Biomolecules

36 pages, 17849 KB

Open AccessReview

Mechanisms of Obesity-Related Kidney Disease: From Adipose Depot Biology to the Chymase–Aldosterone and Ghrelin–Leptin Axes

by Hsuan-Chu Hsu, Li-Jane Shih, Yi-Chou Hou and Kuo-Cheng Lu

Biomolecules 2026, 16(8), 1155; https://doi.org/10.3390/biom16081155 (registering DOI) - 8 Aug 2026

Abstract

Obesity is an increasingly important and modifiable driver of chronic kidney disease (CKD), with effects that extend well beyond its associations with type 2 diabetes, hypertension, and dyslipidemia. To synthesize the evidence that excess adiposity is a causal and modifiable determinant of kidney [...] Read more.

Obesity is an increasingly important and modifiable driver of chronic kidney disease (CKD), with effects that extend well beyond its associations with type 2 diabetes, hypertension, and dyslipidemia. To synthesize the evidence that excess adiposity is a causal and modifiable determinant of kidney disease, and to examine how specific adipose depots injure the glomerulus and the tubulointerstitium, and then map these mechanisms onto established and emerging therapies. Throughout, obesity-related kidney disease (ORKD) denotes the full spectrum of diposity-driven renal injury, whereas obesity-related glomerulopathy (ORG) is reserved for the biopsy-defined glomerular lesion. Central, visceral, perirenal and renal-sinus adiposity act first through structural and haemodynamic mechanisms, promoting glomerular hyperfiltration, mechanical renal compression and activation of the adipose-derived renin–angiotensin–aldosterone system (RAAS). In parallel, these depots drive cellular and metabolic injury through lipotoxicity, adipokine imbalance, sterile inflammation, oxidative stress, gut dysbiosis, mitochondrial dysfunction, epigenetic remodelling and cellular senescence. Ectopic lipid accumulation within the renal parenchyma—fatty kidney—offers a unifying description of these changes and is most marked in type 2 diabetes mellitus. These interacting processes converge on podocyte stress, tubular metabolic failure, endothelial dysfunction and interstitial fibrosis, producing a phenotypic continuum that ranges from early albuminuria to obesity-related glomerulopathy and progressive CKD. Within the RAAS limb we highlight two comparatively underappreciated, adiposity-linked routes to injury: adipocyte-derived leptin directly upregulates adrenal aldosterone synthase (CYP11B2), and mast-cell chymase generates angiotensin II independently of angiotensin-converting enzyme, together reinforcing aldosterone- and angiotensin II–mediated damage that conventional RAAS blockade only partially interrupts. We further consider the counter-regulatory ghrelin–leptin axis, in which the suppression of ghrelin that accompanies obesity may withdraw an antioxidant, anti-inflammatory and podocyte-protective signal precisely as leptin-driven glomerular injury intensifies, positioning ghrelin as a plausible modulator and candidate biomarker of obesity-related kidney injury. We also examine how obesity complicates renal risk assessment, drug dosing, dialysis delivery and transplant access. Emerging, mechanism-matched therapies—SGLT2 inhibitors, GLP-1 receptor agonists, finerenone, structured lifestyle intervention, metabolic-bariatric surgery and, most recently, aldosterone synthase inhibitors that suppress the chymase- and leptin-driven aldosterone escaping receptor blockade—now enable a precision cardiovascular-kidney-metabolic framework that aligns adipose-depot biology, biomarkers, histology and treatment response to guide mechanism-based care in ORKD. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 46805 KB

Open AccessArticle

by Wenjing Tang, Weixia Wang, Shuyang Zhang, Xin Zhou, Linfeng He and Tianshu Zeng

Biomolecules 2026, 16(8), 1154; https://doi.org/10.3390/biom16081154 - 7 Aug 2026

Abstract

Senescence-related molecular nodes linking hepatic stress with immune dysregulation in metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly defined. This study aimed to identify and experimentally validate a senescence-related gene (SRG) signature associated with immune dysregulation in MASLD. Four transcriptomic datasets (127 controls, [...] Read more.

Senescence-related molecular nodes linking hepatic stress with immune dysregulation in metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly defined. This study aimed to identify and experimentally validate a senescence-related gene (SRG) signature associated with immune dysregulation in MASLD. Four transcriptomic datasets (127 controls, 127 MASLD) were integrated as the discovery cohort. Candidate SRGs were identified through differential expression analysis, weighted gene co-expression network analysis, and three machine learning algorithms. Immune infiltration was assessed using CIBERSORT, and a three-gene signature was evaluated in internal and external cohorts. Potential GADD45G-associated compounds were predicted by molecular docking. Experimental validation was performed in high-fat diet (HFD)-induced obese mice and palmitic acid (PA)-stimulated bone marrow-derived macrophages (BMDMs). Single-cell RNA sequencing analysis of GSE300744 was further performed to evaluate GADD45G distribution in hepatic cell populations. SOCS1, SOCS2, and GADD45G were identified as core SRGs. Their expression was reduced in MASLD liver tissues and correlated with histological features and immune alterations. The three-gene signature showed favorable classification performance in validation cohorts. In HFD mice, GADD45G expression was decreased at both mRNA and protein levels, with reduced immunoreactivity in F4/80-positive hepatic macrophages. Single-cell analysis further supported macrophage-associated expression of Gadd45g. In PA-stimulated BMDMs, reduced GADD45G protein expression was partially restored by camptothecin and myristicin treatment. Overall, SOCS1, SOCS2, and GADD45G represent a candidate senescence-related immune signature associated with MASLD. The macrophage-associated reduction in GADD45G and its modulation in vitro provide preliminary evidence for a potential role of GADD45G in MASLD-associated immune dysregulation. Full article

(This article belongs to the Section Molecular Biomarkers)

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24 pages, 2078 KB

Open AccessArticle

Molecular Interactions and Antioxidant Properties of White Wine Phytochemicals: A Mechanistic Study of Serum Protein Binding

by Dinorah Barasch, Alina Nemirovski, Emmanuelle Merquiol, Joseph Deutsch, Dejian Huang, Pitipong Thobunluepop, Alma Leticia Martinez-Ayala, Patricia Arancibia-Avila, Fernando Toledo-Montiel, Paweł Paśko and Shela Gorinstein

Biomolecules 2026, 16(8), 1153; https://doi.org/10.3390/biom16081153 - 7 Aug 2026

Abstract

This study investigated the interactions between phenolic compounds from Israeli and Chilean white wines and human serum carrier proteins, including human serum albumin (HALB), gamma-globulin (HGLO), and fibrinogen (HFB), to characterize their antioxidant capacity and serum protein-binding behavior under controlled experimental conditions. The [...] Read more.

This study investigated the interactions between phenolic compounds from Israeli and Chilean white wines and human serum carrier proteins, including human serum albumin (HALB), gamma-globulin (HGLO), and fibrinogen (HFB), to characterize their antioxidant capacity and serum protein-binding behavior under controlled experimental conditions. The analyzed wines included Israeli Chardonnay (ICR), Chilean Chardonnay (CCR), Israeli Sauvignon Blanc (ISB), and Chilean Sauvignon Blanc (CSB). HPLC and FTIR fingerprinting revealed cultivar- and region-dependent differences in phenolic composition, with Chardonnay wines showing stronger protein-binding behavior and Sauvignon Blanc samples displaying high antioxidant efficiency relative to their phenolic content. ICR exhibited the highest total binding capacity, 46.44%, and the strongest albumin interaction, with a binding constant (Kb) of 8.44 × 10⁴ M⁻¹ and a Gibbs free energy (ΔG) value of −35.03 kJ/mol. Empirical fluorescence quenching kinetics demonstrated that white wine phenolics establish stable physical complexes with human serum proteins, displaying a distinct preferential affinity for HALB as the protein showing the strongest apparent interaction among the proteins tested. Two- and three-dimensional fluorescence spectroscopy confirmed substantial quenching of the intrinsic tryptophan and tyrosine residues, indicating meaningful microenvironmental alterations within the protein’s active transport sites. These empirical interactions were closely mirrored by complementary molecular docking simulations, which provided a structural visualization of the physical binding interactions. ICR also showed the highest antioxidant capacity, with DPPH and CUPRAC values of 1.66 and 2.91 mmol TE/L, respectively. Ethanol control showed negligible effects, indicating that the observed bioactivity was mainly associated with the polyphenolic matrix. Among the investigated samples, Chardonnay showed higher apparent protein-binding capacity, whereas Sauvignon Blanc showed relatively high antioxidant efficiency in relation to its phenolic content. Full article

(This article belongs to the Special Issue Phytochemicals: Bioactivity in Disease Prevention, Anti-Inflammation, and Animal/Human Health)

23 pages, 1231 KB

Open AccessArticle

Non-Work-Matched HIIT and MIIT Partially Restore Exerkine-Related and Mitochondrial Gene Expression in Diabetic Rat Skeletal Muscle

by Saeed Rezae, Payam Abasian Mehr, Parisa Pournemati, Ismail Laher, Özgür Eken and Monira I. Aldhahi

Biomolecules 2026, 16(8), 1152; https://doi.org/10.3390/biom16081152 - 7 Aug 2026

Abstract

Skeletal muscle mitochondrial dysfunction and altered myokine signaling contribute to insulin resistance in type 2 diabetes. This study compared the effects of non-work-matched high-intensity interval training (HIIT) and moderate-intensity interval training (MIIT) on skeletal muscle exerkine/myokine- and mitochondrial biogenesis-related gene expression and systemic [...] Read more.

Skeletal muscle mitochondrial dysfunction and altered myokine signaling contribute to insulin resistance in type 2 diabetes. This study compared the effects of non-work-matched high-intensity interval training (HIIT) and moderate-intensity interval training (MIIT) on skeletal muscle exerkine/myokine- and mitochondrial biogenesis-related gene expression and systemic metabolic indices in streptozotocin-nicotinamide-induced diabetic rats. Twenty-four male Wistar rats were initially allocated to healthy control, diabetic control, MIIT, or HIIT groups; after predefined treadmill-familiarization exclusions, five animals per group were analyzed. Training was performed for 6 weeks, three sessions per week, with MIIT prescribed at 70% maximal aerobic speed and HIIT at 90% maximal aerobic speed. Gastrocnemius expression of FNDC5, OSTN, PGC-1α, TFAM, CCO, and UCP3 was quantified by RT-qPCR, and fasting glucose, insulin, lipid variables, HOMA-IR, HOMA-β, QUICKI, and TyG index were assessed. Diabetes reduced all targeted transcripts and impaired insulin-related metabolic indices. Both MIIT and HIIT partially restored myokine- and mitochondrial-related transcripts compared with diabetic controls, with no significant differences between training protocols for most molecular outcomes. HIIT produced lower fasting insulin and HOMA-IR than MIIT but imposed a greater estimated cumulative workload. These findings indicate that interval training partly attenuates diabetes-associated transcriptional and insulin-related metabolic disturbances, while intensity-specific conclusions require work-matched designs. Full article

(This article belongs to the Special Issue Exerkines as Mediators of Exercise Benefits: Mechanisms, Functions and Applications)

17 pages, 1617 KB

Open AccessArticle

Lipid Conjugation of a Photoprotective Meadowfoam (Limnanthes alba) Glucolimnanthin Derivative Reduces Cytotoxicity, Attenuates UV-Induced DNA Damage and Activates DNA Repair in Human Keratinocytes Following UV Radiation

by Evan L. Carpenter, Wenbin Wu, Ewa Podgórska, Vajravathi Lakkim, Saiashish G. Singh, Andrzej T. Slominski, Gitali Ganguli-Indra, Jan F. Stevens and Arup K. Indra

Biomolecules 2026, 16(8), 1151; https://doi.org/10.3390/biom16081151 - 7 Aug 2026

Abstract

Ultraviolet B (UVB) radiation is a primary cause of DNA damage in the skin, which is often a precursor to skin cancer. Natural products represent a rich source of compounds with unexplored photoprotective properties. Our previous work identified 3-methoxybenzyl isothiocyanate (MBITC), a meadowfoam [...] Read more.

Ultraviolet B (UVB) radiation is a primary cause of DNA damage in the skin, which is often a precursor to skin cancer. Natural products represent a rich source of compounds with unexplored photoprotective properties. Our previous work identified 3-methoxybenzyl isothiocyanate (MBITC), a meadowfoam derivative, as a promising UVB-absorptive agent that reduces DNA damage and cell proliferation; however, its clinical use is limited by dose-dependent cytotoxicity. To address this, we synthesized a novel amide lipid conjugate of MBITC, N-(3-methoxybenzyl)eicos-5-enamide (MBA), and evaluated its photoprotective efficacy and mechanism of action. Our findings demonstrate that MBA exhibited remarkably reduced cytotoxicity compared to its parent compound, while effectively retaining its photoprotective properties. In human primary keratinocyte cultures, MBA significantly reduced UVB-induced DNA damage, as evidenced by a decrease in cyclobutane pyrimidine dimers (p < 0.05) and γ-H2A.X (p < 0.05). Furthermore, MBA increased the expression of DNA damage response (DDR) proteins and DNA damage-binding protein 1 (DDB1) (p < 0.05) and the activation of Ataxia Telangiectasia and Rad3-related protein (ATR) (p < 0.05), a master regulator of DDR and repair pathways. These findings suggest that MBA acts through direct UVB absorption and/or the engagement of DDR pathways following irradiation, highlighting its potential use as a novel photoprotective compound. Full article

(This article belongs to the Special Issue Advances in Melanoma Targeted Therapy)

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Graphical abstract

28 pages, 8275 KB

Open AccessReview

Exosome-Associated Proteins as Mediators and Biomarkers of Ovarian Cancer Dissemination

by Aleksei Shefer, Ekaterina Ivanova, Alyona Chernyshova and Svetlana Tamkovich

Biomolecules 2026, 16(8), 1150; https://doi.org/10.3390/biom16081150 - 7 Aug 2026

Abstract

Ovarian cancer (OC) remains the most lethal gynecological malignancy, mostly due to its frequent diagnosis at advanced stages, early peritoneal dissemination, ascites formation, and limited sensitivity of currently available approaches for early detection. Extracellular vesicles (EVs), particularly exosomes, mediate intercellular communication through the [...] Read more.

Ovarian cancer (OC) remains the most lethal gynecological malignancy, mostly due to its frequent diagnosis at advanced stages, early peritoneal dissemination, ascites formation, and limited sensitivity of currently available approaches for early detection. Extracellular vesicles (EVs), particularly exosomes, mediate intercellular communication through the transfer of proteins, lipids, metabolites, and nucleic acids. In OC, EV-associated protein profiles reflect both tumor-cell-intrinsic programs and the complex interactions between malignant cells and the peritoneal microenvironment. This review summarizes current evidence regarding the involvement of exosomal proteins in OC progression, with particular emphasis on epithelial–mesenchymal transition, mesothelial reprogramming, extracellular matrix remodeling, angiogenesis, immune suppression, peritoneal dissemination, and platinum resistance. Mechanistic studies indicate that exosomal proteins, including CD44, the integrin α5β1/asparaginyl endopeptidase complex, annexin A2, low-density lipoprotein receptor-related protein 1, and programmed death-ligand 1, can directly contribute to metastatic niche formation and tumor progression. In parallel, proteomic studies of plasma-, serum-, ascites-, peritoneal-fluid-, and uterine-lavage-derived EVs have identified candidate liquid-biopsy biomarkers, including MUC1, EpCAM, FOLR1, integrins, complement- and coagulation-related proteins, and proteins associated with treatment resistance. To integrate the biological significance of proteins reported in OC-associated exosomes, we additionally performed protein–protein interaction and functional enrichment analyses. These analyses revealed interconnected protein groups associated with cell adhesion, oxidative stress adaptation, secretory remodeling, lipid metabolism, extracellular matrix organization, and inflammatory signaling. Taken together, the available evidence supports exosomal proteome profiling as a promising approach for investigating OC dissemination and developing minimally invasive diagnostic and prognostic tools. However, standardized EV isolation, quantitative proteomics, functional validation, and independent clinical cohorts remain essential for translation into clinical practice. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Their Roles in Cancer Progression)

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17 pages, 2988 KB

Open AccessArticle

A Tailored Workflow for Circular RNA Enrichment and Analysis from Human Whole Blood

by Federica Cieri, Valeria Valsecchi, Lorenzo d’Amico di S. Domenico, Raffaele Dubbioso, Marco Salvatore, Lucio Annunziato and Giuseppe Pignataro

Biomolecules 2026, 16(8), 1149; https://doi.org/10.3390/biom16081149 - 7 Aug 2026

Abstract

CircRNAs are covalently closed ncRNAs originating through back splicing; their expression is finely regulated, displaying specific patterns across different cell types, tissues, and developmental stages. While the molecular functions of circRNAs are not completely elucidated, their regulatory involvement in physiological processes is well [...] Read more.

CircRNAs are covalently closed ncRNAs originating through back splicing; their expression is finely regulated, displaying specific patterns across different cell types, tissues, and developmental stages. While the molecular functions of circRNAs are not completely elucidated, their regulatory involvement in physiological processes is well established, alongside their dysregulation in several human disorders. These features, together with their higher stability compared to other ncRNAs, make this class of molecules promising theragnostic agents, particularly in biomarker discovery. Accordingly, it is crucial to develop and standardize experimental strategies that improve circRNA analysis, ensuring accurate and effective isolation of these molecules. In biomarker discovery, selecting the appropriate biological matrix is critical; whole blood is often preferred for its accessibility and minimally invasive collection. Because circRNAs are present in human peripheral blood and show promise as disease theragnostic biomarkers, we established a preliminary workflow tailored to isolate and analyze circRNAs from whole blood. The promising effectiveness and robustness of this workflow were demonstrated by qPCR analysis, suggesting highly reproducible detection and reliability in isolating and analyzing circRNAs. This, together with their stability and specific expression profiles, supports the utility of circRNAs in biomarker discovery and advanced circRNA research and contributes to accelerating their future integration into theragnostic applications in clinical settings. Full article

(This article belongs to the Topic Biomarker Development and Application, 2nd Edition)

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29 pages, 937 KB

Open AccessReview

Redox-Mediated Mitochondrial Dysfunction as a Common Pathogenic Axis in Acute Kidney Injury and Chronic Kidney Disease

by Ewelina Młynarska, Kinga Bojdo, Katarzyna Hossa, Wiktoria Lisińska, Katarzyna Krawiranda, Natalia Krupińska, Natalia Kustosik, Anna Wieczorek, Jacek Rysz and Beata Franczyk

Biomolecules 2026, 16(8), 1148; https://doi.org/10.3390/biom16081148 - 7 Aug 2026

Abstract

Acute kidney injury (AKI), chronic kidney disease (CKD), and diabetic kidney disease (DKD) are interconnected disorders linked by shared mechanisms involving redox imbalance and mitochondrial dysfunction. This review summarizes current evidence on the role of excessive reactive oxygen species (ROS) production, impaired oxidized [...] Read more.

Acute kidney injury (AKI), chronic kidney disease (CKD), and diabetic kidney disease (DKD) are interconnected disorders linked by shared mechanisms involving redox imbalance and mitochondrial dysfunction. This review summarizes current evidence on the role of excessive reactive oxygen species (ROS) production, impaired oxidized nicotinamide adenine dinucleotide (NAD⁺) metabolism, altered mitochondrial bioenergetics, disrupted mitochondrial dynamics, and defective mitochondrial quality control pathways, including mitophagy and the mitochondrial unfolded protein response (UPR^mt), in kidney disease progression. Experimental and clinical studies indicate that these mechanisms contribute to inflammation, fibrosis, apoptosis, and maladaptive repair, promoting progression from AKI to CKD and worsening DKD. The review also discusses emerging biomarkers and therapeutic strategies targeting oxidative stress and mitochondrial dysfunction. Overall, redox-mediated mitochondrial injury represents a shared pathogenic axis and a potential therapeutic target across kidney diseases. Full article

(This article belongs to the Special Issue Redox Dysregulation and Mitochondrial Adaptation in Kidney Disease)

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17 pages, 2371 KB

Open AccessHypothesis

Role of Mechanotransduction in Cancer: A Complex Problem Involving Gene Mutations and Altered Levels of Connection Components

by Frederick H. Silver

Biomolecules 2026, 16(8), 1147; https://doi.org/10.3390/biom16081147 - 7 Aug 2026

Abstract

Background: External and internal forces and tissue energy influence the structure and function of mammalian tissues during life in a gravitational field. Changing force (stress) and energy equilibria provide a dynamic means to regulate cell and tissue growth during development and maturation. However, [...] Read more.

Background: External and internal forces and tissue energy influence the structure and function of mammalian tissues during life in a gravitational field. Changing force (stress) and energy equilibria provide a dynamic means to regulate cell and tissue growth during development and maturation. However, genetic mutations and changes in expression of macromolecules involved in cell and extracellular matrix (ECM) equilibria lead to tumor formation. Methods: A model is presented illustrating connections between ECM, cell membranes, cell cyto- and nucleoskeletons, cell nucleus, and cell–cell junctions that promote energy storage, transmission, and dissipation. The effects of mutations involving changes in P53 and Coll 11A1 genes and changes in expression of collagens and collagen receptors, integrins, ILK, FAK, Talin, Paxillin, Kindlins, c-SRC, Actin, myosin light chain, Filamin A, E-cadherin, and beta catenin that have been reported to occur in cancerous lesions are examined. Results: When mutations or altered component expressions occur, mechanotransduction pathways are activated that lead to modified epithelial–mesenchymal (EMT) and endothelial–mesenchymal (ENT) transitions resulting in new cell division and deposition of ECM. Conclusions: It is hypothesized that changes in genes and expression of proteins in the connections between ECM and bound cells alter energy storage and dissipation. This leads to local stress concentrations that alter force and energy dynamic equilibria required to maintain homeostasis. Excess energy associated with broken connections within cells is dissipated through changes in myosin structure and function. Full article

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

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14 pages, 3679 KB

Open AccessReview

NMDA Receptor Regulation by Calmodulin and α-Actinin-1

by Aritra Bej, Johannes W. Hell and James B. Ames

Biomolecules 2026, 16(8), 1146; https://doi.org/10.3390/biom16081146 - 7 Aug 2026

Abstract

N-methyl-D-aspartate (NMDA) receptors (NMDARs) are Ca²⁺-permeable ionotropic glutamate receptors in the brain that have critical roles in learning, memory, neural development, and synaptic plasticity. NMDARs are heterotetrameric Ca²⁺ channels, which open upon binding to the neurotransmitters, glutamate and glycine. Channel [...] Read more.

N-methyl-D-aspartate (NMDA) receptors (NMDARs) are Ca²⁺-permeable ionotropic glutamate receptors in the brain that have critical roles in learning, memory, neural development, and synaptic plasticity. NMDARs are heterotetrameric Ca²⁺ channels, which open upon binding to the neurotransmitters, glutamate and glycine. Channel opening causes Ca²⁺ influx that activates a range of Ca²⁺-dependent cellular processes, including activation of Ca²⁺-dependent enzymes, which mediates various forms of synaptic plasticity. Prolonged channel opening elevates the intracellular Ca²⁺ level to a cytotoxic concentration. To maintain Ca²⁺ homeostasis, NMDAR channel activity is finely regulated by α-actinin (ACTN), which promotes channel opening by reducing the closed time, and by calmodulin (CaM), which promotes Ca²⁺-dependent channel desensitization (CDD). Defects in the regulation of NMDAR function are associated with a spectrum of neurological diseases. In this review, we integrate cryo-EM structures of NMDARs, NMR structures of the NMDAR cytosolic C0 domain of the GluN1 and GluN2A subunits bound to Ca²⁺-bound CaM (Ca²⁺-CaM), and various structures of α-actinin-1 (ACTN1) to construct structural models of NMDAR in the open channel state bound to Ca²⁺-free ACTN1 and the agonist-bound, desensitized channel state bound to Ca²⁺-CaM. These structural models provide insights into the Ca²⁺-dependent conformational changes that promote CDD. Full article

(This article belongs to the Section Cellular Biochemistry)

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16 pages, 4801 KB

Open AccessArticle

Sex-Specific Screening Mitigates Basal Metabolic Dimorphism Bias and Reveals DIV1 Survival-Associated Metabolic Signatures in Macrobrachium rosenbergii

by Yunpeng Fan, Haiqi Zhang, Yang Xu, Xilian Li, Haihua Cheng, Chenhui Wu, Chaofan Yu and Qiang Gao

Biomolecules 2026, 16(8), 1145; https://doi.org/10.3390/biom16081145 - 6 Aug 2026

Abstract

Decapod Iridescent Virus 1 (DIV1) causes severe economic losses in Macrobrachium rosenbergii farming. Serum metabolic biomarkers are valuable tools for disease-resistant breeding, yet most existing studies employ mixed-sex samples, and the impact of sexual dimorphism on screening reliability remains poorly quantified. In this [...] Read more.

Decapod Iridescent Virus 1 (DIV1) causes severe economic losses in Macrobrachium rosenbergii farming. Serum metabolic biomarkers are valuable tools for disease-resistant breeding, yet most existing studies employ mixed-sex samples, and the impact of sexual dimorphism on screening reliability remains poorly quantified. In this study, non-targeted serum metabolomics was performed on 28 healthy M. rosenbergii (14 females and 14 males), which were divided into marginally resistant and susceptible groups after DIV1 challenge. We compared results from mixed-sex and sex-specific screening strategies, and separately analyzed the overlap of upregulated and downregulated differential metabolites. Significant basal sexual dimorphism was observed in serum metabolism. Mixed-sex analysis identified 247 differential metabolites, while male-specific and female-specific analyses identified 121 and 161, respectively. Only 26 metabolites showed consistent directional changes across all three comparisons, accounting for 10.5% of total mixed-sex differential metabolites. Nearly 90% of mixed-sex results were either sex-specific signals or independent of sex. Analyses that do not account for sex introduce a large number of sex-unrelated differential markers and mask sex-specific metabolic features, and sex-specific screening is a necessary strategy to obtain reliable metabolic biomarkers for crustacean disease-resistant breeding. Full article

(This article belongs to the Section Molecular Biomarkers)

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20 pages, 3933 KB

Open AccessArticle

Mitochondrial Membrane Damage Is Prevented by an Anthocyanin-Rich Fraction of Callistemon citrinus in 6-OHDA-Exposed SH-SY5Y Cells

by Martina Farina, Giuseppe Tancredi Patanè, Stefano Putaggio, Ester Tellone, Davide Barreca, Alessandro Maugeri and Michele Navarra

Biomolecules 2026, 16(8), 1144; https://doi.org/10.3390/biom16081144 - 6 Aug 2026

Abstract

Neurodegenerative diseases represent a significant clinical challenge. Understanding the pathogenic mechanisms is essential for developing more effective therapies, and mitochondria appear to play a key role in these processes. Since current treatments are limited to symptom management, natural strategies capable of preserving mitochondrial [...] Read more.

Neurodegenerative diseases represent a significant clinical challenge. Understanding the pathogenic mechanisms is essential for developing more effective therapies, and mitochondria appear to play a key role in these processes. Since current treatments are limited to symptom management, natural strategies capable of preserving mitochondrial function could represent a promising preventive and therapeutic approach in neurodegeneration. This study aims at investigating the molecular mechanisms underlying the neuroprotective potential of an anthocyanin-rich extract from Callistemon citrinus flower (Cce) in differentiated SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA). Exposure of cells to 6-OHDA inhibited cell viability and caused cell death, events hindered by the pre-treatment with Cce. Furthermore, it restored normal cell cycle distribution, as well as hampered 6-OHDA-induced apoptosis. Given the pro-oxidant effect of 6-OHDA, we observed that Cce reduced reactive oxygen species in stressed SH-SY5Y cells, along with recovering their antioxidant protection system. Focusing on mitochondria, Cce was able to protect their membranes from 6-OHDA, as suggested by the restoration of mitochondrial membrane potential. This led to a reduction in release of cytochrome c and the consequent activation of caspases 9 and 3, characteristic of the intrinsic apoptotic pathway, supporting our initial findings. Our results indicate that Cce prevents SH-SY5Y cell death induced by 6-OHDA via the preservation of mitochondrial integrity mainly through to its antioxidant properties, encouraging further studies to support its exploitation in the management of neurodegeneration. Full article

(This article belongs to the Special Issue Bioactive Compounds as Modifiers of Mitochondrial Function)

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21 pages, 2437 KB

Open AccessReview

Mapping Protein Diffusion from the Plasma Membrane to the Nucleus: Insights from Fluorescence Correlation Spectroscopy

by Zahra Nadia Saadatmand, Nazanin Ghaderinejad and Elizabeth Hinde

Biomolecules 2026, 16(8), 1143; https://doi.org/10.3390/biom16081143 - 6 Aug 2026

Abstract

Fluorescence correlation spectroscopy (FCS) measures spontaneous temporal fluorescence fluctuations within a femtolitre observation volume to extract, with single-molecule sensitivity, the concentration, mobility, oligomeric state, and interactions of proteins in living cells. This review traces how FCS and its spatiotemporal derivatives, implemented on different [...] Read more.

Fluorescence correlation spectroscopy (FCS) measures spontaneous temporal fluorescence fluctuations within a femtolitre observation volume to extract, with single-molecule sensitivity, the concentration, mobility, oligomeric state, and interactions of proteins in living cells. This review traces how FCS and its spatiotemporal derivatives, implemented on different types of optical microscopes, have mapped protein trafficking across the three physically distinct environments a protein must navigate from the cell surface to its genomic targets. At the plasma membrane, FCS resolves nanodomains with millisecond confinement times and distinguishes cytoskeletal corralling from cholesterol-dependent trapping through the FCS diffusion law, revealing how receptor signalling is organised below the diffraction limit. In the cytoplasm, FCS quantifies how macromolecular crowding slows protein diffusion by a factor of 3–4 relative to water, drives anomalous sub-diffusion, and coexists with directed transport, while resolving the markedly slower dynamics of liquid–liquid phase-separated condensates. In the nucleus, FCS-derived pair correlation and brightness analyses show that chromatin acts as a size-selective filter where an inert protein dimer can take more than 10-fold longer than its monomer to traverse the same nuclear distance, and that this oligomeric-state-dependent gating governs the genomic access of transcription factors. Across all three compartments, a protein’s diffusive behaviour is not incidental to its function but is itself a direct readout of the physical organisation of its environment, establishing FCS as a uniquely quantitative bridge between molecular dynamics and cellular decision-making. 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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22 pages, 6219 KB

Open AccessArticle

Neosaxitoxin Downregulates Inflammation in an Equine In Vivo Model of Osteoarthritis

by Cristóbal Dörner, Néstor Lagos, Lissette Oyaneder, Carlos González, Galia Ramírez-Toloza and Bruno C. Menarim

Biomolecules 2026, 16(8), 1142; https://doi.org/10.3390/biom16081142 - 6 Aug 2026

Abstract

Chronic synovial inflammation is a hallmark of osteoarthritis progression and is tightly regulated by synovial macrophages. Recently, voltage-gated sodium channels (NaV) have emerged as potent modulators of macrophage-driven inflammation, positioning them as novel therapeutic targets. Among selective NaV channel blockers, neosaxitoxin exerts remarkable [...] Read more.

Chronic synovial inflammation is a hallmark of osteoarthritis progression and is tightly regulated by synovial macrophages. Recently, voltage-gated sodium channels (NaV) have emerged as potent modulators of macrophage-driven inflammation, positioning them as novel therapeutic targets. Among selective NaV channel blockers, neosaxitoxin exerts remarkable anesthetic and immunomodulatory effects; however, its effects on joint inflammation upon intra-articular delivery remain unexplored. Using an equine model of bilateral carpal osteoarthritis, this study evaluated the immunomodulatory and tissue-preserving effects of intra-articular neosaxitoxin. Sixteen horses were randomized into two experimental groups (n = 8/each): Neosaxitoxin in one joint and triamcinolone (+control) in the contralateral joint; or neosaxitoxin in one joint and saline (−control) in the contralateral joint. Clinical parameters, synovial fluid cytology and cytokine profiles, and histological changes in synovium and cartilage were assessed over 30 days. Neosaxitoxin reduced synovial inflammation, evidenced by decreased synovial effusion and surface temperature, along with improved joint flexion. Furthermore, synovial fluid from neosaxitoxin-treated joints exhibited lower counts of erythrocytes, neutrophils, total protein, and key pro-inflammatory mediators (IL-1β and IL-6) compared to saline-treated controls. Histologically, neosaxitoxin-treated joints exhibited modest synovial inflammatory cell infiltration and minor cartilage abnormalities. In contrast, control joints exhibited synovial hyperplasia, fibrovascular proliferation, and cartilage degeneration. Our data suggests that intra-articular neosaxitoxin better preserved joint homeostasis by limiting synovial inflammation and cartilage damage. These results warrant further investigation on Neosaxitoxin as a candidate treatment for inflammatory arthropathies. Full article

(This article belongs to the Special Issue Biomarkers in Musculoskeletal and Orthopedic Disorders)

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12 pages, 5985 KB

Open AccessArticle

Wheat GT-1-like Transcription Factor Boosts Cutin Biosynthesis

by Yuxi Shan, Minawar Yusup, Haoyu Li, Pengfei Zhi, Xiaoyu Wang, Jiao Liu and Cheng Chang

Biomolecules 2026, 16(8), 1141; https://doi.org/10.3390/biom16081141 - 5 Aug 2026

Abstract

Cutin matrices in the cuticle cover plant epidermis, facilitating plant adaptation to stressful environments. Although cutin biosynthesis is extensively explored in the model plant Arabidopsis thaliana, the molecular mechanism governing cutin biosynthesis in the agriculturally important crop bread wheat (Triticum aestivum [...] Read more.

Cutin matrices in the cuticle cover plant epidermis, facilitating plant adaptation to stressful environments. Although cutin biosynthesis is extensively explored in the model plant Arabidopsis thaliana, the molecular mechanism governing cutin biosynthesis in the agriculturally important crop bread wheat (Triticum aestivum L.) remains largely unknown. The aim of the study is the characterization of the function and transcriptional regulation of a wheat gene involved in cutin biosynthesis. Long-chain acyl-CoA synthetase TaLACS2 was identified as an essential component of the wheat cutin biosynthetic machinery. Silencing of the wheat TaLACS2 gene by barley stripe mosaic virus-induced gene silencing assay resulted in remarkably reduced cutin accumulation and increased cuticle permeability. Furthermore, wheat GT-1-like transcription factor TaGT-3b was identified as a positive regulator of cutin biosynthesis. Silencing of the wheat TaGT-3b gene led to significantly decreased cutin accumulation and enhanced cuticle permeability. Importantly, we found that TaGT-3b could occupy the promoter regions of the TaLACS2 gene and that it functions as a transcriptional activator to activate TaLACS2 gene transcription. Collectively, these results elucidated that wheat GT-1-like transcription factor TaGT-3b boosts cutin biosynthesis, probably by activating TaLACS2 gene transcription, contributing to genetically improving cutin-associated traits in bread wheat. Full article

(This article belongs to the Section Molecular Biology)

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23 pages, 5403 KB

Open AccessArticle

Chitosan–Unconjugated Bilirubin Microspheres Alleviate Dysbiosis, Immune Dysregulation, and Intestinal Barrier Damage in Ulcerative Colitis

by Xinyu Lyu, Xiaotong Xu, Mengqi Shi, Rui Wang, Xiaoqing Yu, Yan Liu, Xiangyu Xue, Fengmin Zhang and Xiuhong Wang

Biomolecules 2026, 16(8), 1140; https://doi.org/10.3390/biom16081140 - 5 Aug 2026

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by immune dysregulation, microbiota imbalance, and intestinal barrier damage. Unconjugated bilirubin (UCB) shows promise in treating UC due to its anti-inflammatory properties but is limited by poor solubility and potential toxicity. This study [...] Read more.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by immune dysregulation, microbiota imbalance, and intestinal barrier damage. Unconjugated bilirubin (UCB) shows promise in treating UC due to its anti-inflammatory properties but is limited by poor solubility and potential toxicity. This study developed a chitosan-based controlled-release microsphere (CBMS) treatment to overcome these issues. CBMS utilizes the mucoadhesive properties of chitosan to achieve targeted, controlled UCB release in the colon, enhancing its stability and bioavailability. In a DSS-induced UC mouse model, CBMS alleviated clinical symptoms, reduced colon shortening, and improved histological outcomes, including reduced inflammation and enhanced mucosal repair. The mechanism involves CBMS retention in the intestinal lumen, UCB inactivation of digestive proteases, and restoration of microbiota balance, suppressing pro-inflammatory pathways. CBMS offers a promising new therapeutic strategy for UC and insights into polysaccharide-based drug delivery systems. Full article

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

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2 pages, 508 KB

Open AccessCorrection

Correction: Wagner et al. Impact of Primary RPE Cells in a Porcine Organotypic Co-Cultivation Model. Biomolecules 2022, 12, 990

by Natalie Wagner, Armin Safaei, José Hurst, Pia A. Vogt, H. Burkhard Dick, Stephanie C. Joachim and Sven Schnichels

Biomolecules 2026, 16(8), 1139; https://doi.org/10.3390/biom16081139 - 5 Aug 2026

Abstract

In the original publication [...] Full article

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18 pages, 1295 KB

Open AccessReview

Current Techniques for Inorganic Polyphosphate Detection and Characterisation

by Johanna G. Rodríguez and Thomas Renné

Biomolecules 2026, 16(8), 1138; https://doi.org/10.3390/biom16081138 - 5 Aug 2026

Abstract

Polyphosphate (polyP) is an evolutionarily conserved linear polymer of orthophosphate residues with diverse functions across organisms from bacteria to mammals. In addition to its roles in phosphate and energy storage, polyP has been implicated in thrombosis, inflammation, cancer, metabolism, cytoskeletal regulation, and neurodegenerative [...] Read more.

Polyphosphate (polyP) is an evolutionarily conserved linear polymer of orthophosphate residues with diverse functions across organisms from bacteria to mammals. In addition to its roles in phosphate and energy storage, polyP has been implicated in thrombosis, inflammation, cancer, metabolism, cytoskeletal regulation, and neurodegenerative diseases. PolyP also acts as a molecular scaffold interacting with lysine-rich proteins and may contribute to protein folding and amyloid formation. However, biochemical heterogeneity, including variation in chain-length, subcellular localisation, and supramolecular organisation together with the absence of clearly defined mammalian biosynthetic pathways, has limited mechanistic understanding of polyP biology. Reliable detection and quantification remain challenging because current methods often suffer from limited specificity, chain length bias, insufficient quantitative robustness, and interference from other highly anionic biomolecules such as DNA or RNA. This review summarises current methodologies for polyP detection and characterisation. Emerging polyP-specific probes, including recombinant polyP-binding domains derived from polyphosphatases and conserved histidine α-helical domains may improve qualitative and quantitative analysis of polyP in complex biological systems. Improved analytical strategies will be essential to define the physiological roles of polyP and evaluate its potential as a biomarker and therapeutic target. Full article

(This article belongs to the Special Issue Detection of Cell-Associated Biomolecules)

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14 pages, 2197 KB

Open AccessArticle

In Vitro Assessment of Nintedanib in Keratoconus Corneal Stromal Microenvironment

by Yasamin Moradi, Pawan Shrestha, Steve Mabry, Purnima Sharma, Karanpreet S. Multani, Kamran M. Riaz and Dimitrios Karamichos

Biomolecules 2026, 16(8), 1137; https://doi.org/10.3390/biom16081137 - 5 Aug 2026

Abstract

Keratoconus (KC) is a degenerative corneal disease, characterized by stromal thinning and abnormal ECM remodeling, leading to fibrosis. Corneal fibrosis is a leading cause of visual impairment. Corneal stromal keratocytes differentiate into myofibroblasts, which alters extracellular matrix (ECM) protein deposition. Nintedanib (NIN) is [...] Read more.

Keratoconus (KC) is a degenerative corneal disease, characterized by stromal thinning and abnormal ECM remodeling, leading to fibrosis. Corneal fibrosis is a leading cause of visual impairment. Corneal stromal keratocytes differentiate into myofibroblasts, which alters extracellular matrix (ECM) protein deposition. Nintedanib (NIN) is an antifibrotic FDA-approved tyrosine kinase inhibitor, but its function in the cornea is largely unknown. This study examined the impact of NIN within the human corneal stromal microenvironment. Healthy corneal stromal fibroblasts (HCFs) and KC fibroblasts (HKCs) in 2D and 3D in vitro cultures were treated with 1 μM or 2.5 μM NIN. Cell types were evaluated in 2D cultures for metabolic activity, viability, and migration. Protein expression of alpha-smooth muscle actin (α-SMA), collagens (COLs) 1, 3, and 5, cellular fibronectin containing extra domain A (EDA-FN), and thrombospondin-1 (TSP-1) were evaluated in 3D cultures. NIN reduced metabolic activity in HKCs without affecting cell viability. NIN reduced cell migration, downregulated COL3, COL5, EDA-FN, and TSP-1 expression in HCFs and HKCs. COL1 was upregulated in HCFs, whereas α-SMA was upregulated in HKCs. Overall, these findings demonstrate that NIN modulates corneal stromal cell migration and fibrotic marker expression, highlighting its potential as a therapeutic strategy for reducing corneal fibrosis associated with keratoconus. Full article

(This article belongs to the Special Issue Ocular Surface and Corneal Diseases: From Cellular and Molecular Biology to Therapeutic Strategies)

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