecessary autophagy. The alteration to the nervous system that yields nicotine dependence further exacerbates the negative impact that nicotine use has on public health. Nicotine use has also been found to cause alterations in exosome content, especially miRNA. Conversely, exosomes have also had promising results as treatments for nicotine-mediated alterations in protein and miRNA levels. However, although nicotine has been shown to both alter exosome content and exacerbate stroke outcomes, the relationship between these two functions is poorly understood. This review examines multiple sources to compare available data. Several factors in nicotine’s effect on exosome content were thus found that imply a correlation. Also, exosome contents are not only a viable biomarker for multiple conditions, including ischemic brain damage and tobacco use, but they are also able to influence the cells of test subjects, both as a treatment for ischemic stroke and as a regulator of healthy brain function in stroke-free test subjects. Taken together, previous evidence suggests that nicotine-mediated alterations in neuronal exosome content have an effect on the progression of stroke in nicotine users. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 3497 KB

Open AccessArticle

Systemic Oxidative Stress and Oxidized Albumin Mediate the Pathogenic Kidney-to-Gut Crosstalk by Disrupting Intestinal Barrier Integrity

by Jie Cheng, Yang Sui, Xin Wang, Yijun Xu, Rui Jiang, Yingyu Zhang, Zhuheng Shi, Mika Suda, Jianglin Fan and Jian Yao

Biomolecules 2026, 16(3), 462; https://doi.org/10.3390/biom16030462 - 18 Mar 2026

Cited by 1 | Viewed by 892

Abstract

Deleterious crosstalk between the gut and distant organs is a key factor behind disease progression. Currently, the molecular signals mediating this communication remain elusive. We hypothesized that systemic oxidative stress and oxidatively modified serum proteins transmit injury signals from extraintestinal sites to the [...] Read more.

Deleterious crosstalk between the gut and distant organs is a key factor behind disease progression. Currently, the molecular signals mediating this communication remain elusive. We hypothesized that systemic oxidative stress and oxidatively modified serum proteins transmit injury signals from extraintestinal sites to the gut. In various murine models of organ injury, primary damage was consistently associated with systemic oxidative stress and intestinal damage. Specifically, ischemia/reperfusion (I/R)-induced acute kidney injury caused profound colonic barrier defects. Depleting the microbiota with antibiotics markedly improved survival and attenuated both renal and colonic injury, implicating translocated microbes in exacerbating pathology. Mechanistically, these changes were linked to systemic oxidative stress and were largely prevented by the antioxidant N-acetylcysteine. Furthermore, serum from I/R mice disrupted epithelial barrier integrity and induced cell death in vitro, effects that were recapitulated by exposure to oxidized serum proteins. Characterization of serum components identified albumin as the predominantly oxidized protein, which displayed potent cytotoxicity toward cultured intestinal epithelial cells. Our findings establish oxidative stress and oxidized serum albumin as key pathogenic factors mediating the detrimental interaction between remote organs and the gut. These data suggest that targeting oxidative modifications offers a promising therapeutic strategy to disrupt this pathological loop in critical illness. Full article

(This article belongs to the Special Issue Bioactive Molecules in the Control of Oxidative Stress and Oxidative Stress-Related Diseases)

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25 pages, 2467 KB

Open AccessArticle

The Degeneration Paradox: Severely Degenerated Cervical Nucleus Pulposus Cells Display Enhanced Mechanoplasticity Under Moderate Cyclic Tensile Strain

by Yuwen Wang, Yi Chen, Bowei Xiao, Baining Zhang, Juying Huang, Nan Zhang, Binxuan Wu, Tianhua Rong and Baoge Liu

Biomolecules 2026, 16(3), 461; https://doi.org/10.3390/biom16030461 - 18 Mar 2026

Viewed by 742

Abstract

Cervical Intervertebral Disc Degeneration (CIVDD) involves significant microenvironmental physical stiffening, forcing nucleus pulposus cells (NPCs) into a rigid phenotype via F-actin over-assembly. It remains unclear if cyclic tensile strain (CTS) can reverse this physical stiffening, particularly in severe degeneration. This study stratified 18 [...] Read more.

Cervical Intervertebral Disc Degeneration (CIVDD) involves significant microenvironmental physical stiffening, forcing nucleus pulposus cells (NPCs) into a rigid phenotype via F-actin over-assembly. It remains unclear if cyclic tensile strain (CTS) can reverse this physical stiffening, particularly in severe degeneration. This study stratified 18 patients into Mild, Moderate, and Severe cohorts based on MRI. Primary NPCs were subjected to physiological 5% CTS (1 Hz, 24 h). Atomic Force Microscopy (AFM) and immunofluorescence were utilized to evaluate Young’s modulus and cytoskeletal remodeling. Results demonstrated that baseline cellular stiffness increased significantly with degeneration severity. Following CTS, all groups exhibited universal de-stiffening and F-actin depolymerization. Crucially, a “Degeneration Paradox” emerged: the Severe group displayed the highest relative elastic modulus recovery rate, significantly surpassing the Mild group. This microscopic recovery correlated inversely with preoperative disc height loss and range of motion. We conclude that severely degenerated cells are not metabolically quiescent but “physically locked” by a rigid cytoskeleton. Physiological CTS restores compliance via mechanical unloading, confirming that severe cells retain superior relative mechanoplasticity and may benefit from mechanotherapy-based “unlocking” strategies. Full article

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

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14 pages, 3087 KB

Open AccessArticle

Longitudinal Analysis of Rat Gut Microbiome Composition and Fecal Metabolism Markers Following Prolonged Morphine Exposure

by Bianka Micke and Jiri Novotny

Biomolecules 2026, 16(3), 460; https://doi.org/10.3390/biom16030460 - 18 Mar 2026

Viewed by 713

Abstract

This study investigated temporal group-level changes in gut microbiome composition and fecal metabolic markers in Wistar rats following a 10-day administration of morphine. Fecal samples were collected at predefined post-discontinuation time points and analyzed using 16S rRNA gene sequencing and GC×GC-TOF/MS-based metabolomics, with [...] Read more.

This study investigated temporal group-level changes in gut microbiome composition and fecal metabolic markers in Wistar rats following a 10-day administration of morphine. Fecal samples were collected at predefined post-discontinuation time points and analyzed using 16S rRNA gene sequencing and GC×GC-TOF/MS-based metabolomics, with a focus on short-chain fatty acids (SCFAs). Morphine exposure was associated with transient alterations in gut microbiome structure at early post-treatment time points, including changes in alpha diversity and shifts in the relative abundance of major bacterial taxa. Unsupervised multivariate analysis of fecal metabolomic profiles revealed substantial inter-individual variability without persistent global separation between control and morphine-treated groups. Targeted analysis identified transient reductions in the relative signal intensities of selected SCFAs shortly after morphine withdrawal, while no significant differences were observed at later time points. These findings suggest that morphine-associated perturbations of the gut microbiome and fecal metabolome are predominantly time-dependent and tend to diminish during extended post-discontinuation phases. Full article

(This article belongs to the Section Chemical Biology)

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24 pages, 3350 KB

Open AccessArticle

Divergent HIV-1 Restriction Phenotypes of IFITMs Expressed in Target Cells and Incorporated into Virions

by Smita Verma, David Prikryl, Mariana Marin, Ruben M. Markosyan, Andrea Cimarelli and Gregory B. Melikyan

Biomolecules 2026, 16(3), 459; https://doi.org/10.3390/biom16030459 - 18 Mar 2026

Viewed by 954

Abstract

Interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral factors that restrict the entry of many enveloped viruses, including HIV-1, by modifying host membrane properties and trapping fusion at the hemifusion stage. Beyond blocking entry in target cells, IFITMs also reduce the infectivity of virions [...] Read more.

Interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral factors that restrict the entry of many enveloped viruses, including HIV-1, by modifying host membrane properties and trapping fusion at the hemifusion stage. Beyond blocking entry in target cells, IFITMs also reduce the infectivity of virions produced from IFITM-expressing cells, a phenomenon termed “negative imprinting”. Conserved motifs, such as the amphipathic helix and oligomerization motifs, have been reported to be essential for IFITM-mediated protection of target cells from viral infection. Yet, the impact of IFITM incorporation on progeny virion infectivity remains poorly defined. Here, we show that IFITM3 mutants defective in target cell protection activity still markedly impair HIV-1 fusion/infection upon incorporating into virions, without affecting viral maturation or Env incorporation. Immunofluorescence studies suggest mislocalization of the IFITM3 mutants as the reason for the lack of antiviral activity in target cells. Testing the antiviral activity of chimeras between antiviral and non-antiviral IFITM orthologs failed to clearly identify a domain responsible for reduction of HIV-1 infectivity, suggesting that multiple domains may be required for negative imprinting. Interestingly, co-incorporation of non-antiviral dog IFITM1 with human IFITM3 did not interfere with IFITM3’s negative imprinting activity, despite forming mixed hetero-oligomers. This finding implies a dominant, oligomerization-independent antiviral phenotype of IFITM3 in virions. Our findings suggest that IFITMs may protect target cells and negatively imprint progeny virions through distinct mechanisms, underscoring the need to further characterize the molecular basis for the reduced fusion competence of IFITM-containing HIV-1 particles. Full article

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

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29 pages, 1035 KB

Open AccessReview

Dose-Dependent and Non-Autonomous Signaling in CAKUT: A Lineage-Specific Framework from Conditional Knockout Studies

by Nela Kelam, Petar Todorović, Patricija Bajt, Nikola Pavlović, Tomislav Rakić, Katarina Vukojević and Anita Racetin

Biomolecules 2026, 16(3), 458; https://doi.org/10.3390/biom16030458 - 18 Mar 2026

Viewed by 1218

Abstract

Background/Objectives: Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of pediatric chronic kidney disease, yet the molecular mechanisms underlying these malformations remain incompletely understood. While genetic studies have identified numerous CAKUT-associated genes, conventional knockout approaches often result in [...] Read more.

Background/Objectives: Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of pediatric chronic kidney disease, yet the molecular mechanisms underlying these malformations remain incompletely understood. While genetic studies have identified numerous CAKUT-associated genes, conventional knockout approaches often result in embryonic lethality or fail to reveal tissue-specific gene functions. This review aims to synthesize findings from conditional knockout mouse studies that have elucidated the spatiotemporal requirements of key signaling pathways during kidney development. Methods: We conducted a narrative synthesis of studies employing Cre-loxP conditional gene targeting in mouse models, identified through systematic searches of PubMed and cross-referencing of key primary research. Studies were selected based on their use of lineage-specific Cre drivers (Six2-Cre, Hoxb7-Cre, Foxd1-Cre) to investigate nephron progenitor maintenance, ureteric bud branching morphogenesis, and stromal–epithelial interactions. Results: Conditional knockout studies have redefined CAKUT pathogenesis as a disorder of dose-dependent signaling, temporal regulation, and inter-compartmental communication. WNT/β-catenin signaling operates in a biphasic, dose-dependent manner in nephron progenitors, with Six2-Cre-mediated β-catenin deletion causing premature progenitor depletion. BMP and FGF pathways demonstrate dose-dependent and context-specific functions in progenitor maintenance, while GDNF/RET signaling is essential for ureteric bud outgrowth and branching. Importantly, stromal-specific deletions have uncovered non-cell-autonomous mechanisms regulating nephron formation. Haploinsufficiency studies demonstrate that partial pathway disruption can reduce nephron endowment without overt CAKUT, predisposing to adult-onset hypertension and chronic kidney disease. Conclusions: Conditional gene targeting has mechanistically redefined CAKUT from a collection of structural malformations to a spectrum of disorders arising from quantitative perturbations in lineage-specific signaling networks. These findings establish that phenotypic severity is determined by the degree of pathway disruption, the developmental timing of insult, and the compartment affected, providing a framework for interpreting oligogenic interactions and variable penetrance in human CAKUTs. Full article

(This article belongs to the Section Molecular Biology)

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68 pages, 5065 KB

Open AccessReview

Nuclear Mechanics and Nuclear Mechanotransduction in Cancer Cell Migration and Invasion

by Claudia Tanja Mierke

Biomolecules 2026, 16(3), 457; https://doi.org/10.3390/biom16030457 - 18 Mar 2026

Viewed by 2397

Abstract

Nuclear mechanics and mechanotransduction are involved in the migration and invasion process, such as those in which the cells need to deform themselves to pass through constrictions. Specifically, properties like nuclear softness, viscoelasticity, plasticity (like nuclear pore complexes) and deformability are critical in [...] Read more.

Nuclear mechanics and mechanotransduction are involved in the migration and invasion process, such as those in which the cells need to deform themselves to pass through constrictions. Specifically, properties like nuclear softness, viscoelasticity, plasticity (like nuclear pore complexes) and deformability are critical in cancer and its malignant progression. The nucleus represents a physical barrier for the migration and invasion in dense 3D extracellular matrix (ECM) scaffolds. Therefore, the deformability of the nucleus seems to determine the migration limit in circumstances where the enzymatic remodeling of the surroundings is impaired. There are still significant knowledge gaps regarding effects of nuclear deformation during cancer dissemination. It seems that nuclear deformation can alter gene transcription, induce alternative splicing processes, impact nuclear envelope rupture, nuclear pore complex dilatation, damage the DNA, and increase the genomic instability. These mechanically induced alterations can in turn impact the migratory behavior of the cancer cells. The stiffness of the nucleus relies on the condensation of chromatin, and the nuclear lamina, which consists of a network of intermediate filaments underneath the nuclear envelope. All of this is discussed in the review and it is argued that nuclear deformability is universally found in various cancer types. Another focus is placed on the nuclear envelope proteins like emerin, and the SUN-KASH complex and how they contribute to the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which consequently couples the nucleus and the cytoskeleton. It is argued that this connection is crucial for force transmission, which governs nuclear stiffness dynamically, depending on the force applied. In this review, recent findings are described that couple ECM-induced nuclear mechanosensing and mechanotransduction with the migration and invasion of cancer cells. Moreover, it is suspected that changes in the mechanosensory characteristics of the cell nucleus could play a pivotal part in the malignancy of cancer cells and the heterogeneity of tumors. Finally, it is discussed what impact the individual elements of the nucleus offer to mechanically alter cellular migration and invasion in cancer and its malignant progression. Full article

(This article belongs to the Special Issue Feature Papers in "Molecular Biology" Section 2026)

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29 pages, 1931 KB

Open AccessReview

Peptide Drugs in Gastrointestinal Tumors: Integrating Targeting, Delivery, and Therapeutic Actions for Synergistic Strategies

by Qian Ouyang, Guifang Wu, Anyi Chen, Rui Zhang, Shuai Xiao, Dong Guo, Qi Zhang, Chaojun Yan, Xing-Zhen Chen, Jingfeng Tang and Hao Lyu

Biomolecules 2026, 16(3), 456; https://doi.org/10.3390/biom16030456 - 18 Mar 2026

Viewed by 1788

Abstract

Gastrointestinal malignant tumors account for approximately one-third of global cancer-related deaths, primarily including colorectal, gastric, pancreatic ductal adenocarcinoma, and hepatocellular carcinomas. These tumors have a high incidence, are often asymptomatic, and are prone to metastasis and recurrence, posing a significant public health burden. [...] Read more.

Gastrointestinal malignant tumors account for approximately one-third of global cancer-related deaths, primarily including colorectal, gastric, pancreatic ductal adenocarcinoma, and hepatocellular carcinomas. These tumors have a high incidence, are often asymptomatic, and are prone to metastasis and recurrence, posing a significant public health burden. Although traditional methods such as radiotherapy and chemotherapy can delay disease progression, their nonspecific effects often lead to severe side effects and drug resistance, resulting in limited efficacy. Therefore, developing novel treatment strategies with high target specificity and favorable biological safety is a critical scientific issue in this field. Peptide drugs offer advantages such as good biocompatibility, low immunogenicity, diverse structures, and ease of modification, collectively demonstrating unique potential for tumor treatment. They can not only achieve precise delivery by specifically recognizing tumor receptors but can also directly interfere with signal transduction, metabolism, and immune regulation, producing multi-target antitumor effects. This article systematically reviews the research progress of peptide drugs in gastrointestinal tumors, focusing on their molecular mechanisms, delivery modification strategies, and the latest applications. It also summarizes the challenges and future directions for clinical translation, providing a theoretical foundation and future perspectives for the precise treatment of gastrointestinal tumors and the design of new drugs. Full article

(This article belongs to the Section Molecular Biology)

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16 pages, 1396 KB

Open AccessReview

Insights into Tardigrade Damage-Suppression Protein, Dsup

by Tyler J. Woodward and M. Todd Washington

Biomolecules 2026, 16(3), 455; https://doi.org/10.3390/biom16030455 - 18 Mar 2026

Viewed by 1948

Abstract

Tardigrades are microscopic invertebrates capable of surviving extreme environmental conditions through unique molecular adaptations. Among the proteins implicated in their remarkable resilience is a novel protein known as damage suppressor (Dsup), a key factor in protecting cellular DNA from elevated levels of radiation. [...] Read more.

Tardigrades are microscopic invertebrates capable of surviving extreme environmental conditions through unique molecular adaptations. Among the proteins implicated in their remarkable resilience is a novel protein known as damage suppressor (Dsup), a key factor in protecting cellular DNA from elevated levels of radiation. Since its discovery, numerous studies have explored the biochemical, structural, and functional properties of Dsup. In this review, we summarize the current knowledge surrounding these properties and describe several proposed mechanisms by which Dsup may confer protection. For each proposed mechanism, we outline the foundational model, present supporting evidence, and highlight critical gaps in our understanding. Taken together, we believe that Dsup likely employs multiple complementary mechanisms to protect DNA. Finally, we discuss emerging applications of Dsup and Dsup-inspired technologies for human health. Overall, this review synthesizes our current understanding and provides a framework to guide future investigations into this remarkable protein. Full article

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

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23 pages, 857 KB

Open AccessReview

Vinpocetine—An “Old” Drug with a New Face: Moving Toward a Better Understanding of Its Neuroprotective Mechanism of Action

by E. Sylvester Vizi and Béla Kiss

Biomolecules 2026, 16(3), 454; https://doi.org/10.3390/biom16030454 - 17 Mar 2026

Cited by 3 | Viewed by 2110

Abstract

Synthesized more than 60 years ago, vinpocetine—the active ingredient of Cavinton^®, with over five decades of clinical use—has remained the subject of extensive investigation, particularly during the past 15 years. During this time, a large body of experimental preclinical evidence has [...] Read more.

Synthesized more than 60 years ago, vinpocetine—the active ingredient of Cavinton^®, with over five decades of clinical use—has remained the subject of extensive investigation, particularly during the past 15 years. During this time, a large body of experimental preclinical evidence has accumulated demonstrating its neuroprotective potential and complex mechanisms of action in cerebral ischemia–hypoxia. Comprehensive in vitro studies and animal experiments have significantly elucidated the molecular basis of vinpocetine and the signaling pathways through which it prevents or mitigates ischemic injury. In this review, we summarize earlier and more recent experimental results that highlight the multifaceted nature of vinpocetine’s neuroprotective actions, which include inhibition of phosphodiesterase type 1, blockade of voltage-dependent NaV1.8 channels, reduction of oxidative stress, and suppression of neuroinflammatory processes triggered by cerebral ischemia–hypoxia. Taken together, it can be hypothesized that, under in vivo conditions, vinpocetine’s individual actions are additive or synergistic, thereby contributing in a combined manner to recovery from cerebral ischemic insult. Full article

(This article belongs to the Special Issue Inflammatory Mechanisms and Molecular Targets in Neurological Disorders: Effects of Neuroprotective Drugs)

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16 pages, 885 KB

Open AccessReview

Therapeutic Potential Target of Adenosine for Epilepsy: Focusing on Its Interaction with the Molecular Epileptogenic Network

by Xiaoning Zhao, Jiahui Deng, Zhonghua Xiong and Tianfu Li

Biomolecules 2026, 16(3), 453; https://doi.org/10.3390/biom16030453 - 17 Mar 2026

Cited by 2 | Viewed by 1249

Abstract

Epilepsy is a neurological disorder characterized by a long-lasting predisposition to recurrently generate unprovoked seizures. Epilepsy affects over 70 million people worldwide, with approximately one-third suffering from pharmacoresistant seizures. Currently, the clinical antiseizure drugs lack efficacy in preventing epileptogenesis. Adenosine, as an endogenous [...] Read more.

Epilepsy is a neurological disorder characterized by a long-lasting predisposition to recurrently generate unprovoked seizures. Epilepsy affects over 70 million people worldwide, with approximately one-third suffering from pharmacoresistant seizures. Currently, the clinical antiseizure drugs lack efficacy in preventing epileptogenesis. Adenosine, as an endogenous anticonvulsant, inhibits the development of epilepsy via interaction with the molecular epileptogenic network on several levels: (i) Activation of A1 receptor inhibits glutamate release via presynaptic inhibition, and hyperpolarizes the synaptic potentials in postsynaptic neurons. (ii) The A2A receptor on astrocytes interacts with astroglial glutamate transporter GLT-1, controlling glial glutamate homeostasis. (iii) Activation of the A3 receptor inhibits GABA transporter type 1-mediated GABA uptake. (iv) Adenosine kinase (ADK) is highlighted as a pathological hallmark of epilepsy, with its distinct isoforms driving different mechanisms. The cytoplasmic short isoform (ADK-S) in astrocytes controls extracellular adenosine and receptor-mediated pathways, whereas the nuclear long isoform (ADK-L) in astrocytes and specific neurons regulates epigenetic mechanisms without relying on adenosine receptors. Collectively, this review clarifies the adenosine system’s critical regulatory role in the epileptogenic network, highlights adenosine receptors and ADK isoforms as promising therapeutic targets for epilepsy, and provides a theoretical basis for developing novel disease-modifying therapies for pharmacoresistant epilepsy while laying a foundation for subsequent preclinical and clinical translation. Full article

(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)

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