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Biomolecules
Volume 16
Issue 4
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Biomolecules, Volume 16, Issue 4 (April 2026) – 134 articles

Cover Story (view full-size image): This cover illustrates the role of skeletal muscle-derived MG53 as a regenerative myokine for the human heart. Although MG53 is highly enriched in skeletal muscle, its expression in adult human cardiomyocytes is minimal. The human heart may therefore rely on circulating MG53, released from skeletal muscle as an endocrine “repair reservoir” to help preserve myocardial integrity following injury. MG53 promotes cardioprotection by stabilizing damaged membranes, preserving mitochondrial function, and modulating inflammatory responses. View this paper
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20 pages, 1220 KB  
Review
Brain Lymphatic Dysfunction in Subarachnoid Hemorrhage: Pathophysiology and Clinical Implications
by Shuangyi Guo, John H. Zhang, Warren Boling and Lei Huang
Biomolecules 2026, 16(4), 616; https://doi.org/10.3390/biom16040616 - 21 Apr 2026
Viewed by 869
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) remains a devastating cerebrovascular disorder with high morbidity and mortality, despite advances in aneurysm securing and neurocritical care. Clinical outcomes are determined by early brain injury (EBI), delayed cerebral ischemia (DCI), hydrocephalus, and long-term cognitive impairment, extending beyond the [...] Read more.
Aneurysmal subarachnoid hemorrhage (SAH) remains a devastating cerebrovascular disorder with high morbidity and mortality, despite advances in aneurysm securing and neurocritical care. Clinical outcomes are determined by early brain injury (EBI), delayed cerebral ischemia (DCI), hydrocephalus, and long-term cognitive impairment, extending beyond the traditional focus on large-vessel vasospasm alone. Emerging evidence identifies the dysfunction of the glymphatic system and meningeal lymphatic pathway, the brain’s primary clearance pathways, as a central and unifying mechanism linking acute hemorrhagic injury to delayed and chronic neurological sequelae. Following SAH, acute intracranial pressure elevation, subarachnoid blood clot burden, loss of arterial pulsatility, venous congestion, astrocytic aquaporin-4 perivascular depolarization, and neuroinflammation converge to suppress cerebrospinal fluid–interstitial fluid exchange and outflow in glymphatic system and subsequent meningeal lymphatic drainage. Persistent clearance failure promotes the retention of blood breakdown products, inflammatory mediators, and metabolic waste, amplifying microvascular dysfunction, cortical spreading depolarizations, blood–brain barrier disruption, and secondary ischemic injury. Importantly, accumulating data highlight venous pathology and meningeal lymphatic impairment as critical, yet underappreciated, contributors to delayed injury and post-SAH hydrocephalus. In this review, we synthesize the current knowledge of the physiological organization of glymphatic and meningeal lymphatic systems, delineate the mechanistic and molecular drivers of their dysfunction after SAH, and discuss clinical implications for EBI, DCI, hydrocephalus, and long-term cognitive outcomes. We further outline future directions, including translational imaging, biomarker development, and therapeutic strategies targeting clearance pathways, to advance disease-modifying approaches in SAH. 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, 6337 KB  
Article
Cigarette Smoke Induces Canonical Stress Granule Formation in Human Bronchial Epithelial Cells in Reactive Oxygen Species- and PERK-Dependent Manners
by Mousumi Bhowmik, Chenkun Zheng, Bisrat Bekele, Jessica Failler, Carlie Klatt, Souren Farimani, Bryant Jones, Chung-Chun Tyan and Asmahan Abu-Arish
Biomolecules 2026, 16(4), 615; https://doi.org/10.3390/biom16040615 - 21 Apr 2026
Viewed by 951
Abstract
Cigarette smoke (CS) is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). Investigating the impact of CS on human airway epithelium is important for understanding COPD development and combating its effects. While some studies show that long exposure [...] Read more.
Cigarette smoke (CS) is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). Investigating the impact of CS on human airway epithelium is important for understanding COPD development and combating its effects. While some studies show that long exposure to CS activates inflammasome formation in airway epithelium, leading to cytokines’ maturation and release, its acute effect on inflammation regulation requires further elucidation. Due to the importance of acute cellular responses in modulating cell survival and controlling inflammatory outcomes, we examined the effect of acute cigarette smoke extract exposure on human bronchial epithelial cells. Due to the high reactive oxygen species content in CS, we hypothesize that acute CS exposure activates the integrated stress response (ISR) pathway leading to stress granules (SG) formation to facilitate oxidative stress resolution and promote cell survival. Immunostaining, fluorescence confocal imaging, quantitative analyses, and immunoblotting were performed to test our hypothesis. We report here that acute exposure to CS extract triggers canonical SG formation by activating the ISR pathway via the PERK/eIF2α arm in a reactive oxygen species-dependent manner. SG formation is abolished upon inhibiting PERK or eIF2α function, or by scavenging oxidants prior to smoke exposure. Characterizing SG formation in terms of measuring SG size and abundance and the sequestration of the SG marker G3BP1 reveals that SG formation is maximal at 15% CS extract exposure for 2 h and undergoes gradual disassembly at longer exposure times. This is closely dependent on cytoplasmic p-eIF2α levels. These results demonstrate that acute exposure to CS activates the protective ISR pathway to potentially reduce the detrimental effects of CS and promote stress resolution and cell survival. Full article
(This article belongs to the Special Issue Inflammation and Immunity in Lung Disease)
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16 pages, 4837 KB  
Article
Resilience to Diabetic Retinopathy (RDR) Is Associated with a Pre-Retinopathy Transcriptional Program Induced by Diabetes
by Janani Rajasekar, Maria Paula Zappia, Maximilian A. McCann, Maxim V. Frolov and Andrius Kazlauskas
Biomolecules 2026, 16(4), 614; https://doi.org/10.3390/biom16040614 - 21 Apr 2026
Viewed by 805
Abstract
The purpose of this project was to define gene expression changes associated with the acquisition and loss of resilience to diabetic retinopathy (RDR) in individual retinal cell types. A non-immune form of type 1 diabetes mellitus (DM) was induced by injecting male C57Bl6J [...] Read more.
The purpose of this project was to define gene expression changes associated with the acquisition and loss of resilience to diabetic retinopathy (RDR) in individual retinal cell types. A non-immune form of type 1 diabetes mellitus (DM) was induced by injecting male C57Bl6J mice with streptozotocin. Single-cell RNA sequencing was performed on retinas from mice that experienced DM for 5 or 15 days, along with retinas from age-matched, non-DM mice. The resulting data sets were analyzed to identify DM-associated differentially expressed genes and pathway enrichments after each duration of DM. We observed that acquisition of RDR, previously shown to arise after 5 days of DM was linked to altered expression of genes in a subset of retinal cells, mainly Müller cells. Pathway analysis indicated enhancement of numerous modes of protection, including reinforced neurovascular and structural homeostasis through phagocytosis, integrin signaling, and interferon-mediated defense. After 15 days of DM, when we previously showed that RDR is waning this pro-protection surge in gene expression subsided. We conclude that a duration of DM that is too short to cause diabetic retinopathy (DR) nonetheless evoked a profound change in the gene expression profile within a subset of retinal cell types. The nature and timing of this molecular shift indicated that it was not the preamble to DM-related damage that eventually develops. Rather, DM engaged numerous defense programs within Müller cells. The temporal alignment between RDR and activation of Müller cell-based defense provides a molecular foundation for the retina’s transient ability to remain healthy in the face of DM. Full article
(This article belongs to the Special Issue From Molecular Mechanisms to Therapies: Advances in Retinal Disease Research)
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30 pages, 1637 KB  
Review
Emerging Insights into the Liver–Pancreas Axis: A Central Hub in the Pathogenesis of Diabetes and Metabolic Diseases
by Hengqian Dai and Ziyi Zhang
Biomolecules 2026, 16(4), 613; https://doi.org/10.3390/biom16040613 - 21 Apr 2026
Viewed by 908
Abstract
Diabetes and related metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD), are increasingly recognized as diseases of inter-organ metabolic dysregulation rather than disorders of a single organ. The core of this process is the liver–pancreas axis, which integrates metabolic signals to maintain [...] Read more.
Diabetes and related metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD), are increasingly recognized as diseases of inter-organ metabolic dysregulation rather than disorders of a single organ. The core of this process is the liver–pancreas axis, which integrates metabolic signals to maintain glucose and lipid homeostasis. Under physiological conditions, insulin and glucagon work together to regulate glucose production in the liver. The liver, in turn, regulates pancreatic β-cell function through hepatokines, metabolites and extracellular vesicles. Axis disorder driven by liver insulin resistance, lipid accumulation, inflammation or changes in hepatokine secretion exacerbates β-cell dysfunction, glucotoxicity and lipotoxic stress, thereby accelerating disease progression. This imbalance is involved in the pathogenesis of type 2 diabetes, type 1 diabetes, gestational diabetes, and monogenic diabetes, and makes MASLD a driving factor and early predictor of diabetes onset. This review summarizes the key molecular mechanisms behind liver–pancreas crosstalk and explores potential therapeutic strategies aimed at restoring coordinated metabolic regulation between the organs. Full article
(This article belongs to the Section Biological Factors)
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25 pages, 723 KB  
Review
Targeting Oxidative Stress to Treat Vitiligo: Clinical and Molecular Evidence
by Noemi Aprile, Simona Scano, Barbara Bellei, Alberto Marini and Angela Filoni
Biomolecules 2026, 16(4), 612; https://doi.org/10.3390/biom16040612 - 21 Apr 2026
Viewed by 836
Abstract
Vitiligo is a chronic autoimmune disease characterized by the destruction of epidermal melanocyte, resulting in well-demarcated white patches on the skin. Despite the established use of corticosteroids and calcineurin inhibitors and the recent introduction of Janus kinase (JAK) inhibitors, a breakthrough targeted therapy [...] Read more.
Vitiligo is a chronic autoimmune disease characterized by the destruction of epidermal melanocyte, resulting in well-demarcated white patches on the skin. Despite the established use of corticosteroids and calcineurin inhibitors and the recent introduction of Janus kinase (JAK) inhibitors, a breakthrough targeted therapy that interrupts the IFN-γ signaling pathway, stable repigmentation remains a major clinical challenge, necessitating deeper investigation into its pathogenesis. Among the factors contributing to vitiligo, including genetic predisposition and autoimmunity, oxidative stress is a central driver of melanocyte damage and the subsequent autoimmune response. Chronic oxidative disequilibrium (high ROS level and impaired mitochondrial activity) and reduced antioxidant capacity (Nrf2/ARE pathway and catalase deficiency) function as triggering factors upstream of most other pathogenic pathways. Consequently, targeting oxidative stress, either as a monotherapy or in synergy with emerging targeted treatments, remains a pivotal area of therapeutic interest even in the current era of targeted therapies. Still, a significant gap remains the lack of standardized oxidative biomarkers to monitor disease activity and therapeutic response. Identifying these indicators is essential for personalized clinical management in vitiligo. This review examines how chronic oxidative disequilibrium and a reduced antioxidant capacity initiate and sustain the autoimmune cascade, leading to disease onset and progression. Full article
(This article belongs to the Section Cellular Biochemistry)
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23 pages, 2298 KB  
Review
Dual Roles and Therapeutic Prospects of Proximal Tubular Epithelial Cell Senescence in Acute Kidney Injury
by Yifan Qiao, Jin Zhao, Minna Liu, Jie Liu, Qiao Zheng, Ruotong Xu, Xiaoxuan Ning, Shiren Sun and Xiangmei Chen
Biomolecules 2026, 16(4), 611; https://doi.org/10.3390/biom16040611 - 20 Apr 2026
Cited by 2 | Viewed by 845
Abstract
Acute kidney injury (AKI), a life-threatening disorder marked by abrupt renal dysfunction, is increasingly recognized as a global healthcare challenge. It not only triggers immediate organ dysfunction but also heightens long-term risks of chronic kidney disease (CKD). The senescence of proximal tubular epithelial [...] Read more.
Acute kidney injury (AKI), a life-threatening disorder marked by abrupt renal dysfunction, is increasingly recognized as a global healthcare challenge. It not only triggers immediate organ dysfunction but also heightens long-term risks of chronic kidney disease (CKD). The senescence of proximal tubular epithelial cells (PTECs) has a major impact on the occurrence and development of AKI. This review systematically analyzes existing evidence, which suggests that the senescence of PTECs may have a dual effect. Acute cellular senescence typically mitigates uncontrolled replication of damaged cells by inducing cell cycle arrest, thereby limiting the further expansion of tissue damage. In contrast, the pathological retention of chronic senescent cells and the excessive production of the senescence-associated secretory phenotype (SASP) exacerbate the local inflammatory response and the process of fibrosis, accelerating the transformation of AKI into CKD. Despite incomplete elucidation of the spatiotemporal mechanisms governing the transition from acute to chronic cellular senescence, therapeutic interventions can be precisely targeted to specific disease stages based on their characteristic progression dynamics. This review summarizes the intervention strategies applicable at different stages of AKI, including prevention, early induction of senescence, senoreverse, senolysis, and senomorphics. Additionally, we highlight potential therapeutic targets to provide a theoretical basis for optimizing clinical management. Full article
(This article belongs to the Section Cellular Biochemistry)
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18 pages, 21273 KB  
Article
Polysaccharide Peptide from Ganoderma lucidum Reduces Acute Kidney Injury Through Regulating the Integrin β3/Fn1 Axis
by Hatungimana Mediatrice, Hongjian Luo, Lianfu Wang, Yang Yao, Zhujun Liu, Nsanzinshuti Aimable, Yingping Hu, Yukun Zhang, Zhanxi Lin and Dongmei Lin
Biomolecules 2026, 16(4), 610; https://doi.org/10.3390/biom16040610 - 20 Apr 2026
Viewed by 583
Abstract
Acute kidney injury (AKI) continues to pose a significant clinical challenge due to its high morbidity rates and limited therapeutic options. Recent evidence suggests that natural compounds may provide renoprotective benefits by modulating oxidative stress and inflammation. This study examines the protective effects [...] Read more.
Acute kidney injury (AKI) continues to pose a significant clinical challenge due to its high morbidity rates and limited therapeutic options. Recent evidence suggests that natural compounds may provide renoprotective benefits by modulating oxidative stress and inflammation. This study examines the protective effects of a novel polysaccharide peptide extracted from Ganoderma lucidum (GL-PPQ1) against renal ischemia–reperfusion (I/R) injury, with particular emphasis on the integrin β3/Fibronectin 1 (Fn1) signaling axis. A murine model of renal I/R injury was established, and GL-PPQ1 was administered orally for seven days before surgery. The assessment included renal function, histopathology, oxidative stress markers, and inflammatory cytokines. Additionally, transcriptomic profiling and protein expression analyses were conducted to elucidate the underlying mechanisms. The results revealed that GL-PPQ1 pretreatment significantly reduced renal tubular damage, lowered serum creatinine and blood urea nitrogen levels, and diminished oxidative stress and inflammatory responses. RNA sequencing revealed that GL-PPQ1 affected gene sets associated with extracellular matrix remodeling and cell adhesion. Western blot and immunohistochemistry further confirmed that GL-PPQ1 decreased the expression of integrin β3 and Fn1, suggesting a regulatory effect on their interaction during I/R injury. These findings demonstrate that GL-PPQ1 offers substantial kidney protection by mitigating oxidative stress, inflammation, and dysregulation of the integrin β3/Fn1 signaling pathway. Thus, this study supports that polysaccharide peptides derived from Ganoderma lucidum could have the potential to serve as both a dietary supplement and a therapeutic agent in the treatment of AKI. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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23 pages, 2800 KB  
Article
Lysine Acetyltransferase 6A Drives M1 Macrophage Polarization Through Metabolic Reprogramming in Sepsis-Induced Acute Lung Injury
by Xin Wang, Junlin Chen, Yimei Lai, Yumeng Wang, Kaixia Hu, Mengshi Wu, Niansheng Yang and Yuefang Huang
Biomolecules 2026, 16(4), 609; https://doi.org/10.3390/biom16040609 - 20 Apr 2026
Viewed by 687
Abstract
Macrophage-mediated inflammation is a key driver of sepsis-induced acute lung injury (ALI). M1 macrophage polarization relies on metabolic reprogramming, yet the upstream regulatory factors remain unclear. Lysine acetyltransferase 6A (KAT6A), a MYST-family acetyltransferase, regulates transcriptional programs in immune cells, but its role in [...] Read more.
Macrophage-mediated inflammation is a key driver of sepsis-induced acute lung injury (ALI). M1 macrophage polarization relies on metabolic reprogramming, yet the upstream regulatory factors remain unclear. Lysine acetyltransferase 6A (KAT6A), a MYST-family acetyltransferase, regulates transcriptional programs in immune cells, but its role in macrophage function and ALI progression remains unknown. Public single-cell and bulk transcriptomic datasets were used to assess KAT6A expression changes and its association with inflammatory and metabolic pathways in macrophages. KAT6A inhibition with WM1119 was used to evaluate effects on M1 polarization, cytokine production, metabolic reprogramming, and PI3K-AKT-mTOR signaling. The therapeutic potential of KAT6A inhibition was validated in a cecal ligation and puncture (CLP)-induced sepsis model by assessing lung injury, bacterial clearance, and survival. KAT6A expression was upregulated in sepsis and particularly enriched in M1 macrophages. Inhibition of KAT6A reduced inflammatory and glycolytic transcriptional programs, suppressed glycolysis and enhanced oxidative phosphorylation, leading to decreased cytokine production and limited M1 polarization accompanied by suppression of PI3K-AKT-mTOR pathway. In CLP-induced septic mice, treatment with the KAT6A inhibitor WM1119 alleviated lung injury, improved bacterial clearance, and prolonged survival. KAT6A expression is associated with macrophage glucose metabolism, pro-inflammatory responses, and M1 macrophage polarization in sepsis-induced acute lung injury. Pharmacologic inhibition of KAT6A may provide a promising therapeutic strategy for reducing macrophage-driven lung injury. Full article
(This article belongs to the Section Cellular Biochemistry)
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24 pages, 741 KB  
Review
Extracellular Vesicles as Biomarkers for Vascular Disease
by Davide Costa, Michele Andreucci, Nicola Ielapi, Teresa Faga, Antonio Mazza, Giulio Accarino, Umberto Marcello Bracale and Raffaele Serra
Biomolecules 2026, 16(4), 608; https://doi.org/10.3390/biom16040608 - 20 Apr 2026
Viewed by 756
Abstract
Vascular diseases (VD) remain a leading global cause of morbidity and mortality, often developing silently before manifesting as severe complications like stroke or ischemia. Traditional diagnostic imaging provides essential anatomical data but frequently fails to capture the dynamic molecular processes underlying vascular pathology. [...] Read more.
Vascular diseases (VD) remain a leading global cause of morbidity and mortality, often developing silently before manifesting as severe complications like stroke or ischemia. Traditional diagnostic imaging provides essential anatomical data but frequently fails to capture the dynamic molecular processes underlying vascular pathology. This narrative review summarizes current evidence regarding Extracellular Vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, as emerging biomarkers and mediators in vascular conditions. The review evaluates the biological mechanisms of EVs across several disorders, including arterial aneurysms, peripheral artery disease, carotid stenosis, and venous thromboembolism. Findings indicate that EVs concentration and molecular cargo, particularly microRNAs and proteins, reflect the physiological state of parent cells, offering a “liquid biopsy” for vascular inflammation, endothelial dysfunction, and plaque vulnerability. Furthermore, the review explores the therapeutic potential of stem cell-derived EVs in promoting angiogenesis and tissue repair in chronic vascular ulcers. Despite these advances, the review concludes that the clinical implementation of EV-based diagnostics faces significant hurdles, primarily due to the lack of standardized isolation and characterization methods. Addressing these methodological challenges is crucial for translating EV research into routine clinical practice. Full article
(This article belongs to the Special Issue Biomolecular Sciences and Precision Medicine in Vascular Disease)
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21 pages, 8773 KB  
Article
APOC3 Promotes DGAT2-Dependent Triglyceride Accumulation in Hepatocytes During Early Metabolic Dysfunction
by Thi Nhi Nguyen, Hye-Jeong Kim, Hye Min Shim, Junho Kang, Eun Young Ha, Hochan Cho and Jae-Hyung Park
Biomolecules 2026, 16(4), 607; https://doi.org/10.3390/biom16040607 - 20 Apr 2026
Viewed by 639
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic triglyceride accumulation in the setting of obesity and insulin resistance. Although apolipoprotein C-III (APOC3) is a well-established regulator of plasma triglyceride metabolism, its hepatocyte-intrinsic role in intracellular lipid accumulation remains unclear. In this [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic triglyceride accumulation in the setting of obesity and insulin resistance. Although apolipoprotein C-III (APOC3) is a well-established regulator of plasma triglyceride metabolism, its hepatocyte-intrinsic role in intracellular lipid accumulation remains unclear. In this study, we investigated whether APOC3 contributes to hepatocellular triglyceride synthesis during early metabolic dysfunction. In 6-week-old db/db mice, early hepatic lipid accumulation was observed without detectable fibrosis. Transcriptomic profiling identified APOC3 as an upregulated gene associated with lipid metabolic pathways, and its hepatic upregulation was confirmed at both mRNA and protein levels. Gain- and loss-of-function experiments in HepG2 cells demonstrated that APOC3 overexpression significantly increased intracellular triglyceride content, whereas APOC3 knockdown reduced triglyceride accumulation. Mechanistically, APOC3 selectively regulated diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step of triglyceride synthesis, without significantly affecting major lipogenic transcription factors. Furthermore, under de novo lipogenesis-inducing conditions triggered by the liver X receptor agonist T0901317 and insulin, APOC3 markedly amplified DGAT2 expression and triglyceride accumulation. Collectively, these findings suggest a hepatocyte-intrinsic role for APOC3 in promoting triglyceride accumulation through DGAT2-dependent mechanisms. The APOC3–DGAT2 axis may represent a relevant pathway contributing to hepatic lipid accumulation in metabolic liver disease. Full article
(This article belongs to the Special Issue Cellular Stress, Inflammation, and Metabolic Dysfunction in the Progression of MASLD)
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19 pages, 4373 KB  
Article
Hepatocyte-Specific Deletion of Betaine-Homocysteine Methyltransferase Disrupts Methionine Metabolism and Promotes the Spontaneous Development of Hepatic Steatosis
by Ramachandran Rajamanickam, Sathish Kumar Perumal, Ramesh Bellamkonda, Sundararajan Mahalingam, Kurt W. Fisher, Rolen Quadros, Channabasavaiah B. Gurumurthy, Madan Kumar Arumugam, Karuna Rasineni and Kusum K. Kharbanda
Biomolecules 2026, 16(4), 606; https://doi.org/10.3390/biom16040606 - 20 Apr 2026
Viewed by 729
Abstract
Betaine-homocysteine methyltransferase (BHMT) is an enzyme involved in one-carbon metabolism and plays a crucial role in maintaining liver health. In this study, we investigated the impact of liver-specific deletion of BHMT on liver dysfunction using a mouse model. We generated BHMT floxed mice [...] Read more.
Betaine-homocysteine methyltransferase (BHMT) is an enzyme involved in one-carbon metabolism and plays a crucial role in maintaining liver health. In this study, we investigated the impact of liver-specific deletion of BHMT on liver dysfunction using a mouse model. We generated BHMT floxed mice and bred them with albumin Cre to generate liver-specific BHMT knockout (BHMT LKO) mice. Liver tissues harvested from six-month-old chow-fed BHMT floxed and LKO mice were characterized through histological, biochemical, and molecular analyses. BHMT LKO mice displayed a complete loss of hepatic expression of BHMT mRNA, protein and enzyme activity. Histopathological analysis revealed the development of hepatic steatosis in BHMT LKO mice compared to the floxed mice. These morphological changes were supported by biochemical analysis showing elevated levels of hepatic triglycerides in conjunction with a profound decrease in the methylation potential (i.e., reduced S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio), which was mainly driven by a six- to sevenfold increase in SAH levels. BHMT LKO mice also exhibited increased lipid peroxidation and lysosomal dysfunction compared to floxed mice. Early signs of inflammation were seen in the livers of BHMT LKO mice of both sexes, as evident from significant increase in CD68-positive cells and interleukin 1β levels. Additionally, there was a moderate increase in fibrosis, as evidenced by the upregulated expression of α-smooth muscle actin and collagen II levels and the histological assessment of picrosirius red-stained liver sections of BHMT LKO mice of both sexes compared to their respective counterparts. These findings demonstrate that hepatic BHMT deficiency promotes lipid accumulation, lysosomal/proteasomal dysfunction, and early inflammatory and fibrotic changes in the liver by reducing the methylation potential. Collectively, our results underscore BHMT as a critical regulator of liver homeostasis and a potential therapeutic target in liver-related disorders. Full article
(This article belongs to the Section Cellular Biochemistry)
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28 pages, 14249 KB  
Article
Antibacterial Mechanism of Dipicolinic Acid Against Xanthomonas citri pv. glycines and Its Efficacy for the Management of Soybean Bacterial Pustule Disease
by Lei Chen, Jia-Xuan Shen, Ming-Yi Zhang, Xin-Chi Shi, Lei Xu, Si-Yuan Liu, Daniela D. Herrera-Balandrano, Pere Clapés, Jie Gong, Dong Liu, Su-Yan Wang and Pedro Laborda
Biomolecules 2026, 16(4), 605; https://doi.org/10.3390/biom16040605 - 19 Apr 2026
Viewed by 447
Abstract
Bacillus species are extensively studied, utilized, and commercialized biocontrol agents, demonstrating significant effectiveness in managing a variety of plant diseases. Bacillus possesses a robust intrinsic biosynthetic ability, capable of producing a diverse array of antimicrobial metabolites, including dipicolinic acid (DPA; 2,6-pyridinedicarboxylic acid), which [...] Read more.
Bacillus species are extensively studied, utilized, and commercialized biocontrol agents, demonstrating significant effectiveness in managing a variety of plant diseases. Bacillus possesses a robust intrinsic biosynthetic ability, capable of producing a diverse array of antimicrobial metabolites, including dipicolinic acid (DPA; 2,6-pyridinedicarboxylic acid), which exhibits antifungal properties and serves as a principal structural component of Bacillus spores. This study revealed that DPA exhibits significant antibacterial activity against the hazardous soybean pathogen Xanthomonas citri pv. glycines (Xcg), with an EC50 value of 53.2 μg/mL. DPA inhibited Xcg swimming motility, extracellular protease activity, and biofilm formation, while inducing significant membrane irregularities in Xcg cells. DPA treatment downregulated the expression of several Xcg membrane integrity-related genes, including cirA, czcA, czcB, emrE, and tolC. The preventive and curative application of 500 μg/mL DPA reduced Xcg symptoms by 82.7% and 83.8%, respectively, and induced the accumulation of the isoflavone genistin in soybean leaves. DPA exhibited only weak toxicity in the zebrafish model, suggesting its potential suitability for agricultural commercialization. Overall, this study provides the first detailed characterization of the antibacterial mechanism of DPA against a phytopathogenic bacterium, Xcg, and identifies DPA as a previously underexplored antibacterial metabolite from Bacillus and Paecilomyces with potential for disease management. Full article
(This article belongs to the Section Natural and Bio-derived Molecules)
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18 pages, 5215 KB  
Article
Histone Demethylase JMJD2D Suppresses Influenza A Virus Infection by Promoting RIG-I Expression
by Xiaochun Xia, Jiadi Liang, Hanshi Guo, Fudong Zhang, Junjie Zhang, Chundong Yu, Pingli Mo and Yilin Hong
Biomolecules 2026, 16(4), 604; https://doi.org/10.3390/biom16040604 - 18 Apr 2026
Viewed by 692
Abstract
The efficacy of the host antiviral response against Influenza A virus (IAV), a leading cause of global pandemics, hinges upon the rapid recognition of the pathogen and the prompt activation of immune mechanisms. Nevertheless, the epigenetic landscape that orchestrates this antiviral response remains [...] Read more.
The efficacy of the host antiviral response against Influenza A virus (IAV), a leading cause of global pandemics, hinges upon the rapid recognition of the pathogen and the prompt activation of immune mechanisms. Nevertheless, the epigenetic landscape that orchestrates this antiviral response remains largely elusive. Here, we identify histone demethylase JMJD2D as a critical regulator in defense against IAV infection. A significant upregulation of JMJD2D expression was observed clinically in response to IAV infection, indicating that JMJD2D may play a role in regulating IAV infection. Indeed, JMJD2D-deficient mice exhibit increased susceptibility to IAV, characterized by elevated viral loads, severe lung tissue damage, and reduced survival rates, suggesting that JMJD2D plays an essential role in defense against IAV infection. Consistently, knockdown or pharmacological inhibition of JMJD2D in lung cells suppressed IAV replication and the IAV-triggered innate immune response. Mechanistically, JMJD2D suppressed IAV infection by removing H3K9me3 at the promoter region of retinoic acid inducible gene-I (RIG-I) and cooperating with NF-κB to enhance the expression of RIG-I, a critical sensor for IAV RNA. This study identifies JMJD2D as an epigenetic rheostat that governs RIG-I-mediated antiviral signaling, highlighting its potential as a therapeutic target for mitigating severe IAV infection. Full article
(This article belongs to the Section Cellular Biochemistry)
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30 pages, 3826 KB  
Article
Biochemical and Pharmacological Studies on Kynurenic Acid Metabolism in the Helix pomatia—Snail Model of Learning and Memory
by Halina Baran and Carina Kronsteiner
Biomolecules 2026, 16(4), 603; https://doi.org/10.3390/biom16040603 - 18 Apr 2026
Viewed by 598
Abstract
Kynurenic acid (KYNA), a metabolite of the L-kynurenine pathway of L-tryptophan degradation, is an endogenous blocker of glutamate ionotropic excitatory amino acid (EAA) receptors and nicotinic acetylcholine receptors (nAChRs). KYNA plays a significant role in various neuropsychiatric disorders and the aging process. Some [...] Read more.
Kynurenic acid (KYNA), a metabolite of the L-kynurenine pathway of L-tryptophan degradation, is an endogenous blocker of glutamate ionotropic excitatory amino acid (EAA) receptors and nicotinic acetylcholine receptors (nAChRs). KYNA plays a significant role in various neuropsychiatric disorders and the aging process. Some researchers have suggested that KYNA may contribute to memory impairment. In this study, we examined the impact of L-kynurenine (a KYNA substrate) and the anti-dementia drugs D-cycloserine and Cerebrolysin on kynurenine aminotransferase (KAT) activity, an enzyme forming KYNA, in liver homogenates of Helix pomatia snails. Furthermore, a memory model was established using these snails, wherein tentacle shortening served as an indicator of learning activity. In vitro experiments on Helix pomatia demonstrated the significant impact of L-kynurenine and anti-dementia drugs on KYNA synthesis. KYNA levels increased significantly in the presence of L-kynurenine in liver homogenate. However, KYNA formation decreased when anti-dementia drugs, including Cerebrolysin or D-cycloserine, were administered to the snails’ liver homogenate. L-kynurenine has been shown to impair the learning process in vivo in snails, but an anti-dementia drug has been demonstrated to reverse this effect. Significant inhibition of tentacle lowering was observed in response to L-kynurenine treatment, which corresponded with elevated KYNA levels in the central nervous system. Administering D-cycloserine or Cerebrolysin alongside L-kynurenine reversed its effects. The Helix pomatia memory model is a valuable tool for studying learning and memory formation in various conditions and in the presence of different pharmacological agents. A drug or natural extract that blocks KYNA synthesis has the ability to increase tentacle lowering and could be considered an anti-dementia agent. Furthermore, this metabolite may also protect against aging and delay damage to the central nervous system related to memory. Full article
(This article belongs to the Special Issue The Kynurenine Pathway in Mood Disorders: From Mechanisms to Therapeutics)
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15 pages, 4408 KB  
Article
Immunohistochemical Expression of Integrin αvβ6 in Surgically Resected Pulmonary Inflammatory Lesions Mimicking Malignancy on 18F-FDG PET/CT: Implications for the Specificity of 68Ga-Trivehexin PET/CT
by Muin Tuffaha, Amro Tuffaha, Wael Hananeh, Mohammad Khalifeh, Jenny Sonke and Michael Starke
Biomolecules 2026, 16(4), 602; https://doi.org/10.3390/biom16040602 - 18 Apr 2026
Viewed by 541
Abstract
18F-fluorodeoxyglucose (FDG) PET/CT is widely used for the evaluation of pulmonary lesions but lacks specificity, as increased FDG uptake is frequently observed in inflammatory and reparative processes. This limitation may lead to false-positive interpretations and unnecessary surgical resections. This study aimed to [...] Read more.
18F-fluorodeoxyglucose (FDG) PET/CT is widely used for the evaluation of pulmonary lesions but lacks specificity, as increased FDG uptake is frequently observed in inflammatory and reparative processes. This limitation may lead to false-positive interpretations and unnecessary surgical resections. This study aimed to evaluate the immunohistochemical expression of integrin αvβ6 in 18 surgically resected pulmonary lesions that were falsely classified as malignant on FDG PET/CT, in order to find out if 68Ga-Trivehexin PET/CT could have superior preoperative diagnostic specificity. Histopathological examination classified all lesions as non-neoplastic inflammatory processes of varying etiologies. Integrin αvβ6 expression was detected in all immunohistochemically examined tissue specimens (18/18 cases (100%)), with moderate membranous overexpression in 2/18 cases (11.11%) and strong membranous overexpression in 16/18 cases (88.89%) observed in the alveolar and bronchial epithelium of inflammatory lung lesions. Our findings indicate that integrin αvβ6 is upregulated not only in neoplastic lung tissue but also in inflammatory lesions, suggesting that integrin αvβ6 may have limited specificity for distinguishing primary neoplastic from inflammatory pulmonary lesions when used alone. Its interpretation requires integration with other clinical imaging modalities and histopathological data. Full article
(This article belongs to the Section Molecular Medicine)
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20 pages, 1568 KB  
Article
A Highly Conserved Glycine in a Hotspot for Neurological Disease Mutations in Na+,K+-ATPase Is Critical to Na+ and K+ Occlusion
by Mads S. Toustrup-Jensen, Rikke Holm, Jens Peter Andersen and Bente Vilsen
Biomolecules 2026, 16(4), 601; https://doi.org/10.3390/biom16040601 - 17 Apr 2026
Viewed by 484
Abstract
Na+,K+-ATPase possesses a highly conserved glycine (G358 in the α3 isoform) that—together with a nearby isoleucine (I363 in α3)—is targeted by mutations causing some of the most severe neurological phenotypes of the clinical spectrum of α3-Na+,K+ [...] Read more.
Na+,K+-ATPase possesses a highly conserved glycine (G358 in the α3 isoform) that—together with a nearby isoleucine (I363 in α3)—is targeted by mutations causing some of the most severe neurological phenotypes of the clinical spectrum of α3-Na+,K+-ATPase mutations. The disease mutations α3-G358V and α3-I363N affect Na+ and K+ transport to an extent incompatible with cell growth. However, alanine replacement of the corresponding glycine G363 in the α1 isoform is compatible with cell growth, allowing the effects on Na+,K+-ATPase function to be addressed using enzymatic assays on plasma membranes isolated from transfected cells. Occlusion of Na+ appears to be defective in mutant G363A, resulting in a reduced rate of phosphorylation from ATP. Furthermore, the mutation displaces the major conformational equilibrium of Na+,K+-ATPase such that the K+-occluded state is destabilized and occluded K+ is released faster, thereby leading to accumulation of a non-productive state without bound Na+ or K+. The critical function of the glycine can be ascribed to a strategic location at the bending point between an α helix and a β strand, where it connects the catalytic ATP hydrolysis site in the cytoplasmic P domain with the ion-binding region in the membrane and coordinates important intramolecular domain movements during the Na+,K+-ATPase transport cycle. Full article
(This article belongs to the Section Cellular Biochemistry)
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25 pages, 6277 KB  
Review
Emerging Role of Transcription Factor 19 (TCF19) in Inflammatory Disease and Cancer
by Xiang Li, Yi-Fang Jiang, Ran Wang, Jing Yu, Yan-Jun Liu, Yun-Fei Dang, Guan-Jun Yang and Jiong Chen
Biomolecules 2026, 16(4), 600; https://doi.org/10.3390/biom16040600 - 17 Apr 2026
Viewed by 984
Abstract
Transcription factor 19 (TCF19) is a multifunctional biomolecule located within the major histocompatibility complex (MHC) class I region on chromosome 6p21.3. Structurally, TCF19 contains a plant homeodomain (PHD) finger that recognizes histone H3 lysine 4 trimethylation (H3K4me3) and a forkhead-associated (FHA) domain with [...] Read more.
Transcription factor 19 (TCF19) is a multifunctional biomolecule located within the major histocompatibility complex (MHC) class I region on chromosome 6p21.3. Structurally, TCF19 contains a plant homeodomain (PHD) finger that recognizes histone H3 lysine 4 trimethylation (H3K4me3) and a forkhead-associated (FHA) domain with yet-uncharacterized functions. Emerging evidence positions TCF19 as a multifunctional regulator associated with cell cycle progression, transcriptional regulation, cancer progression, and immune modulation through epigenetic and signaling mechanisms. This review provides the first systematic synthesis of TCF19’s structural domains, regulatory networks, and context-dependent functions across cancer and non-cancer diseases. We highlight critical knowledge gaps, including the unresolved function of its FHA domain and the lack of direct small-molecule inhibitors. In cancer, TCF19 drives proliferation, metastasis, immune evasion, and therapy resistance. Beyond cancer, TCF19 is involved in metabolic diseases, chronic infections, inflammatory disorders, and sensory deficits. TCF19 serves as a promising molecular biomarker for cancer diagnosis, prognosis, and treatment response monitoring, though direct targeting strategies remain unavailable. Full article
(This article belongs to the Section Molecular Medicine)
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20 pages, 2677 KB  
Article
Fragment-Derived Nicotinic Acid Analogues Inhibit hCA III and Downregulate CA3 Expression in HepG2 Cells
by Areej Abuhammad, Tamara Sabri, Nidaa A. Ababneh, Rya A. Ali, Mohammad A. Ismail, Adan Madadha, Dareen T. Yazjeen, Rama J. Alghanem, Ali M. Qaisi, Yusuf Al-Hiari, Kapil Gupta, Imre Berger and Edith Sim
Biomolecules 2026, 16(4), 599; https://doi.org/10.3390/biom16040599 - 17 Apr 2026
Viewed by 641
Abstract
Chronic oxidative stress and lipid imbalance drive metabolic disorders such as obesity and non-alcoholic fatty liver disease, yet few therapies target the upstream redox imbalance in key tissues. Human carbonic anhydrase III (hCA III), a redox-associated enzyme enriched in liver and adipose tissue, [...] Read more.
Chronic oxidative stress and lipid imbalance drive metabolic disorders such as obesity and non-alcoholic fatty liver disease, yet few therapies target the upstream redox imbalance in key tissues. Human carbonic anhydrase III (hCA III), a redox-associated enzyme enriched in liver and adipose tissue, has long remained pharmacologically elusive due to its low catalytic activity and lack of modulators. Here, we identify fragment-like nicotinic acid derivatives as non-sulfonamide hCA III modulators and evaluate their associated cellular effects. Using an esterase activity assay, we screened 25 analogues and identified two fragment-like hits, compound 17 (2-thioethyl) and compound 22 (6-morpholino), with IC50 values of 487 and 361 µM, respectively. Orthogonal thermal shift analysis supported compound-protein interaction, and selected hits were subsequently evaluated in HepG2 cells. Both compounds were associated with reduced CA3 mRNA expression after treatment at 1 µM, while their cellular phenotypes diverged, with compound 22 increasing ROS under oxidative stress conditions and compound 17 affecting mitochondrial membrane potential. Taken together, these findings identify tractable nicotinic acid-derived fragment hits and associated cellular phenotypes that warrant further mechanistic investigation. These fragment-like hits provide a practical starting point for studying the redox-linked biology of hCA III. Full article
(This article belongs to the Section Cellular Biochemistry)
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24 pages, 22347 KB  
Article
The Effects of Baicalin in Combination with Cefotaxime on the Biofilm and Metabolic Reprogramming of Multidrug-Resistant Pseudomonas aeruginosa
by Xin Meng, Chao Ning, Xinyu Lu, Mengna Kang, Yuxuan Yang, Zhiyun Yu, Yu Wang, Yantong Sun and Haiyong Guo
Biomolecules 2026, 16(4), 598; https://doi.org/10.3390/biom16040598 - 17 Apr 2026
Viewed by 567
Abstract
Baicalin, a natural plant-derived compound, holds promise in addressing clinical bacterial resistance when combined with antibiotics. This study evaluated the antibacterial activity of the combination of baicalin and cefotaxime and explored its mechanism of action on the cell wall and biofilm of multidrug-resistant [...] Read more.
Baicalin, a natural plant-derived compound, holds promise in addressing clinical bacterial resistance when combined with antibiotics. This study evaluated the antibacterial activity of the combination of baicalin and cefotaxime and explored its mechanism of action on the cell wall and biofilm of multidrug-resistant Pseudomonas aeruginosa (MRPA). The results showed that the combination of baicalin and cefotaxime exerted a synergistic inhibitory effect on the growth of MRPA, with a fractional inhibitory concentration index (FICI) of 0.28. Mechanistically, compared with cefotaxime alone, the combination of baicalin and cefotaxime enhanced the permeability of the cell membrane and cell wall of MRPA, thereby increasing cell damage. It also exhibited stronger antibiofilm activity by inhibiting numerous virulence factors (pyocyanin, elastase, lectin), reducing cellular metabolic activity, and downregulating the expression of biofilm genes (pslA, pelA, algD) and quorum-sensing genes (lasl, lasR, rhll, rhlR, pqsA, pqsR). The molecular docking results revealed that baicalin could stably bind to wbpE, LasR, and RhlR. Therefore, this interaction may indirectly influence the processes related to antibiotic resistance and biofilm formation in bacterial cells. Metabolomic analysis revealed that the combination of baicalin and cefotaxime upregulated 863 metabolites and downregulated 587 metabolites. These metabolites mainly included amino acids, lipids, nucleotides, carbohydrates, and secondary metabolites. The combination primarily enriched key pathways such as amino acid metabolism, lipid metabolism (sphingolipid metabolism) and secondary metabolite biosynthesis. Through these pathways, it triggers significant metabolic reprogramming, thereby interfering with the supply of cell wall synthesis precursors, membrane structural stability, and the generation of biomembrane matrix. Ultimately, it synergistically enhances the effects of cell wall damage and biomembrane inhibition. In conclusion, this study confirms that the combination of baicalin and cefotaxime exerts significant synergistic antibacterial activity against MRPA. It also reveals the mechanism of action of the combination on the cell wall and biofilm of MRPA at the metabolic level, providing theoretical support for the development of novel strategies to combat MRPA. Full article
(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance)
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26 pages, 6685 KB  
Article
Quercetin Enhances Topotecan Cytotoxicity in Retinoblastoma Cells Through ROS-Associated Stress and Apoptotic Signaling
by Aydın Maçin, Erkan Duman, İlhan Özdemir and Mehmet Cudi Tuncer
Biomolecules 2026, 16(4), 597; https://doi.org/10.3390/biom16040597 - 17 Apr 2026
Viewed by 537
Abstract
Quercetin, a naturally occurring flavonoid, exhibits antiproliferative and pro-apoptotic effects across various cancer models. Topotecan, a topoisomerase I inhibitor, is used in the treatment of retinoblastoma; however, its clinical utility is limited by dose-dependent toxicity. This study aimed to investigate whether quercetin is [...] Read more.
Quercetin, a naturally occurring flavonoid, exhibits antiproliferative and pro-apoptotic effects across various cancer models. Topotecan, a topoisomerase I inhibitor, is used in the treatment of retinoblastoma; however, its clinical utility is limited by dose-dependent toxicity. This study aimed to investigate whether quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma and to explore the underlying mechanisms under both two-dimensional (2D) and three-dimensional (3D) conditions. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the combination index (CI) based on the Chou–Talalay method. Apoptosis was analyzed by Annexin V-FITC/PI staining and flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential were evaluated using fluorometric methods, and N-acetyl-L-cysteine (NAC) was used for functional modulation of oxidative stress. Three-dimensional tumor spheroid models were used to assess treatment effects under conditions that partially recapitulate tumor architecture. Gene expression levels of apoptosis-related markers and PI3K/Akt/mTOR pathway components were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The combination of quercetin and topotecan was associated with synergistic cytotoxic effects in Y79 cells (CI < 1), accompanied by increased ROS levels, mitochondrial membrane depolarization, and elevated apoptotic cell death. NAC co-treatment partially attenuated ROS levels and restored cell viability. In 3D spheroid models, combination treatment induced structural disruption, reduced viability, and increased cell death, effects that were partially reversed by NAC. Gene expression analysis revealed upregulation of pro-apoptotic genes and downregulation of survival-related genes, along with increased PTEN expression. Quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma cells under both 2D and 3D conditions. These effects were associated with ROS-associated cellular stress, mitochondrial dysfunction, and modulation of apoptotic and survival-related pathways. The partial rescue by NAC supports a contributory, but not exclusive, role of oxidative stress. These findings should be interpreted within a preclinical context and suggest that quercetin may represent a potential adjunct strategy warranting further validation in translational and in vivo models. Full article
(This article belongs to the Special Issue Cancer Research: Molecular Insights and Therapeutic Strategies)
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17 pages, 6733 KB  
Article
Ghosts on the Membrane: Cytoskeletal Pinning Influences Nanoscale Cell Membrane Organization
by Shambhavi Pandey and Thorsten Wohland
Biomolecules 2026, 16(4), 596; https://doi.org/10.3390/biom16040596 - 17 Apr 2026
Viewed by 593
Abstract
The lateral organization of the plasma membrane (PM) is vital for cellular signaling, yet the specific mechanisms by which the internal cortical actin meshwork templates the organization of the external lipid leaflet remain poorly understood. While established models like the ‘picket-fence’ emphasize physical [...] Read more.
The lateral organization of the plasma membrane (PM) is vital for cellular signaling, yet the specific mechanisms by which the internal cortical actin meshwork templates the organization of the external lipid leaflet remain poorly understood. While established models like the ‘picket-fence’ emphasize physical barriers to diffusion, recent observations of fiber-like “ghost” structures in the distribution of glycosylphosphatidylinositol-anchored proteins (GPI-APs) suggest a more intricate mode of spatial coordination. In this study, we utilize imaging total internal reflection fluorescence correlation spectroscopy (ITIR-FCS) and variable-angle TIRF to resolve whether these filamentous patterns represent genuine membrane-proximal features or optical artifacts of cytosolic transport. Our results demonstrate that these fiber-like tracks are strictly confined to the immediate PM interface and disappear as the evanescent field probes deeper into the cytosol. While the spatial distribution of GPI-APs is templated by the underlying actin meshwork, quantitative diffusion mapping shows that the lateral dynamics of the probe remains largely uniform and is not significantly modulated by these filamentous patterns. By pharmacologically perturbing the actin scaffold and membrane cholesterol, we show that this transbilayer coupling is contingent upon a cholesterol-dependent cytoskeletal pinning mechanism. These findings demonstrate a decoupling of spatial organization and molecular dynamics, providing evidence for how the actin scaffold patterns nanoscale membrane organization without imposing long-range barriers to diffusion. Full article
(This article belongs to the Special Issue Studies of Protein Dynamics, Interactions, and Concentration by Fluorescence Fluctuation Correlation Spectroscopy (FFCS))
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21 pages, 1137 KB  
Review
Tau and β-Amyloid Relevant Pathology as a Central Therapeutic Target in Alzheimer’s Disease
by Lidia Strużyńska, Kamil Adamiak and Marta Sidoryk-Węgrzynowicz
Biomolecules 2026, 16(4), 595; https://doi.org/10.3390/biom16040595 - 17 Apr 2026
Cited by 3 | Viewed by 1303
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia, responsible for approximately 60–70% of cases globally. AD is a gradually progressive neurodegenerative disorder that is characterized by widespread deposition of β-amyloid (Aβ) plaques, followed by aggregation of tau protein in the neocortex, neurodegeneration, [...] Read more.
Alzheimer’s disease (AD) is the leading cause of dementia, responsible for approximately 60–70% of cases globally. AD is a gradually progressive neurodegenerative disorder that is characterized by widespread deposition of β-amyloid (Aβ) plaques, followed by aggregation of tau protein in the neocortex, neurodegeneration, and cognitive decline. Within these complex pathological interactions, Aβ and tau proteins, together with astrogliosis, neuroinflammation, and other factors, play a key role in the development of clinical AD. Accumulating evidence indicates that the formation of protein oligomers, followed by their aggregation into pathological fibrils, constitutes an early and critical step in the pathogenesis of the disease. Specific pathological proteins are often treated as biomarkers of particular diseases because their presence, concentration, or altered structure reflects an underlying disease process. It is well established that the Aβ and tau proteins are the key hallmarks of AD, and their mutual interaction may significantly influence the pathology of the disease. Early diagnosis is crucial for maximizing the therapeutic benefits of currently available symptomatic treatments, which can alleviate symptoms and modestly delay clinical deterioration in patients with AD. This review highlights the mechanisms involved in protein-dependent neurodegeneration and describes both traditional and novel approaches for the cure of AD. The most important aspect of this publication is the integration of the two key proteins: Aβ and tau, and the resulting shift toward a new therapeutic approach. Full article
(This article belongs to the Special Issue Targeting Protein Misfolding: From Alzheimer's Amyloids to Therapeutic Peptides)
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15 pages, 18673 KB  
Article
Crystal Structure and Activity Analysis of Chlamydophila pneumoniae AP Endonuclease IV
by Jinglin Jin, Yitong Zhang, Shiyang Guo, Lihong Yang, Haixia Liu, Long Liu and Wei Gao
Biomolecules 2026, 16(4), 594; https://doi.org/10.3390/biom16040594 - 17 Apr 2026
Viewed by 503
Abstract
DNA damage requires repair via the endonuclease IV-mediated base excision repair (BER) pathway, which corrects apurinic/apyrimidinic (AP) sites. Chlamydophila pneumoniae AP endonuclease IV (CpEndoIV), the sole AP endonuclease in this pathogen, is crucial for genomic integrity. As humans lack a homologous protein, it [...] Read more.
DNA damage requires repair via the endonuclease IV-mediated base excision repair (BER) pathway, which corrects apurinic/apyrimidinic (AP) sites. Chlamydophila pneumoniae AP endonuclease IV (CpEndoIV), the sole AP endonuclease in this pathogen, is crucial for genomic integrity. As humans lack a homologous protein, it represents a potential therapeutic target. In this study, we report the first crystal structure of CpEndoIV at 1.97 Å resolution. The structure reveals two Zn2+, one Mg2+, and a malonate molecule bound in the active site, marking the first observation of Mg2+ coordination in the EndoIV family. Compared to the three-Zn2+ model with a narrow, deep pocket for precise AP-site cleavage, the Zn2+/Mg2+-bound state has a wider, shallower pocket that might promote diverse catalytic activities. Combined with enzymatic assays, we suggest that the mixed Zn2+/Mg2+ model is better adapted for CpEndoIV to operate under host oxidative stress. Malonate binds to the metal ions, occupying the positions normally coordinated by water molecules. This binding mode may mimic the coordination of the substrate to the metal ions, and the protein conformation resembles that of the enzyme upon substrate binding at the active site. This study provides a structural basis for the functional characterization of CpEndoIV and offers a reference for the development of targeted inhibitors against diseases caused by Chlamydophila pneumoniae. Full article
(This article belongs to the Section Enzymology)
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32 pages, 2698 KB  
Article
Synthesis and Biological Profiling of New 1,2,3,4-Tetrahydrobenzo[h]naphthyridine-Based Hybrids as Dual Inhibitors of β-Amyloid and Tau Aggregation with Anticholinesterase Activity
by Aldrick B. Verano, Anna Sampietro, Ana Mallo-Abreu, Rosaria Spagnuolo, Belén Pérez, Manuela Bartolini, María Isabel Loza, José Brea, Jordi Juárez-Jiménez, Raimon Sabate, Carles Galdeano and Diego Muñoz-Torrero
Biomolecules 2026, 16(4), 593; https://doi.org/10.3390/biom16040593 - 16 Apr 2026
Viewed by 617
Abstract
DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and [...] Read more.
DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal stability. Since these drawbacks might arise from its rather high lipophilicity, in this work we have developed a series of more polar analogues, designed by structural modifications at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker. Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42 and tau anti-aggregating potency of the lead, as well as favourable brain permeation and high plasma stability. While further optimization of microsomal stability is necessary for a potential therapeutic use of this class of compounds, hybrids 16 and 17, with similar or even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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16 pages, 4713 KB  
Article
Eicosapentaenoic Acid Attenuates Inflammation in an LPS-Induced Mouse Model of Mastitis Partly Through Modulation of the PPARγ–NF-κB Signaling Pathway
by Zhiwei Duan, Ting Lu, Kejiang Liu, Xiaoxuan Zhao, Wenkai Bai, Bohao Zhang, Quanwei Zhang, Xingxu Zhao, Weitao Dong and Yong Zhang
Biomolecules 2026, 16(4), 592; https://doi.org/10.3390/biom16040592 - 16 Apr 2026
Viewed by 909
Abstract
Mastitis is a common inflammatory disease that harms mammary gland health. Its development is closely linked to dysregulated inflammatory signaling. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, has potential anti-inflammatory effects. However, its molecular mechanism in mastitis prevention remains unclear. In this [...] Read more.
Mastitis is a common inflammatory disease that harms mammary gland health. Its development is closely linked to dysregulated inflammatory signaling. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, has potential anti-inflammatory effects. However, its molecular mechanism in mastitis prevention remains unclear. In this study, we used both in vivo and in vitro models to evaluate how EPA pretreatment regulates mastitis-related inflammatory signaling. Transcriptome analysis showed that differentially expressed genes after EPA treatment were mainly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In an LPS-induced mastitis model, EPA restored the LPS-reduced PPARγ protein level and suppressed NF-κB p65 activation, consistent with reduced nuclear translocation of p65. Similar effects were observed in mammary epithelial cells, where EPA inhibited NF-κB activation at 50 and 100 μM. Functional experiments further showed that a PPARγ agonist mimicked the inhibitory effect of EPA on p65, whereas PPARγ antagonist partially abrogated EPA-mediated inhibition of p65. Collectively, these data indicate that EPA attenuates mastitis-associated inflammation at least in part through the PPARγ–NF-κB axis. Full article
(This article belongs to the Section Molecular Medicine)
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5 pages, 195 KB  
Editorial
In Silico Drug Design and Discovery: Big Data for Small Molecule Design—2nd Edition
by Carmen Cerchia and Antonio Lavecchia
Biomolecules 2026, 16(4), 591; https://doi.org/10.3390/biom16040591 - 16 Apr 2026
Viewed by 654
Abstract
The volume and heterogeneity of data available to drug discovery have grown at a pace that would have been difficult to predict even a few years ago [...] Full article
(This article belongs to the Special Issue In Silico Drug Design and Discovery: Big Data for Small Molecule Design 2nd Edition)
21 pages, 3101 KB  
Article
Ezetimibe Normalizes Dietary Cholesterol-Induced Exacerbation of Liver Injury in Alcohol-Fed Mice
by Yanchao Xu, Nan Zhang, Piumi B. Wickramasinghe, Kavya Veera, Preethi Parupalli, Alex Dao, Junyu Liu, Rithika Anand, Lyndsey E. Langley, Sreeja Eadha, Hasan Iqbal, Chen Liu, Fang Bian and Lin Jia
Biomolecules 2026, 16(4), 590; https://doi.org/10.3390/biom16040590 - 16 Apr 2026
Viewed by 803
Abstract
Interactions between alcohol and nutrition play an important role in the development and progression of alcohol-associated liver disease (ALD). Although dietary cholesterol was shown to exacerbate fatty liver and liver injury in alcohol-fed mice, findings regarding the combined effect of dietary cholesterol and [...] Read more.
Interactions between alcohol and nutrition play an important role in the development and progression of alcohol-associated liver disease (ALD). Although dietary cholesterol was shown to exacerbate fatty liver and liver injury in alcohol-fed mice, findings regarding the combined effect of dietary cholesterol and heavy alcohol drinking on cholesterol homeostasis remain controversial. Ezetimibe has been widely used as a cholesterol-lowering drug in hypercholesterolemic subjects. It is not fully understood whether ezetimibe blunts the adverse effect of cholesterol on lipid and biliary bile acid metabolism in alcohol-exposed mice. In the current study, wild-type mice were subjected to NIAAA alcohol feeding model. Dietary cholesterol (0.2%, w/v) and ezetimibe (0.001%, w/v) were added to the liquid diets. Cholesterol and triglyceride contents in the liver and circulation were determined. Biliary bile acid composition, as well as hepatic and circulating inflammatory markers were analyzed. We found that ezetimibe protected mice from the synergistic effects of dietary cholesterol and alcohol on hepatic triglyceride accumulation, which was accompanied by enhanced expression of genes involved in hepatic beta oxidation. Dietary cholesterol caused great increases in liver cholesterol content and dramatic reductions in the expression of hepatic cholesterol biosynthetic genes in both control- and alcohol-fed mice. These changes were normalized by ezetimibe treatment. Ezetimibe attenuated dietary cholesterol-induced elevations in total biliary bile acids. Moreover, mice fed a diet containing both cholesterol and alcohol exhibited increased expression of monocyte chemoattractant protein 1 (Mcp1) and tumor necrosis factor alpha (Tnfα) in the distal small intestine. Collectively, our findings indicate that ezetimibe effectively mitigates the adverse effects of dietary cholesterol and alcohol consumption on hepatic lipid accumulation and liver injury. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases: 2nd Edition)
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34 pages, 12496 KB  
Review
Chromatin Remodeling, DNA Double-Strand Break Repair, and Human Disease: How a Breakup Changes You
by Adriana Chiaramida, Christopher B. Cummings and Thomas L. Clarke
Biomolecules 2026, 16(4), 589; https://doi.org/10.3390/biom16040589 - 15 Apr 2026
Viewed by 1202
Abstract
Chromatin architecture is a central determinant of genomic stability. Effective DNA repair requires dynamic chromatin remodeling to grant repair factors timely access to lesions and to orchestrate repair pathway choice. Disruption of chromatin-regulatory mechanisms or DNA damage response pathways undermines repair fidelity and [...] Read more.
Chromatin architecture is a central determinant of genomic stability. Effective DNA repair requires dynamic chromatin remodeling to grant repair factors timely access to lesions and to orchestrate repair pathway choice. Disruption of chromatin-regulatory mechanisms or DNA damage response pathways undermines repair fidelity and contributes to a wide spectrum of human disorders, including developmental syndromes, premature aging, and multiple cancers. Here, we review how chromatin state and remodeling complexes shape detection, signaling, and resolution of DNA double-strand breaks, and we examine how their misregulation drives disease and presents opportunities for therapeutic intervention. Specifically, we discuss how post-translational modifications and ATP-dependent chromatin remodeling complexes contribute to DNA damage repair with a particular focus on DNA double-strand breaks, one of the most deleterious DNA lesions. We summarize how chromatin remodeling and histone post-translational modifications regulate DNA repair pathway choice, and how these processes are essential for safeguarding genomic integrity and preventing human disease. Finally, we discuss emerging concepts and major unanswered questions in the context of chromatin function and DNA double-strand break repair, with a focus on exploring the emerging literature on the role of chromatin compartments and topological associated domains for orchestrating DNA repair within chromatin and safeguarding genomic stability. Full article
(This article belongs to the Special Issue Functional Analysis of Genes Related to DNA Damage)
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16 pages, 1550 KB  
Review
Leucine-Rich Repeat Kinase 2 (LRRK2) in Glucose Metabolism and Metabolic–Neuroinflammatory Crosstalk
by Fumitaka Kawakami, Motoki Imai, Masanori Ogata, Toshiya Habata, Shun Tamaki, Rei Kawashima, Yoshifumi Kurosaki, Sayaka Miyai, Moragot Chatatikun, May Pyone Kyaw and Kenichi Ohba
Biomolecules 2026, 16(4), 588; https://doi.org/10.3390/biom16040588 - 15 Apr 2026
Viewed by 666
Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson’s disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose [...] Read more.
Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson’s disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4–NFκB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic–neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress—characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood–brain barrier disruption—drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD. Full article
(This article belongs to the Section Cellular Biochemistry)
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25 pages, 3055 KB  
Review
Epigenetic Biomarkers for Predicting Nucleoside Analog Drug Response and Resistance in Cancer
by John Kaszycki, Jackson C. Lin, Minji Kim and Hunmin Jung
Biomolecules 2026, 16(4), 587; https://doi.org/10.3390/biom16040587 - 15 Apr 2026
Viewed by 757
Abstract
Nucleoside analogs (NAs) play a central role in cancer therapy, either through direct cytotoxicity or epigenome reprogramming. They are clinically effective but have shortcomings in their long-term effectiveness because of variable patient responses and the emergence of resistance. There is growing evidence that [...] Read more.
Nucleoside analogs (NAs) play a central role in cancer therapy, either through direct cytotoxicity or epigenome reprogramming. They are clinically effective but have shortcomings in their long-term effectiveness because of variable patient responses and the emergence of resistance. There is growing evidence that DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs (ncRNAs) are key factors that determine sensitivity and resistance to NAs. This review summarizes existing evidence on the epigenetic control of cytotoxic and epigenetic nucleoside analogs, discusses predictive biomarkers of human Equilibrative Nucleoside Transporter 1 (hENT1) and deoxycytidine kinase (dCK) promoter methylation, histone modifications, and ncRNA signatures, and assesses the emerging strategies of multi-omic integration. Improvements in detection methods, such as high-resolution sequencing, single-cell profiling, and liquid biopsy, are addressed, along with the issues of reproducibility, tumor heterogeneity, and clinical translation. Epigenetic biomarkers are promising for patient stratification in clinical trials, although a lack of uniformity in technical and methodological approaches currently constrains their full potential. The future focus will be on standardized panels of biomarkers, real-time monitoring, rational combination strategies, and biomarker-directed clinical trial designs. Overall, epigenetic biomarkers are capable of changing nucleoside analog therapy into a more precise, durable, and personalized treatment approach. Full article
(This article belongs to the Special Issue Genomic Instability: Insights into Molecular Mechanisms, Human Diseases, and Therapies)
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