International Journal of Molecular Sciences

13 pages, 637 KB

Open AccessReview

Myostatin in Obesity: A Molecular Link Between Metabolic Dysfunction and Musculotendinous Remodeling

by Leonardo Cesanelli, Petras Minderis, Andrej Fokin, Aivaras Ratkevicius, Danguole Satkunskiene and Hans Degens

Int. J. Mol. Sci. 2026, 27(2), 967; https://doi.org/10.3390/ijms27020967 (registering DOI) - 18 Jan 2026

Abstract

Obesity is increasingly recognized not only as a metabolic disorder but also as a condition marked by the structural and functional deterioration of skeletal muscle and tendon tissues. Central to this process is the dysregulation of the extracellular matrix (ECM) resulting in fibrosis [...] Read more.

Obesity is increasingly recognized not only as a metabolic disorder but also as a condition marked by the structural and functional deterioration of skeletal muscle and tendon tissues. Central to this process is the dysregulation of the extracellular matrix (ECM) resulting in fibrosis and ectopic fat accumulation, factors that contribute to impaired tissue mechanics. Myostatin (GDF-8), a member of the TGF-β superfamily, is known as a negative regulator of muscle mass. It can also mediate interaction between adipose and other tissues including muscles and tendons. In obesity, elevated myostatin levels have been reported to be associated with insulin resistance, muscle atrophy, and activation of SMAD2/3 signaling, while experimental and preclinical studies indicate that myostatin inhibition can improve glucose homeostasis and increase lean mass. Emerging evidence suggests that myostatin also plays a critical role in muscle ECM and tendon remodeling. Restoring its physiological levels may help reverse ECM disorganization and reduce tissue fragility associated with musculotendinous dysfunction. This review highlights the multifaceted role of myostatin in obesity, beyond its role in muscle catabolism, to include modulation of structural integrity, metabolism, and mechanical adaptability of the musculotendinous system. Understanding how myostatin responds to metabolic stress and affects biomechanical remodeling offers novel insights into obesity-related muscle and tendon dysfunction. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 3rd Edition)

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23 pages, 2511 KB

Open AccessArticle

SHIV.D Infection Alters Production and Protein Composition of Myeloid-Derived Extracellular Vesicles

by Rachel M. Podgorski, Amir Yarmahmoodi, Stephen Baak, Rebecca Warfield, Jake A. Robinson, Jennifer Roof, Maurizio Caocci, Hossein Fazelinia, Lynn A. Spruce, Katharine J. Bar and Tricia H. Burdo

Int. J. Mol. Sci. 2026, 27(2), 966; https://doi.org/10.3390/ijms27020966 (registering DOI) - 18 Jan 2026

Abstract

Although neurological disease is common in people with human immunodeficiency virus (HIV) (PWH), the contributing factors and underlying inflammatory mechanisms remain challenging to identify. Extracellular vesicles (EVs) constitute a relatively uncharacterized modality of intercellular communication and bioactive cargo transport in the setting of [...] Read more.

Although neurological disease is common in people with human immunodeficiency virus (HIV) (PWH), the contributing factors and underlying inflammatory mechanisms remain challenging to identify. Extracellular vesicles (EVs) constitute a relatively uncharacterized modality of intercellular communication and bioactive cargo transport in the setting of viral infection and pathogenesis. EVs carry inflammatory mediators to areas of the periphery during antiretroviral therapy (ART) suppression but are understudied in the brain. Using a biologically relevant simian–human immunodeficiency chimeric virus with a clade D HIV envelope (SHIV.D)-infected rhesus macaque (RM) model of HIV persistence in the central nervous system (CNS), we investigate circulating EV populations and the protein cargo of myeloid-derived EVs during SHIV infection. Using EV flow cytometry to quantify specific EV subpopulations, we found a significant increase in TMEM119+ microglial EVs and CD171+ neuronal EVs in RM plasma during viremia and ART suppression. Using primary RM monocyte-derived macrophages (MDMs), we determined that MDMs increased EV production after SHIV infection. Whole proteomic analysis of these EVs demonstrated that myeloid EVs isolated from SHIV.D-infected MDMs carried significantly increased levels of neuropathogenic and inflammatory proteins. Altogether, these studies improve our understanding of the contribution of myeloid EVs to neurological disease during SHIV/HIV infection. Full article

(This article belongs to the Section Molecular Nanoscience)

24 pages, 3351 KB

Open AccessArticle

Comparative Analysis of T-Cell Signatures and Astroglial Reactivity in Parkinson’s Pathology Across Animal Models with Distinct Regenerative Capacities

by Simona Intonti, Volker Enzmann, Amalia Perna, Ferdinando Spagnolo, Claudia Curcio and Federica Maria Conedera

Int. J. Mol. Sci. 2026, 27(2), 965; https://doi.org/10.3390/ijms27020965 (registering DOI) - 18 Jan 2026

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) and the accumulation of misfolded α-synuclein (aSyn). In addition to neuronal pathology, activated microglia are recognized as key mediators of the [...] Read more.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) and the accumulation of misfolded α-synuclein (aSyn). In addition to neuronal pathology, activated microglia are recognized as key mediators of the neuroinflammatory milieu in PD, contributing to DAergic neuron vulnerability. Emerging evidence suggests that the immune system, particularly T-cell-mediated responses, plays a key role in the pathogenesis of PD. However, the heterogeneity of these immune responses across species and preclinical models with varying regenerative capacities remains poorly understood. A comparative analysis of T-cell infiltration, astroglial reactivity, and DAergic neuronal loss across multiple models and species was performed. These included acute DAergic degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), genetically modified mice with accumulation of aSyn (Thy1-aSyn L61 model), adult zebrafish exposed to MPTP-induced neurotoxicity and human post-mortem midbrain tissue obtained from PD patients. Zebrafish exhibited transient DAergic neurodegeneration, followed by neuronal regeneration and temporary CD4⁺ T-cell infiltration accompanied by an astroglial response and activation of microglia. In contrast, MPTP-treated mice showed a permanent neuronal loss, marked microglial activation, increased astrogliosis and CD8⁺ T-cell infiltration that was negatively correlated with neuronal survival. By contrast, L61 mice exhibited progressive aSyn accumulation with chronic astrogliosis, mild activation of microglia and CD4⁺ T-cell infiltration not directly linked to neuronal loss. Unlike age-matched controls, the SN from PD brains exhibited DAergic degeneration, aSyn aggregation, and elevated CD3⁺ T-cell infiltration, and increased microglial activation. These changes correlated with neuronal loss and aSyn burden. These findings emphasize the species- and model-specific immune profiles underlying PD pathology. Our results reveal that CD4⁺ T-cells contribute to neuronal regeneration following injury in zebrafish. This process is absent in the MPTP and L61 mouse models, which are instead driven by CD8⁺ or CD4⁺, respectively. This work underscores the potential of targeted immunomodulation aimed at T cell–glial interactions to slow neurodegeneration and promote repair in PD. Full article

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

16 pages, 539 KB

Open AccessArticle

Whole-Exome Sequencing Identifies Novel Genetic Variants Associated with Unexplained Neurodevelopmental Disorders in Children

by Giancarlo Mancuso, Laura Serventi, Chiara Cocco, Francesco Lai, Consolata Soddu, Monica Marica, Caterina Mereu, Michela Lorrai, Gaia Maria Tosone, Federica Cannas, Giulia Nutile, Matteo Floris, Salvatore Savasta and Sabrina Giglio

Int. J. Mol. Sci. 2026, 27(2), 964; https://doi.org/10.3390/ijms27020964 (registering DOI) - 18 Jan 2026

Abstract

Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions characterised by impairments in cognition, motor function, behaviour, and social interaction. Their genetic basis is highly diverse, and next-generation sequencing has become central to improving diagnostic yield. We retrospectively analysed 94 paediatric patients (0–18 [...] Read more.

Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions characterised by impairments in cognition, motor function, behaviour, and social interaction. Their genetic basis is highly diverse, and next-generation sequencing has become central to improving diagnostic yield. We retrospectively analysed 94 paediatric patients (0–18 years) with NDDs referred to the Paediatric and Rare Diseases Clinic, Microcitemico Hospital “A. Cao,” between January 2019 and July 2024. Each patient underwent detailed clinical evaluation and whole-exome sequencing (WES). Variants were prioritised according to ACMG guidelines. Gene burden analysis of rare predicted loss-of-function variants was performed using the Cohort Allelic Sums Test to detect enrichment in NDD cases relative to controls. WES identified 12 pathogenic variants, 16 likely pathogenic variants, and 10 variants of uncertain significance. Autosomal dominant disorders were the most frequent (n = 35 patients), while autosomal recessive and X-linked dominant conditions were identified in a single case each. The findings of this study further highlight the importance of WES in identifying novel genetic variants and in providing explanations for previously unexplained NDD cases. Moreover, the Cohort Allelic Sums Test (CAST) demonstrated that rare variants are enriched in genes implicated in neuronal development in affected individuals. Full article

(This article belongs to the Special Issue Molecular Genetics and Genomics of Neurodevelopmental Disorders)

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26 pages, 2620 KB

Open AccessReview

EZHIP in Pediatric Brain Tumors: From Epigenetic Mimicry to Therapeutic Vulnerabilities

by Tiziana Servidei, Serena Gentile, Alessandro Sgambato and Antonio Ruggiero

Int. J. Mol. Sci. 2026, 27(2), 963; https://doi.org/10.3390/ijms27020963 (registering DOI) - 18 Jan 2026

Abstract

Enhancer of zeste homologs inhibitory protein (EZHIP) is a eutherian-specific protein, with poorly defined developmental functions and physiological expression restricted to germ cells. Its aberrant re-expression characterizes posterior fossa ependymoma subtype A and a subset of diffuse midline gliomas with wild-type histone H3—aggressive [...] Read more.

Enhancer of zeste homologs inhibitory protein (EZHIP) is a eutherian-specific protein, with poorly defined developmental functions and physiological expression restricted to germ cells. Its aberrant re-expression characterizes posterior fossa ependymoma subtype A and a subset of diffuse midline gliomas with wild-type histone H3—aggressive pediatric brain tumors marked by global loss of the repressive H3 lysine 27 trimethylation (H3K27me3). Functionally analogous to the H3 lysine 27 to methionine (H3K27M) oncohistone, EZHIP inhibits Polycomb repressive complex 2 (PRC2), altering genome-wide H3K27me3 distribution and fate commitment. Unlike H3K27M, EZHIP is epigenetically silenced under physiological conditions yet inducible, suggesting context-dependent oncogenic roles. Its intrinsically disordered structure enables multifunctional interactions and biological versatility. Beyond brain tumors, EZHIP has emerged as an oncogenic driver in osteosarcoma, underscoring broader relevance across cancers. This review integrates current insights into EZHIP—from gene discovery and the mechanism of PRC2 inhibition to its emerging roles in metabolism, DNA repair, 3D chromatin regulation, and development. We outline EZHIP’s clinico-pathological significance in pediatric and adult malignancies, with an emphasis on EZHIP-driven hindbrain tumors. Finally, we discuss therapeutic opportunities, from the direct targeting of intrinsically disordered proteins to the indirect modulation of EZHIP-associated epigenetic and metabolic landscapes, highlighting implications for tumor evolution and precision oncology. Full article

(This article belongs to the Special Issue Molecular Insights into Pediatric Brain Tumors: Unraveling the Complexity of Pathogenesis and Identifying New Therapeutic Targets)

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26 pages, 5532 KB

Open AccessArticle

Euphorbia bicolor Xylene Extract Induces Mitochondrial and Endoplasmic Reticulum Stress-Mediated Apoptotic Pathways in MDA-MB-231 and T47D Cells

by Mafia Mahabub Rumpa, Nguyen Linh Ngo and Camelia Maier

Int. J. Mol. Sci. 2026, 27(2), 962; https://doi.org/10.3390/ijms27020962 (registering DOI) - 18 Jan 2026

Abstract

Breast cancer is a significant cause of death worldwide. Recent research has focused on identifying natural compounds for developing effective cancer treatments. Resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, is a common diterpene in Euphorbia bicolor Engelm. & A. Gray (Euphorbiaceae), [...] Read more.

Breast cancer is a significant cause of death worldwide. Recent research has focused on identifying natural compounds for developing effective cancer treatments. Resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, is a common diterpene in Euphorbia bicolor Engelm. & A. Gray (Euphorbiaceae), a plant native to the southern United States that has not been studied before. We investigated the antiproliferative activities and mechanisms of action of E. bicolor xylene extract in estrogen receptor-positive T47D and triple-negative MDA-MB-231 cell lines. The extract significantly reduced the viability of T47D and MDA-MB-231 cells in a dose-dependent manner. In MDA-MB-231 cells, the extract induced apoptosis via intracellular calcium overload, triggered by TRPV1 activation. This effect was diminished by the TRPV1 antagonist capsazepine and the calcium chelator BAPTA-AM. Intracellular calcium influx was confirmed through Fura-2 AM staining, revealing that E. bicolor phytochemicals activated TRPV1 in MDA-MB-231 cells. Treatment of T47D cells with E. bicolor xylene extract resulted in apoptosis associated with reactive oxygen species (ROS) generation (10-fold higher in T47D cells than in MDA-MB-231 cells) and mitochondrial calcium overload. These effects were significantly blocked when cells were pretreated with N-acetyl-l-cysteine (NAC), a ROS inhibitor. Both cell lines underwent apoptosis via multiple mitochondrial- and endoplasmic reticulum stress–mediated pathways. This was supported by the activation of caspases 3, 8, and 9; increased expression of FAS, XBP1s, and CHOP; upregulation of BAX; and downregulation of BCL-2. In addition, PI3K, AKT, and pAKT protein expressions were also reduced in both cell lines, indicating downregulation of PI3K/Akt signaling pathway. Phytochemicals in E. bicolor xylene extract could become promising ingredients for developing breast cancer therapeutics. Full article

(This article belongs to the Special Issue The Role of Natural Compounds in Cancer and Inflammation, 2nd Edition)

4 pages, 192 KB

Open AccessEditorial

Special Issue: “Structural Dynamics of Macromolecules”

by Ki Hyun Nam

Int. J. Mol. Sci. 2026, 27(2), 961; https://doi.org/10.3390/ijms27020961 (registering DOI) - 18 Jan 2026

Abstract

Understanding the molecular function of macromolecules is fundamental to understanding their biological roles [...] Full article

(This article belongs to the Special Issue Structural Dynamics of Macromolecules)

13 pages, 1179 KB

Open AccessArticle

The Yeast Saccharomyces cerevisiae as a Model to Study the Anti-Aging Activity of Phycocyanin

by Donata Cassamagnaghi, Stefania Citterio, Enzo Martegani and Sonia Colombo

Int. J. Mol. Sci. 2026, 27(2), 960; https://doi.org/10.3390/ijms27020960 (registering DOI) - 18 Jan 2026

Abstract

We recently published that phycocyanin, a phycobiliprotein which accounts for up to 20% of Arthrospira platensis dry weight, has a powerful anti-aging effect, greatly extending the chronological life span (CLS) of yeast cells grown in synthetic-defined medium, both under caloric restriction (CR) conditions [...] Read more.

We recently published that phycocyanin, a phycobiliprotein which accounts for up to 20% of Arthrospira platensis dry weight, has a powerful anti-aging effect, greatly extending the chronological life span (CLS) of yeast cells grown in synthetic-defined medium, both under caloric restriction (CR) conditions (0.2% glucose) or under non-CR conditions (2% glucose). In this study, to explore the molecular mechanisms underlying the effects of phycocyanin, we investigated its impact on key signaling pathways involved in aging. Specifically, we performed CLS experiments using ras2Δ and snf1Δ yeast mutants. The Snf1 pathway is known to promote longevity (anti-aging), whereas the Ras2/PKA pathway accelerates aging (pro-aging). We show that, while in the snf1Δ mutant the anti-aging effect of phycocyanin was still evident, in the ras2Δ mutant, phycocyanin did not appear to exert any anti-aging activity, leading us to hypothesize that the Ras2/PKA pathway may be essential to mediate the anti-aging effect of phycocyanin. To evaluate the activity of phycocyanin under different nutritional conditions, we performed the CLS experiment in a YPDA-rich medium. We show that in this medium, phycocyanin accelerated the chronological aging process of yeast cells, greatly decreasing the CLS, both when glucose was present at low (0.2%) or at high (2%) concentration. Our data suggest that Saccharomyces cerevisiae could serve as a model not only to investigate the anti-aging properties and targets of phycocyanin, but also its potential side effects, which are possibly present in higher eukaryotes under certain conditions. Full article

(This article belongs to the Special Issue Recent Research of Natural Products from Microalgae and Cyanobacteria)

19 pages, 5301 KB

Open AccessArticle

Water Proton Spin Relaxivities and Absolute Fluorescent Quantum Yields of Triply and Quadruply Mixed Lanthanide Oxide Nanoparticles

by Abdullah Khamis Ali Al Saidi, Tirusew Tegafaw, Dejun Zhao, Ying Liu, Endale Mulugeta, Xiaoran Chen, Ziyi Lin, Hansol Lee, Ahrum Baek, Jihyun Kim, Yongmin Chang and Gang Ho Lee

Int. J. Mol. Sci. 2026, 27(2), 959; https://doi.org/10.3390/ijms27020959 (registering DOI) - 18 Jan 2026

Abstract

Multicomponent mixed lanthanide oxide (MMLO) nanoparticles possess considerable potential as multimodal imaging agents because they integrate diverse excellent optical and magnetic properties within a single nanoparticle. Herein, we present triply and quadruply mixed lanthanide oxide nanoparticles, namely, gadolinium (Gd)/dysprosium (Dy)/europium (Eu) oxide (GDEO), [...] Read more.

Multicomponent mixed lanthanide oxide (MMLO) nanoparticles possess considerable potential as multimodal imaging agents because they integrate diverse excellent optical and magnetic properties within a single nanoparticle. Herein, we present triply and quadruply mixed lanthanide oxide nanoparticles, namely, gadolinium (Gd)/dysprosium (Dy)/europium (Eu) oxide (GDEO), Gd/Dy/terbium (Tb) oxide (GDTO), and Gd/Dy/Eu/Tb oxide (GDETO) nanoparticles. Gd³⁺ can strongly induce positive (T₁) contrast in magnetic resonance imaging (MRI), Dy³⁺ and Tb³⁺ can generate negative (T₂) contrast in MRI, and Eu³⁺ and Tb³⁺ emit visible photons that are applicable to fluorescence imaging (FI). All the nanoparticles were grafted with hydrophilic, biocompatible polyacrylic acid (PAA) to enhance colloidal stability and biocompatibility and further grafted with small amounts of an organic photosensitizer, 2,6-pyridinedicarboxylic acid (PDA), to obtain a high absolute fluorescent quantum yield (QY) with an extended fluorescent lifetime (τ). All PAA-MMLO and PAA/PDA-MMLO nanoparticles exhibited nearly monodispersed particle-size distributions with average particle diameters of ~2 nm and displayed considerably higher longitudinal (r₁) and transverse (r₂) water proton spin relaxivities than commercial molecular MRI contrast agents. The PAA/PDA-GDEO, PAA/PDA-GDTO, and PAA/PDA-GDETO nanoparticles exhibited high absolute QYs of 45, 29, and 61%, respectively, and long τ values of 1–2 ms, making them suitable for time-delayed noise-free fluorescence signal detection. These findings confirm the high potential of PAA-MMLO nanoparticles as T₁ and/or T₂ MRI contrast agents and PAA/PDA-MMLO nanoparticles as both T₁ and/or T₂ MRI and FI agents. Full article

(This article belongs to the Special Issue Physicochemical Properties and Applications of Nanomaterials in Biology and Medicine)

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26 pages, 5273 KB

Open AccessReview

Neurometabolic and Neuroinflammatory Consequences of Obesity: Insights into Brain Vulnerability and Imaging-Based Biomarkers

by Miloš Vuković, Igor Nosek, Milica Medić Stojanoska and Duško Kozić

Int. J. Mol. Sci. 2026, 27(2), 958; https://doi.org/10.3390/ijms27020958 (registering DOI) - 18 Jan 2026

Abstract

Obesity is a systemic metabolic disorder characterized by chronic low-grade inflammation and insulin resistance, with growing evidence indicating that the brain represents a primary and particularly vulnerable target organ. Beyond peripheral metabolic consequences, obesity induces region-specific structural, functional, and biochemical alterations within the [...] Read more.

Obesity is a systemic metabolic disorder characterized by chronic low-grade inflammation and insulin resistance, with growing evidence indicating that the brain represents a primary and particularly vulnerable target organ. Beyond peripheral metabolic consequences, obesity induces region-specific structural, functional, and biochemical alterations within the central nervous system, contributing to cognitive impairment, dysregulated energy homeostasis, and increased susceptibility to neurodegenerative diseases. This narrative review examines key neurometabolic and neuroinflammatory mechanisms underlying obesity-related brain vulnerability, including downstream neuroinflammation, impaired insulin signaling, mitochondrial dysfunction, oxidative stress, blood–brain barrier disruption, and impaired brain clearance mechanisms. These processes preferentially affect frontal and limbic networks involved in executive control, reward processing, salience detection, and appetite regulation. Advanced neuroimaging has substantially refined our understanding of these mechanisms. Magnetic resonance spectroscopy provides unique in vivo insight into early neurometabolic alterations that may precede irreversible structural damage and is complemented by diffusion imaging, volumetric MRI, functional MRI, cerebral perfusion imaging, and positron emission tomography. Together, these complementary modalities reveal microstructural, network-level, structural, hemodynamic, and molecular alterations associated with obesity-related brain vulnerability and support the concept that such brain dysfunction is dynamic and potentially modifiable. Integrating neurometabolic and multimodal neuroimaging biomarkers with metabolic and clinical profiling may improve early risk stratification and guide preventive and therapeutic strategies aimed at preserving long-term brain health in obesity. Full article

(This article belongs to the Special Issue Fat and Obesity: Molecular Mechanisms and Pathogenesis)

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3 pages, 259 KB

Open AccessEditorial

Autophagy, Cellular Senescence and Oxidative Stress in Ageing and Age-Related Diseases

by Varvara Trachana

Int. J. Mol. Sci. 2026, 27(2), 957; https://doi.org/10.3390/ijms27020957 (registering DOI) - 18 Jan 2026

Abstract

As our understanding of ageing improves, it is becoming increasingly clear that it is the consequence of systematically interconnected cellular and molecular processes that govern damage management and resilience to acute and chronic stress [...] Full article

(This article belongs to the Special Issue Autophagy, Cellular Senescence and Oxidative Stress in Ageing and Age-Related Diseases)

20 pages, 731 KB

Open AccessReview

Can Phagocytosis, Neutrophil Extracellular Traps, and IFN-α Production in Systemic Lupus Erythematosus Be Simultaneously Modulated? A Pharmacological Perspective

by Stephanie Seidlberger, Sindi Huti, Santos Castañeda, Michael Schirmer, Julian Fenkart, Georg Wietzorrek and Sandra Santos-Sierra

Int. J. Mol. Sci. 2026, 27(2), 956; https://doi.org/10.3390/ijms27020956 (registering DOI) - 18 Jan 2026

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple and heterogeneous clinical manifestations (e.g., skin lesions, kidney damage, neuropsychiatric dysfunction), that primarily affects women and whose etiology remains unclear. Various therapies that regulate and reduce the immune system activity are in use [...] Read more.

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple and heterogeneous clinical manifestations (e.g., skin lesions, kidney damage, neuropsychiatric dysfunction), that primarily affects women and whose etiology remains unclear. Various therapies that regulate and reduce the immune system activity are in use or are being developed; however, many of them have serious side effects. Therefore, new approaches are needed to maximize remission periods and reduce associated side effects. In this review, we summarize the currently recommended therapeutic strategies. Furthermore, we hypothesize that the combined use of drugs targeting various dysregulated cellular processes in SLE (i.e., cytokine production, neutrophil extracellular traps (NETs), phagocytosis) might have therapeutic potential, at least in some disease phenotypes. Preliminary data show that Toll-like receptors 7/8 (TLR 7/8) inhibition (e.g., Enpatoran) may reduce interferon-α (IFN-α) production by monocytes and NET formation by neutrophils. Our hypothesis is that future therapies combining compounds that modulate the three cellular processes might result in a better disease management as current therapies. Full article

(This article belongs to the Special Issue Systemic Lupus: Molecular Research, New Biomarkers and Novel Therapy)

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25 pages, 20668 KB

Open AccessArticle

Total Saponins from Rhizoma Panacis Majoris Promote Wound Healing in Diabetic Rats by Regulating Inflammatory Dysregulation

by Xiang Xu, Mei-Xia Wang, Ya-Ning Zhu, Xiang-Duo Zuo, Di Hu and Jing-Ping Li

Int. J. Mol. Sci. 2026, 27(2), 955; https://doi.org/10.3390/ijms27020955 (registering DOI) - 18 Jan 2026

Abstract

In individuals with diabetes, dysregulation of inflammatory processes hinders the progression of wounds into the proliferative phase, resulting in chronic, non-healing wounds. Total saponins from Rhizoma Panacis majoris (SRPM), bioactive compounds naturally extracted from the rhizome of Panax japonicus C.A.Mey. var. [...] Read more.

In individuals with diabetes, dysregulation of inflammatory processes hinders the progression of wounds into the proliferative phase, resulting in chronic, non-healing wounds. Total saponins from Rhizoma Panacis majoris (SRPM), bioactive compounds naturally extracted from the rhizome of Panax japonicus C.A.Mey. var. major (Burk.) C.Y.Wu and K.M.Feng, have demonstrated extensive anti-inflammatory and immunomodulatory properties. This study aims to elucidate the molecular mechanisms underlying the facilitative effects of SRPM on diabetic wound healing, with particular emphasis on its anti-inflammatory actions. A high-fat diet combined with streptozotocin (STZ) administration was used to induce type 2 diabetes in rats. After two weeks of oral treatment with SRPM suspension, a wound model was established. Subsequently, a two-week course of combined local and systemic therapy was administered using both SRPM suspension and SRPM gel. SRPM markedly reduces the levels of pro-inflammatory mediators, including IL-1α, IL-1β, IL-6, MIP-1α, TNF-α, and MCP-1, in both rat tissues and serum. Concurrently, it increases the expression of anti-inflammatory cytokines such as IL-10, TGF-β1, and PDGF-BB, while also enhancing the expression of the tissue remodelling marker bFGF. Additionally, SRPM significantly decreases the accumulation of apoptotic cells within tissues by downregulating the pro-apoptotic gene Caspase-3, upregulating the anti-apoptotic gene Bcl-2, and increasing the expression of the apoptotic cell clearance receptor MerTK. Moreover, SRPM inhibits neutrophil infiltration and the release of neutrophil extracellular traps (NETs) in tissues, promotes macrophage polarisation towards the M2 phenotype, and activates the Wnt/β-catenin signalling pathway at the molecular level. SRPM promotes the healing of wounds in diabetic rats potentially due to its anti-inflammatory properties. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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19 pages, 842 KB

Open AccessReview

Diagnostic, Prognostic and Therapeutic Utility of MicroRNA-21 in Ischemic Heart Disease

by Boris Burnjaković, Marko Atanasković, Marko Baralić, Aladin Altić, Emil Nikolov, Anastasija Ilić, Aleksandar Sič, Verica Stanković Popović, Ana Bontić, Selena Gajić and Sanja Stankovic

Int. J. Mol. Sci. 2026, 27(2), 954; https://doi.org/10.3390/ijms27020954 (registering DOI) - 18 Jan 2026

Abstract

Ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality despite advances in prevention, diagnosis, and therapy. Traditional clinical risk scores and biomarkers often fail to fully capture the complex molecular processes underlying atherosclerosis, myocardial infarction, and ischemic cardiomyopathy, leaving [...] Read more.

Ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality despite advances in prevention, diagnosis, and therapy. Traditional clinical risk scores and biomarkers often fail to fully capture the complex molecular processes underlying atherosclerosis, myocardial infarction, and ischemic cardiomyopathy, leaving substantial residual risk. MicroRNAs have emerged as promising regulators and biomarkers of cardiovascular disease, among which microRNA-21 (miR-21) has attracted particular attention. MiR-21 is deeply involved in key pathophysiological mechanisms of IHD, including endothelial dysfunction, vascular inflammation, vascular smooth muscle cell proliferation, plaque development and vulnerability, cardiomyocyte survival, and myocardial fibrosis. Accumulating clinical evidence suggests that circulating miR-21 holds diagnostic value across the ischemic continuum, from stable coronary artery disease to acute coronary syndromes, myocardial infarction, and ischemic heart failure. Moreover, miR-21 demonstrates prognostic relevance, correlating with plaque instability, adverse remodeling, heart failure progression, and long-term cardiovascular outcomes. Preclinical studies further indicate that miR-21 represents a double-edged therapeutic target, offering cardio protection in acute ischemic injury while contributing to fibrosis and maladaptive remodeling if dysregulated. This narrative review summarizes current evidence on the diagnostic, prognostic, and therapeutic utility of miR-21 in IHD, highlighting its clinical promise as well as key limitations and future translational challenges. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease: 2nd Edition)

15 pages, 1752 KB

Open AccessReview

Advances in Colorectal Cancer Cell Biology and Clonal Evolution

by Sopozme Toghey, Elizabeth J. Harvey-Jones, Jonathan D. Towler, Charlotte J. H. Hafkamp and Irene Y. Chong

Int. J. Mol. Sci. 2026, 27(2), 953; https://doi.org/10.3390/ijms27020953 (registering DOI) - 18 Jan 2026

Abstract

Colorectal cancer (CRC) develops through evolutionary processes involving genomic alterations, epigenetic regulation, and microenvironmental interactions. While traditionally explained by the stepwise accumulation of driver mutations, contemporary evidence supports a ‘Big Bang’ model in which many early-arising clones expand simultaneously to establish extensive heterogeneity. [...] Read more.

Colorectal cancer (CRC) develops through evolutionary processes involving genomic alterations, epigenetic regulation, and microenvironmental interactions. While traditionally explained by the stepwise accumulation of driver mutations, contemporary evidence supports a ‘Big Bang’ model in which many early-arising clones expand simultaneously to establish extensive heterogeneity. We reviewed recent studies employing spatially resolved multi-omic sequencing of tumour glands combined with computational modelling. These approaches enable high-resolution reconstruction of clonal architecture, transcriptional states, and chromatin accessibility. Findings show that although early clonal mutations shape tumour expansion, gene expression variability can be independent of genetic ancestry and instead reflects phenotypic plasticity driven by microenvironmental cues. Epigenomic analyses identified recurrent somatic chromatin accessibility alterations in promotors and enhancers of oncogenic pathways, frequently in the absence of DNA mutations, suggesting alternative mechanisms of gene regulation. Immune-focused studies demonstrated that early silencing of antigen-presenting genes and loss of neoantigens facilitate immune escape despite active surveillance. CRC is shaped by an interplay of genome, epigenome, and immune evolution, with non-genetic mechanisms and tumour plasticity emerging as important drivers of progression and therapeutic resistance. Full article

(This article belongs to the Special Issue New Molecular Aspects of Colorectal Cancer)

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20 pages, 3566 KB

Open AccessArticle

In Situ Green Synthesis of Red Wine Silver Nanoparticles on Cotton Fabrics and Investigation of Their Antibacterial Effects

by Alexandria Erasmus, Nicole Remaliah Samantha Sibuyi, Mervin Meyer and Abram Madimabe Madiehe

Int. J. Mol. Sci. 2026, 27(2), 952; https://doi.org/10.3390/ijms27020952 (registering DOI) - 18 Jan 2026

Abstract

Antimicrobial resistance (AMR) is a major global health concern, which complicates treatment of microbial infections and wounds. Conventional therapies are no longer effective against drug resistant microbes; hence, novel antimicrobial approaches are urgently required. Silver nanoparticles (AgNPs) offer stronger antimicrobial activity, and in [...] Read more.

Antimicrobial resistance (AMR) is a major global health concern, which complicates treatment of microbial infections and wounds. Conventional therapies are no longer effective against drug resistant microbes; hence, novel antimicrobial approaches are urgently required. Silver nanoparticles (AgNPs) offer stronger antimicrobial activity, and in situ synthesis improves stability, uniformity, cost efficiency, and bioactivity while minimising contamination. These features make AgNPs well-suited for incorporation into textiles and wound dressings. Red wine extract (RW-E), rich in antioxidant and anti-inflammatory compounds was used to hydrothermally synthesise RW-AgNPs and RW-AgNPs-loaded on cotton (RWALC) by optimising pH and RW-E concentration. Characterisation was performed using UV–Vis spectroscopy, dynamic light scattering (DLS), and High Resolution and Scanning electron microscopy (HR-TEM and SEM). Antibacterial activities were evaluated against human pathogens through agar disc diffusion assay for RWALC and microdilution assay for RW-AgNPs. RWALC showed higher potency against both Gram-negative and Gram-positive bacteria, with inhibition zones of 12.33 ± 1.15 to 23.5 ± 5.15 mm, that surpassed those of ciprofloxacin (10 ± 3 to 19.17 ± 1.39 mm at 10 μg/mL). RW-AgNPs exhibited low minimum inhibitory concentrations (MIC: 0.195–3.125 μg/mL) and minimum bactericidal concentrations (MBC: 0.78–6.25 μg/mL). Preincubation with β-mercaptoethanol (β-ME) inhibited the antibacterial activity of RWALC, suggesting that thiolated molecules are involved in AgNPs-mediated effects. This study demonstrated that green-synthesised RW-AgNPs, incorporated in situ into cotton, conferred strong antibacterial properties, warranting further investigation into their mechanisms of action. Full article

(This article belongs to the Special Issue Advancements and Applications of Phyto-Nanotherapy in Targeted Disease Treatment)

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16 pages, 1127 KB

Open AccessArticle

Changes in Blood Cells and Complements During Relapse Prevention Therapies for Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder

by Hiroshi Kuroda, Kazuo Fujihara, Kimihiko Kaneko, Yoshiki Takai, Yuki Matsumoto, Mizuki Otomo, Naoya Yamazaki, Shu Umezawa, Naoki Yamamoto, Naohiro Sakamoto, Chihiro Namatame, Hirohiko Ono, Shuhei Nishiyama, Toshiyuki Takahashi, Tatsuro Misu and Masashi Aoki

Int. J. Mol. Sci. 2026, 27(2), 951; https://doi.org/10.3390/ijms27020951 (registering DOI) - 18 Jan 2026

Abstract

In this study, blood cell counts and serum C3, C4, and CH50 values at baseline and after more than 6-month drug use were measured to elucidate changes in blood cells and complements during relapse prevention therapies for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder [...] Read more.

In this study, blood cell counts and serum C3, C4, and CH50 values at baseline and after more than 6-month drug use were measured to elucidate changes in blood cells and complements during relapse prevention therapies for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD). A total of 70 patients with AQP4+ NMOSD (87% female, median age 56 years) were enrolled. They were divided into the following treatment groups: glucocorticoids and/or immunosuppressants (GC/IS, n = 22), inebilizumab/rituximab (anti-CD19/20, n = 13), satralizumab (anti-IL-6R, n = 22), and eculizumab/ravulizumab (anti-C5, n = 13). At baseline, the blood counts and complement levels did not differ among the groups. At follow-up, the neutrophil and platelet counts in the anti-IL-6R group decreased from those at baseline (p < 0.0001 and p < 0.001, respectively). Compared with the GC/IS, anti-CD19/20, and anti-C5 groups, the anti-IL-6R group had lower levels of C3 (p < 0.0001, p < 0.01, and p < 0.05, respectively) and C4 (p < 0.0001, p < 0.01, p < 0.001, respectively). Furthermore, the anti-C5 group had significantly lower CH50 levels than the GC/IS, anti-CD19/20, and anti-IL-6R groups (p < 0.0001, p < 0.0001, p < 0.05, respectively). In addition, the anti-IL-6R group had lower CH50 levels than the GC/IS and anti-CD19/20 groups (p < 0.001 and p < 0.05, respectively). The present study demonstrated that anti-IL-6R therapy broadly and mildly suppressed the complement system and decreased the neutrophil and platelet counts. It also showed that anti-C5 therapy strongly suppressed total complement activity but did not affect the C3 and C4 levels or blood counts. These findings may have implications for the mode of action of the drugs and the risk of adverse drug reactions, including infections. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 3rd Edition)

57 pages, 958 KB

Open AccessReview

Oxidative Stress and SIRT1-Nrf2 Anti-Ferroptotic Pathways in Granulosa Cells: A Molecular Key to Follicular Atresia and Ovarian Aging

by Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Spyridon Polykalas, Despoina Mavrogianni, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Vasiliki Kanaka, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Charalampos Tsimpoukelis, Athanasios Karpouzos, Maria Anastasia Daskalaki, Nikolaos Kanakas, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis Show full author list Hide full author list

Int. J. Mol. Sci. 2026, 27(2), 950; https://doi.org/10.3390/ijms27020950 (registering DOI) - 18 Jan 2026

Abstract

The functional deterioration of granulosa cells (GCs), essential for follicular growth, steroidogenesis, and oocyte competence, indicates ovarian aging and reduced fertility. An expanding corpus of research indicates that oxidative stress is a primary molecular contributor to granulosa cell dysfunction, culminating in mitochondrial impairment, [...] Read more.

The functional deterioration of granulosa cells (GCs), essential for follicular growth, steroidogenesis, and oocyte competence, indicates ovarian aging and reduced fertility. An expanding corpus of research indicates that oxidative stress is a primary molecular contributor to granulosa cell dysfunction, culminating in mitochondrial impairment, reduced metabolic support for oocytes, and the activation of regulated apoptotic pathways that end in follicular atresia. Ferroptosis, an emergent type of iron-dependent lipid peroxidation, has been identified as a crucial mechanism contributing to chemotherapy-induced ovarian insufficiency, polycystic ovary syndrome (PCOS), and granulosa cell death in aging ovaries, in addition to conventional apoptosis. The SIRT1-Nrf2 axis acts as a crucial anti-oxidative and anti-ferroptotic system that protects GC viability, maintains mitochondrial homeostasis, and upholds redox equilibrium. SIRT1 promotes mitochondrial biogenesis and metabolic resilience by deacetylating downstream proteins, including FOXO3 and PGC-1α. Nrf2 simultaneously controls the transcriptional activation of detoxifying and antioxidant enzymes, including HO-1, SOD2, NQO1, and GPX4, which are critical inhibitors of ferroptosis. Disruption of SIRT1-Nrf2 signalling accelerates GC senescence, follicular depletion, and reproductive aging. In contrast, pharmaceutical and nutraceutical therapies, including metformin, melatonin, resveratrol, and agents that increase NAD⁺ levels, may reverse ovarian deterioration and reactivate SIRT1-Nrf2 activity. This narrative review highlights innovative treatment prospects for ovarian aging, fertility preservation, and assisted reproduction by synthesising current evidence on ferroptotic pathways, SIRT1-Nrf2 interactions, and oxidative stress in granulosa cells. An understanding of these interrelated biological networks enables the development of tailored therapies that postpone ovarian ageing and enhance reproductive outcomes for women receiving fertility therapy. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

15 pages, 1297 KB

Open AccessArticle

Anti-Inflammatory Effects of Alpha-Lipoic Acid Modulate Cystathionine-γ-Lyase Expression in RAW 264.7 Macrophages

by Aqsa Shahid, Stephen Chambers, Amy Scott-Thomas, Masuma Zawari and Madhav Bhatia

Int. J. Mol. Sci. 2026, 27(2), 949; https://doi.org/10.3390/ijms27020949 (registering DOI) - 18 Jan 2026

Abstract

Alpha-lipoic acid (ALA) is a naturally occurring organosulfur compound with antioxidant and anti-inflammatory activities. The time-dependent effects of ALA and mechanism of interaction with cystathionine-γ-lyase (CSE—an enzyme responsible for hydrogen sulfide—H₂S synthesis) in RAW 264.7 macrophages remain unknown. In this study, [...] Read more.

Alpha-lipoic acid (ALA) is a naturally occurring organosulfur compound with antioxidant and anti-inflammatory activities. The time-dependent effects of ALA and mechanism of interaction with cystathionine-γ-lyase (CSE—an enzyme responsible for hydrogen sulfide—H₂S synthesis) in RAW 264.7 macrophages remain unknown. In this study, we report results supporting the hypothesis that anti-inflammatory effects of ALA are associated with the reduction in CSE expression. To investigate the temporal effect of ALA in lipopolysaccharide (LPS—a potent stimulator of inflammation) treated RAW 264.7 macrophages, ALA was administered 1 h before LPS stimulation and 1, 3, and 6 h post LPS stimulation. Effects of ALA on different inflammatory and oxidative stress biomarkers including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), catalase activity (CAT), and malondialdehyde (MDA) levels were investigated. LPS stimulation significantly increased TNF- α, IL-6, MCP-1, MDA levels, and CSE expression and decreased CAT activity compared with the control group (p < 0.05 to 0.0001). ALA treatment at 1000 µM significantly attenuated LPS-stimulated inflammatory response in the macrophages across different time points (p < 0.05 to 0.0001). Furthermore, we found that ALA treatment reduced the expression of CSE in both pre- and post-treated LPS-stimulated macrophages in a time-dependent manner. In conclusion, this study demonstrated for the first time that the protective effects of ALA are dependent on the reduction in CSE expression in LPS-stimulated RAW 264.7 macrophages. Full article

(This article belongs to the Special Issue Bioactive Compounds in the Prevention of Chronic Diseases)

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