International Journal of Molecular Sciences

30 pages, 712 KB

Open AccessReview

Beyond the Core: The Role of Supplementary Short Tandem Repeats in Forensic Genetics

by Vitória Ramos, Benedita Ferreira-Silva, Jennifer Fadoni, António Amorim and Laura Cainé

Int. J. Mol. Sci. 2026, 27(13), 5756; https://doi.org/10.3390/ijms27135756 (registering DOI) - 25 Jun 2026

Conventional forensic DNA profiling predominantly utilizes established core sets of autosomal short tandem repeats (STRs), such as the FBI’s Combined DNA Index System (CODIS) and the European Standard Set (ESS). While these panels are effective for standard forensic casework, they may be inadequate [...] Read more.

Conventional forensic DNA profiling predominantly utilizes established core sets of autosomal short tandem repeats (STRs), such as the FBI’s Combined DNA Index System (CODIS) and the European Standard Set (ESS). While these panels are effective for standard forensic casework, they may be inadequate in more demanding scenarios, including severely degraded samples, complex multi-contributor mixtures, and kinship cases with deficiencies, where enhanced discriminatory capability is crucial. Additional non-core STR loci address these challenges while maintaining the non-coding, phenotypically uninformative nature that ensures the legal and ethical acceptability of forensic genetic evidence in court. This review assesses the forensic applications, population genetic parameters, validation requirements, and ethical considerations associated with non-core STR loci. A representative supplementary STR panel is presented as a case study to illustrate both the forensic value and the analytical requirements associated with the implementation of extended non-core STR systems. Challenges in implementation were identified in areas such as nomenclature standardization, backward compatibility with existing national databases, and geographic gaps in population reference data. The review concludes that a hybrid strategy, which retains core capillary electrophoresis (CE)-based profiling for routine casework and employs extended non-core panels for complex cases, represents the most practical path for the field. Full article

(This article belongs to the Special Issue Research Progress of Forensic Genetics)

25 pages, 997 KB

Open AccessReview

Propolis: A Natural Bioactive Compound with Emerging Roles in Functional Food Applications

by Mohamed Hussein Hamdy Roby, Mohamed Mahmoud Shaban Hassan, Adel Abdelrazek Abdelazim Mohdaly and Tugba Ozdal

Int. J. Mol. Sci. 2026, 27(13), 5755; https://doi.org/10.3390/ijms27135755 (registering DOI) - 25 Jun 2026

Abstract

Propolis, a resinous substance biosynthesized by honeybees from plant exudates and beeswax, has been valued for centuries in traditional medicine and is now increasingly recognized as a promising natural bioactive compound for functional food applications. Its complex phytochemical profile, mainly comprising flavonoids, phenolic [...] Read more.

Propolis, a resinous substance biosynthesized by honeybees from plant exudates and beeswax, has been valued for centuries in traditional medicine and is now increasingly recognized as a promising natural bioactive compound for functional food applications. Its complex phytochemical profile, mainly comprising flavonoids, phenolic acids, and terpenoids, confers potent antioxidant, antimicrobial, and anti-inflammatory properties that position it as a compelling candidate for use as a natural food preservative and bioactive additive. Despite this considerable potential, the widespread incorporation of propolis into food systems remains largely constrained by two main physicochemical limitations: its intense characteristic aroma, attributable to volatile terpenes and phenolic esters, which adversely affects sensory acceptance, and its inherent hydrophobicity, which prevents uniform dispersion in aqueous food matrices. This review critically examines three major technological strategies developed to overcome these barriers: (i) microencapsulation employing biopolymer wall materials, including alginate, chitosan, whey protein, and arabic gum, to mask organoleptic properties and enable controlled release; (ii) nanoemulsification to enhance water dispersibility and improve oral bioavailability; and (iii) the formulation of water-soluble propolis extracts through polyethylene glycol-based solvents or cyclodextrin complexation. In addition, this review provides a comprehensive assessment of the global chemical diversity of propolis and its bioactive properties as they relate to food preservation efficacy. Notwithstanding recent technological advances, critical research gaps persist regarding optimal effective concentrations, validated delivery systems, and scalable formulation strategies necessary for commercial food-grade applications. Addressing these gaps is essential for propolis to fulfill its considerable potential as a safe, widely accepted, and commercially viable natural food additive in next-generation functional food systems. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

29 pages, 1351 KB

Open AccessReview

Curcumin in Alzheimer’s Disease: From Mechanistic Insights to Translational Challenges and Emerging Curcuminoid Strategies

by Katarzyna Stępnik

Int. J. Mol. Sci. 2026, 27(13), 5754; https://doi.org/10.3390/ijms27135754 (registering DOI) - 25 Jun 2026

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder driven by complex interactions between protein aggregation, oxidative stress, neuroinflammation, and cellular dysfunction. Among plant-derived compounds, curcumin has emerged as one of the most extensively studied polyphenols due to its broad spectrum of biological activities. [...] Read more.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder driven by complex interactions between protein aggregation, oxidative stress, neuroinflammation, and cellular dysfunction. Among plant-derived compounds, curcumin has emerged as one of the most extensively studied polyphenols due to its broad spectrum of biological activities. This review provides a critical synthesis of the mechanistic, preclinical, and clinical evidence on curcumin in AD. Experimental studies consistently demonstrate that curcumin modulates key pathogenic processes, including neuroinflammatory signaling, oxidative stress, and amyloid-β aggregation, with more limited evidence for effects on tau pathology. While in vitro studies offer detailed mechanistic insights, in vivo models provide more integrated evidence, including improvements in cognitive performance and reductions in pathological markers. Despite this strong preclinical foundation, the clinical evidence remains limited and inconsistent. Randomized controlled trials have not demonstrated clear therapeutic efficacy, with outcomes strongly influenced by formulation, bioavailability, and study design. Poor solubility, rapid metabolism, and limited brain exposure remain key translational barriers. In response, increasing attention has been directed toward formulation strategies and structurally related compounds. Emerging curcuminoids, such as bisdemethoxycurcumin (BDMC), are discussed as potential next-generation candidates. Preliminary evidence suggests that BDMC may modulate oxidative stress, autophagy, astrocyte senescence, and amyloid-related processes, although the data remain largely preclinical. Overall, curcumin represents a mechanistically rich and preclinically promising multi-target compound but with unresolved translational limitations. Future research should prioritize pharmacokinetic optimization, formulation-dependent validation, and exploration of novel curcuminoid strategies to bridge the gap between experimental findings and clinical application in AD. Full article

(This article belongs to the Special Issue The Role of Medicinal Plants in the Treatment of Neurodegenerative Diseases: Advances, Challenges, and Future Perspectives)

12 pages, 962 KB

Open AccessArticle

A Dysbiosis–Urolithin A Depletion–Low 6-Sulfatoxymelatonin Triad as a Composite Biomarker Framework Across Age-Related Vascular and Malignant Disease States

by Alexandre Tavartkiladze, Levan Tavartkiladze, Gaiane Simonia, Michel Burnier, Russel J. Reiter, Ruite Lou, Dinara Kasradze, Nana Okrostsvaridze, Pati Revazishvili, Irine Andronikashvili, Pirdara Nozadze and Rusudan Khutsishvili

Int. J. Mol. Sci. 2026, 27(13), 5753; https://doi.org/10.3390/ijms27135753 (registering DOI) - 25 Jun 2026

Abstract

Urolithin A (UA) is a gut microbiota-derived postbiotic generated from dietary ellagitannins, while urinary 6-sulfatoxymelatonin (6-SMT) is a surrogate marker of nocturnal melatonin output. We explored whether dysbiosis, UA depletion, and low 6-SMT define an ordered biomarker pattern across healthy aging, salt-sensitive hypertension, [...] Read more.

Urolithin A (UA) is a gut microbiota-derived postbiotic generated from dietary ellagitannins, while urinary 6-sulfatoxymelatonin (6-SMT) is a surrogate marker of nocturnal melatonin output. We explored whether dysbiosis, UA depletion, and low 6-SMT define an ordered biomarker pattern across healthy aging, salt-sensitive hypertension, and advanced cancer. In this pilot observational study, patients with advanced solid tumors were classified as Cancer Group 1 (higher aggressiveness; n = 231) or Cancer Group 2 (lower aggressiveness; n = 118) and compared with healthy older controls (n = 117) and elderly participants with salt-sensitive hypertension (n = 333). Plasma UA decreased stepwise from controls (2.24 [1.38–3.12] nmol/L) to salt-sensitive hypertension (1.20 [0.76–1.89] nmol/L), Cancer Group 2 (0.60 [0.32–0.91] nmol/L), and Cancer Group 1, in which most samples were at or below the assay limit (overall p < 0.0001; trend p < 0.0001). Twenty-four-hour urinary 6-SMT declined in parallel, whereas the dysbiosis score, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and malondialdehyde (MDA) increased, and antioxidant indices decreased across the ordered groups (all p < 0.0001). These cross-sectional findings support a hypothesis-generating biomarker framework linking dysbiosis, postbiotic depletion, circadian disruption, inflammation, and redox imbalance across age-related disease states. Full article

(This article belongs to the Special Issue Microbiome Connections in Age-Related Diseases)

27 pages, 1934 KB

Open AccessArticle

Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome

by Yajuan Zhang, Weixin Qian, Miao Li, Ying-Ying Zou, Zhonghua Lu, Zhihui Huang, Robert K. Naumann and Hong Wang

Int. J. Mol. Sci. 2026, 27(13), 5752; https://doi.org/10.3390/ijms27135752 (registering DOI) - 25 Jun 2026

Abstract

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency. While brain pathology has been extensively studied, the retina remains underexplored. This study investigated retinal structural, functional, vascular, and cellular changes in a Scn1a^+/− rat model of DS. [...] Read more.

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency. While brain pathology has been extensively studied, the retina remains underexplored. This study investigated retinal structural, functional, vascular, and cellular changes in a Scn1a^+/− rat model of DS. Anatomical quantification revealed thinning of the retinal nerve fiber layer and thickening of the outer plexiform layer. Electroretinography (ERG) showed selectively reduced oscillatory potential amplitudes, suggesting dysfunction of neurovascular coupling. Consistent with these findings, immunohistochemistry demonstrated aberrant vascular morphology, including increased vessel curvature and reduced branching density. In addition, we observed robust microglial activation in the outer and inner plexiform layers; however, astrocyte morphology remained largely unchanged. Fenfluramine, an approved anti-seizure drug for DS, attenuated microglial activation but failed to rescue retinal structural or vascular deficits, indicating a dissociation between its anti-inflammatory and disease-modifying effects. Our findings suggest that multimodal retinal assessment could serve as a noninvasive biomarker platform for monitoring disease progression and therapeutic response in DS. Full article

(This article belongs to the Special Issue Molecular Insights in Neuro-Ophthalmology)

34 pages, 12944 KB

Open AccessArticle

Anticancer Activity of Miswak Root Extract in Breast Cancer Cell Line: HRLC-MS/MS Profiling, In Vitro Evaluation, and In Silico Analysis

by Abrar Turki, Md. Abul Barkat, Yasmin Basheer Ahmed, Harshita Barkat, Raghad Rashed Alotaibi, Khursheed Ahmad, Rumana Ahmad and Sahabjada Siddiqui

Int. J. Mol. Sci. 2026, 27(13), 5751; https://doi.org/10.3390/ijms27135751 (registering DOI) - 25 Jun 2026

Abstract

Breast cancer is among the most commonly diagnosed malignancies in women and remains difficult to treat due to therapy resistance and the adverse effects associated with conventional chemotherapeutic regimens. In this study, the anticancer activity of the ethanolic root extract of Salvadora persica [...] Read more.

Breast cancer is among the most commonly diagnosed malignancies in women and remains difficult to treat due to therapy resistance and the adverse effects associated with conventional chemotherapeutic regimens. In this study, the anticancer activity of the ethanolic root extract of Salvadora persica (S. persica), commonly known as Miswak, was evaluated in human breast cancer cells using a combination of in vitro assays, phytochemical profiling, and computational analyses. HRLC-MS/MS characterization revealed a wide range of bioactive constituents, including alkaloids, flavonoid derivatives, glucosinolates, and fatty acid–based molecules detected under both ionization modes. The extract exhibited a concentration-dependent cytotoxic effect on breast cancer MCF-7 and MDA-MB-231 cells, with IC₅₀ values of 144.1 and 176.3 µg/mL, respectively, as determined by the MTT assay, while exerting negligible toxicity toward normal Vero cells. Miswak extract enhanced intracellular ROS production, disruption of MMP, nuclear condensation, and increased apoptotic cell populations, along with S-phase cell cycle arrest, pointing toward activation of mitochondrial-mediated apoptosis. In silico docking results indicated that key phytoconstituents exhibit strong binding interactions with multiple breast cancer–relevant targets such as ERα, PR, EGFR, HER3, IGF-1R, and GPER. Additionally, pharmacokinetic and toxicity predictions suggested favorable drug-like properties with minimal safety concerns. Thus, these findings support its potential as a promising plant-derived therapeutic candidate for breast cancer. Full article

(This article belongs to the Special Issue Molecular Studies of Natural Compounds and Plant Extracts—3rd Edition)

19 pages, 36787 KB

Open AccessArticle

FOXP2+ Chief Cells and CXCL14+ Fibroblasts Drive Fibrotic Remodeling in Carotid Body Tumors

by Kangxi Cao, Jiazhi Yu, Guangnan Ao, Zongli Han, Zhongzheng Wang, Yunfeng Han and Tao Wang

Int. J. Mol. Sci. 2026, 27(13), 5750; https://doi.org/10.3390/ijms27135750 (registering DOI) - 25 Jun 2026

Abstract

Carotid body tumors (CBTs) exhibit pronounced clinical heterogeneity, particularly in fibrotic progression, yet the underlying cellular mechanisms remain poorly defined. Here, we performed single-cell RNA sequencing on 64,944 cells from three fibrotic CBT (FCBT) and three non-fibrotic CBT (nFCBT) specimens to construct a [...] Read more.

Carotid body tumors (CBTs) exhibit pronounced clinical heterogeneity, particularly in fibrotic progression, yet the underlying cellular mechanisms remain poorly defined. Here, we performed single-cell RNA sequencing on 64,944 cells from three fibrotic CBT (FCBT) and three non-fibrotic CBT (nFCBT) specimens to construct a high-resolution cellular atlas of CBT fibrosis. Integrated analyses revealed that FCBTs are distinguished by a FOXP2+ chief cell subpopulation exhibiting a metabolic shift toward mitochondrial respiration and enhanced MIF signaling, which may facilitate macrophage recruitment. Endothelial cells expanded in FCBTs and acquired pro-angiogenic signatures driven by macrophage-derived CXCL signaling. Notably, CXCL14+ fibroblasts emerged as the principal effectors of extracellular matrix deposition, with lineage inference suggesting their origin from smooth muscle cells. Immune cells, including T/NK and mast cells, further modulated the fibrotic niche through cytokine interactions. This study provides the first comprehensive single-cell dissection of CBT fibrosis, identifies FOXP2+ chief cells as initiators of stromal remodeling, and highlights CXCL14+ fibroblasts as key matrix-producing effectors. These findings nominate FOXP2 and CXCL14 as potential therapeutic targets for mitigating fibrosis in CBT patients. Full article

(This article belongs to the Collection Advances in Cell and Molecular Biology)

20 pages, 853 KB

Open AccessReview

Lactic Acid Bacteria-Derived Antimicrobial and Anti-Biofilm Strategies: Mechanisms, Functional Molecules, and Emerging Biomaterial Applications

by Weichen Gong, Harum Fadhilatunnur, Miaya Kanazawa, Julio Villena, Keita Nishiyama and Haruki Kitazawa

Int. J. Mol. Sci. 2026, 27(13), 5749; https://doi.org/10.3390/ijms27135749 (registering DOI) - 25 Jun 2026

Abstract

Lactic acid bacteria (LAB), particularly members of the genus Lactobacillus, have emerged as promising biological agents with antimicrobial and anti-biofilm properties. While numerous individual studies have reported their inhibitory effects against pathogenic microorganisms, a systematic understanding that integrates their functional components, molecular [...] Read more.

Lactic acid bacteria (LAB), particularly members of the genus Lactobacillus, have emerged as promising biological agents with antimicrobial and anti-biofilm properties. While numerous individual studies have reported their inhibitory effects against pathogenic microorganisms, a systematic understanding that integrates their functional components, molecular mechanisms, and material-based applications remains lacking. In this review, we provide a comprehensive and component-oriented overview of LAB-mediated antimicrobial strategies. We first summarize secreted factors, including organic acids, bacteriocins, hydrogen peroxide, and extracellular vesicles, which collectively contribute to direct pathogen inhibition and environmental modulation. We then discuss cell-associated components such as surface-layer proteins and exopolysaccharides, highlighting their roles in adhesion interference and competitive exclusion. In addition, we examine whole-cell effects, including niche competition, quorum sensing disruption, and host immune modulation. Importantly, we place particular emphasis on the anti-biofilm activity of lactobacilli, detailing mechanisms involved in the prevention of the pathogen initial adhesion, disruption of extracellular polymeric substance matrices, and destabilization of mature biofilms. Finally, we explore emerging strategies that integrate lactobacilli with biomaterials, particularly hydrogel-based systems, to achieve controlled delivery, enhanced stability, and sustained antimicrobial activity. These biohybrid approaches represent a promising direction for the development of next-generation antimicrobial materials. These findings support the concept of LAB-based living antimicrobial materials as a next-generation strategy to combat biofilm-associated infections. Overall, this review aims to bridge the gap between molecular functions and translational applications of lactobacilli, providing new insights into its potential as a versatile platform for antimicrobial and anti-biofilm interventions. Full article

(This article belongs to the Special Issue Antimicrobial Materials: Molecular Developments and Applications)

14 pages, 3151 KB

Open AccessArticle

Aronia Bioactive Fraction–Alginic Acid Nanocomplex–Modulates Tau Phosphorylation and Aggregation in Cell Models of Alzheimer’s Disease

by Hye-Yeon Kang, Bong-Keun Jang, Seong-Hoon Yun, Hee-Yeong Jeong, Eunkuk Park, Kang-Il Oh, Junhwan Jeong and Seon-Yong Jeong

Int. J. Mol. Sci. 2026, 27(13), 5748; https://doi.org/10.3390/ijms27135748 (registering DOI) - 25 Jun 2026

Abstract

Preventing or reversing Tau hyperphosphorylation and aggregation represent critical objectives in the development of effective therapies for Alzheimer’s disease. The present study investigated the potential of a novel Aronia bioactive fraction—alginic acid nanocomplex (AANCP)—to simultaneously inhibit pathological features of Alzheimer’s disease. Evaluations of [...] Read more.

Preventing or reversing Tau hyperphosphorylation and aggregation represent critical objectives in the development of effective therapies for Alzheimer’s disease. The present study investigated the potential of a novel Aronia bioactive fraction—alginic acid nanocomplex (AANCP)—to simultaneously inhibit pathological features of Alzheimer’s disease. Evaluations of Aronia bioactive fraction (ABF) and low-molecular-weight alginic acid (LAA), utilized both individually and as AANCP, were conducted in HEK293-TauP301L and SH-SY5Y-TauP301L cell models of Alzheimer’s disease. Both ABF and LAA reduced the expression of total Tau and Tau phosphorylated at Ser396 in a concentration-dependent manner, with AANCP demonstrating significant synergistic activity of its components. Notably, the optimal AANCP ratio was 1:1 and 1:8 for inhibiting Tau phosphorylation and Tau aggregation, respectively. Mechanistically, AANCP inhibited Tau phosphorylation by upregulating p-Akt (phosphorylated protein kinase B) and p-GSK-3β (phosphorylated glycogen synthase kinase-3 beta), while also enhancing the activity of methylated PP2A, a key Tau phosphatase. Furthermore, AANCP exhibited superior efficacy in inhibiting heparin-induced Tau aggregation compared to the individual components. Analysis of autophagy markers indicated that the nanocomplex enhanced Tau clearance, as shown by increased LC3-II and Beclin-1 levels and reduced p62 levels. These results suggest AANCP as a promising therapeutic candidate that simultaneously reduces Tau phosphorylation and aggregation and facilitates autophagic Tau clearance, offering a potent, synergistic strategy for treating Alzheimer’s disease. Full article

(This article belongs to the Special Issue Emerging Molecular Mechanisms and Therapeutic Targets in Neurodegenerative Diseases and Brain Cancers)

10 pages, 518 KB

Open AccessArticle

Association of Selected Genetic Variants in CYP1A1, CYP2D6, NAT1 and NAT2 with Endometrial Cancer Risk: A Preliminary Case–Control Study

by Maciej Skrzypek, Monika Gogolewska, Andrzej Bieńkiewicz, Katarzyna Wójcik-Krowiranda, Ireneusz Majsterek and Jacek Kabziński

Int. J. Mol. Sci. 2026, 27(13), 5747; https://doi.org/10.3390/ijms27135747 (registering DOI) - 25 Jun 2026

Abstract

Cancer risk may be influenced by genetic variation and altered expression of xenobiotic-metabolizing enzymes, yet their role in endometrial cancer remains incompletely understood. This study evaluated the association between four polymorphisms in xenobiotic metabolism-related genes CYP1A1 rs1799814, CYP2D6 rs3892097, NAT1 rs72554606, and NAT2 [...] Read more.

Cancer risk may be influenced by genetic variation and altered expression of xenobiotic-metabolizing enzymes, yet their role in endometrial cancer remains incompletely understood. This study evaluated the association between four polymorphisms in xenobiotic metabolism-related genes CYP1A1 rs1799814, CYP2D6 rs3892097, NAT1 rs72554606, and NAT2 rs1799930 and the risk of endometrial cancer, and assessed CYP1A1 and CYP2D6 expression in tumor and control tissues. Genetic association analyses, including multivariate and histology-stratified models, were performed, and gene expression levels were compared between cancer and control tissues. Variants in NAT2, CYP1A1, and CYP2D6 were significantly associated with an increased risk of endometrial cancer, whereas NAT1 rs72554606 showed a protective effect, particularly in the dominant model. The strongest association was observed for NAT2 rs1799930 in additive and recessive models. Expression analysis revealed significantly higher CYP1A1 and CYP2D6 levels in tumor tissues than in control tissues. Stratified analyses showed generally consistent effects, especially for endometrioid carcinoma, although estimates for the serous subtype were limited by sample size. These findings suggest that polymorphisms and altered expression of xenobiotic-metabolizing genes may contribute to endometrial carcinogenesis. Further studies, including independent validation and analyses of gene–environment interactions, are needed. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancers: Advances and Challenges, 2nd Edition)

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20 pages, 10282 KB

Open AccessArticle

Wound-Healing Effects of Birch Bark and Propolis Extracts on Epidermolysis Bullosa Keratinocytes

by Thomas Kissas, Dimitra Kiritsi, Ioannis Athanasiou, Alexander Nyström, Alexandros Onoufriadis and Ioannis Mourtzinos

Int. J. Mol. Sci. 2026, 27(13), 5746; https://doi.org/10.3390/ijms27135746 (registering DOI) - 25 Jun 2026

Abstract

Epidermolysis bullosa (EB) is a group of genetic diseases characterized by skin fragility. Although therapeutic options aim to accelerate wound-healing, improvement is needed; therefore, birch bark and propolis were investigated due to their beneficial biological properties. A representative ethanolic extract was analyzed by [...] Read more.

Epidermolysis bullosa (EB) is a group of genetic diseases characterized by skin fragility. Although therapeutic options aim to accelerate wound-healing, improvement is needed; therefore, birch bark and propolis were investigated due to their beneficial biological properties. A representative ethanolic extract was analyzed by reversed-phase high-performance liquid chromatography with diode array detection (RP-HPLC-DAD) for chemical profiling of the raw materials. A hydrophobic natural deep eutectic solvent (HNaDES) for birch bark extraction, as well as a hydrogel and a bigel enriched with propolis and birch bark extract, were prepared and characterized by Fourier transform infrared (FT-IR) spectroscopy. Cytotoxicity and wound-healing potential were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch assays in six human keratinocyte cell lines: two from healthy individuals, two from recessive dystrophic ΕΒ patients (RDEB), and two from laminin-332-deficient junctional EB patients (JEB). RP-HPLC-DAD revealed the presence of phenolic compounds (e.g., chrysin, pinocembrin, pinobanksin) and pentacyclic triterpenes (e.g., betulin and betulinic acid), characteristic of propolis and birch bark, respectively. FT-IR confirmed HNaDES formation and indicated physical interactions within the gels. All systems exhibited no cytotoxicity at 1 μg/mL and increased cell vitality. Moreover, in keratinocytes derived from JEB patients, hydrogel improved wound- healing significantly at 24 h, whereas bigel showed significant improvement at 8 h. The developed systems could be promising topical treatments. Full article

(This article belongs to the Special Issue Molecular Insight into Skin Infection and Inflammation)

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24 pages, 33781 KB

Open AccessReview

A Global Analysis of the Complex Structural Organization of KCTD Proteins and Their Functional Implications

by Nicole Balasco, Luciana Esposito, Simone Di Micco and Luigi Vitagliano

Int. J. Mol. Sci. 2026, 27(13), 5745; https://doi.org/10.3390/ijms27135745 (registering DOI) - 25 Jun 2026

Abstract

KCTD proteins exhibit significant structural complexity, arising from their modular organization, oligomerization, and intricate biological partnerships. Although their biological importance has been assessed for two decades, the biochemical basis of their activities is only partially understood. This is certainly due to the limited [...] Read more.

KCTD proteins exhibit significant structural complexity, arising from their modular organization, oligomerization, and intricate biological partnerships. Although their biological importance has been assessed for two decades, the biochemical basis of their activities is only partially understood. This is certainly due to the limited structural information that was available until a few years ago. Fortunately, some recent insightful structural studies and the advent of machine-learning-based approaches are rapidly changing the scenario. By surveying the literature and structural databases and integrating this information with ad hoc 3D-structure predictions, we provide a detailed view of the structural biology of these proteins at different levels: individual domains, full-length oligomers, functional hetero-oligomers formed by different family members, and complexes with functional partners. Collectively, these surveys and analyses provide insights into the family’s evolutionary history and its structure–function relationships. The family-wide coverage of structural information also indicates the extent to which structural similarities are reflected in functional analogies. Finally, the potential functional implications of the intricate architecture of these multimeric proteins and the tendency of their members to hetero-oligomerize are discussed from a functional perspective. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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21 pages, 2553 KB

Open AccessArticle

Vitronectin Modulates Plasma Aβ Oligomerization Propensity Within Altered Albumin Interactome Networks in Alzheimer’s Disease

by Hojin Kang, Hongju Kim, Woo Jung Kim, Leon French, Hyunjung Oh and Seong Soo A. An

Int. J. Mol. Sci. 2026, 27(13), 5744; https://doi.org/10.3390/ijms27135744 (registering DOI) - 25 Jun 2026

Abstract

Amyloid beta (Aβ) oligomers are key mediators of synaptic dysfunction and neural circuit impairment in Alzheimer’s disease (AD). While plasma Aβ oligomerization propensity (OAβ) correlates with cerebral amyloid pathology and cognitive decline, the systemic modulators of OAβ remain poorly understood. In this study, [...] Read more.

Amyloid beta (Aβ) oligomers are key mediators of synaptic dysfunction and neural circuit impairment in Alzheimer’s disease (AD). While plasma Aβ oligomerization propensity (OAβ) correlates with cerebral amyloid pathology and cognitive decline, the systemic modulators of OAβ remain poorly understood. In this study, we identified the albumin interactome (albumin and its associated proteins) as a critical regulator of OAβ. Selective depletion of the albumin interactome from plasma eliminated the OAβ difference between amyloid PET (A-PET)- and A-PET+ individuals. Proteomic analysis revealed widespread network alterations within the albumin interactome of A-PET+ individuals. Notably, vitronectin (VTN) was identified as a key hub protein that was significantly reduced in A-PET+ individuals. Functional assays and in silico modeling demonstrated that VTN directly bound to Aβ and inhibited its oligomerization. Additionally, plasma VTN levels distinguished A-PET status. These findings suggest that systemic changes in the albumin interactome, particularly the reduction in VTN, are associated with dysregulated Aβ dynamics in plasma. Our results provide novel insights into systemic mechanisms underlying AD pathology and identify VTN as a potential peripheral modulator and biomarker of cerebral amyloid pathology. Full article

(This article belongs to the Special Issue Molecular and Systems Mechanisms of Neural Circuit Function and Plasticity)

19 pages, 2125 KB

Open AccessArticle

In Silico Identification of Conserved ‘Fungal Islands’ in Human Septin9: Evidence for Atavistic Therapeutic Targets

by Ömer Eren Özcan, Ayhan Bilir and Berna Yıldırım

Int. J. Mol. Sci. 2026, 27(13), 5743; https://doi.org/10.3390/ijms27135743 (registering DOI) - 25 Jun 2026

Abstract

Metastasis, the primary cause of cancer mortality, relies on malignant cells acquiring extreme mobility and mechanical plasticity. We posit that this physical transition is driven not by de novo genetic innovations but by an atavistic reversion to highly conserved cytoskeletal blueprints, termed “Fungal [...] Read more.

Metastasis, the primary cause of cancer mortality, relies on malignant cells acquiring extreme mobility and mechanical plasticity. We posit that this physical transition is driven not by de novo genetic innovations but by an atavistic reversion to highly conserved cytoskeletal blueprints, termed “Fungal Islands.” Through in silico sequence alignments and molecular docking, we investigated structural homology between human septin-9 (SEPT9) and its yeast ortholog, Cdc3. Our analysis reveals structural and thermodynamic parity within the G1/P-loop catalytic core across billions of years of eukaryotic divergence. This precise preservation of spatial configuration provides strong evidence against convergent evolution, demonstrating the core septin engine is constrained by intense purifying selection. Consequently, we argue that malignant cells exapt these functionally immutable ancestral nodes to drive a biomechanical shift, mirroring the invasive mechanics of fungal hyphal tips. This identifies a non-mutating structural template for next-generation ‘migrastatic’ therapies, offering a strategy to disable cancer’s migratory machinery while evading the mutational resistance typical of modern kinase inhibitors. Full article

(This article belongs to the Special Issue Advanced in In Silico Methods for Rational Drug Design and Predictive Toxicology)

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24 pages, 10606 KB

Open AccessArticle

Phytochemical Characterization and Immunometabolic Modulation by Mangifera indica (Mahajanaka) Pulp Extract in Diabetic and Hypertensive Rat Models

by Wachiraporn Tipsuwan, Hathairat Thananchai, Anusara Pongjanta, Suphatta Yubo, Tawat Taesothikul, Duangta Kanjanapothi, Yanping Zhong and Somdet Srichairatanakool

Int. J. Mol. Sci. 2026, 27(13), 5742; https://doi.org/10.3390/ijms27135742 (registering DOI) - 25 Jun 2026

Abstract

Mango (Mangifera indica L.) pulp contains bioactive compounds with potential therapeutic effects against metabolic and immune-related disorders. However, the integrated effects of mango pulp extract on metabolic, cardiovascular, and immunomodulatory functions remain insufficiently characterized. Therefore, this study aimed to characterize the phytochemical [...] Read more.

Mango (Mangifera indica L.) pulp contains bioactive compounds with potential therapeutic effects against metabolic and immune-related disorders. However, the integrated effects of mango pulp extract on metabolic, cardiovascular, and immunomodulatory functions remain insufficiently characterized. Therefore, this study aimed to characterize the phytochemical composition and evaluate the activity of M. indica (Mahajanaka) pulp ethanolic extract (MPEE) in rat models. Streptozotocin (STZ)-induced diabetic rats and N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats were used to assess metabolic and cardiovascular effects, while immune function was examined through neutrophil phagocytosis, splenocyte proliferation, lymphocyte subpopulation analysis, and cytokine secretion. MPEE exhibited a rich phytochemical profile, particularly phenolic compounds, along with strong antioxidant activity (339 ± 8.9 mg gallic acid equivalent/g extract). In STZ-induced diabetic rats, MPEE at 300 mg/kg significantly reduced plasma triglyceride (36.7%) and total cholesterol (45.3%) levels compared with untreated diabetic controls, although its antihyperglycemic effect was modest (6.8%). In L-NAME-induced hypertensive rats, MPEE at 400 mg/kg produced the greatest reduction in blood pressure (42.7%) and heart rate (53.5%). Furthermore, MPEE enhanced neutrophil phagocytic activity (43%), with significant increases observed at doses of 100–400 mg/kg. These findings indicate that MPEE exerts antioxidant, hypolipidemic, antihypertensive, and innate immunostimulatory activities. Full article

(This article belongs to the Special Issue Recent Advances in Bioactive Compounds in Human Health)

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16 pages, 3351 KB

Open AccessArticle

Decoding the Microcin J25 Biosynthetic Cluster: Modulation of the mcjA Promoter by the Novel Overlapping Gene mcjX

by Emilse Masias, Juan I. Ramirez, Lucía Lanza, Jorge A. Lachenicht, María E. Vázquez, Leonardo Acuña, Carlos J. Minahk and Raul A. Salomón

Int. J. Mol. Sci. 2026, 27(13), 5741; https://doi.org/10.3390/ijms27135741 (registering DOI) - 25 Jun 2026

Abstract

A comprehensive analysis of the microcin J25 (MccJ25) biosynthetic gene cluster revealed a previously uncharacterized 96-base pair overlapping gene, designated mcjX. This gene features a +1 reading frame shift relative to the primary sequence and encodes a 31-amino acid peptide. Notably, 53 [...] Read more.

A comprehensive analysis of the microcin J25 (MccJ25) biosynthetic gene cluster revealed a previously uncharacterized 96-base pair overlapping gene, designated mcjX. This gene features a +1 reading frame shift relative to the primary sequence and encodes a 31-amino acid peptide. Notably, 53 nucleotides overlap with the 3′ terminus of the structural gene mcjA. Such significant overlaps are rare features in the Escherichia coli genome, highlighting the hidden complexity of microbial operon architectures. In this study, we demonstrate that mcjX is actively translated. Functional assays, including green fluorescent protein reporter systems, suggest that McjX acts as a negative regulator of the mcjA promoter, modulating MccJ25 expression. This discovery represents the first report of a regulatory mechanism mediated by an overlapping gene within a lasso peptide operon, providing new perspectives on how microbial genomes fine-tune the production of antimicrobial peptides through compact genetic organization. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Biosynthesis, Molecular Mechanisms and Biomedical Applications)

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18 pages, 2964 KB

Open AccessArticle

The Phylogeny of Brassicaceae YABBYs and the CRC-Mediated Regulation of Stigma Development in Brassica napus

by Lin Dai, Jinxiang Gao, Cheng Li, Tao Han, Zhengshu Tian, Yunyun Zhang, Yusong Zhang, Yanqing Luo, Kaiqin Zhao, Xiaoyan Yuan, Canzhi Zhang, Tao Liu, Feng Zu and Pei Qin

Int. J. Mol. Sci. 2026, 27(13), 5740; https://doi.org/10.3390/ijms27135740 (registering DOI) - 25 Jun 2026

Abstract

The YABBY family consists of plant-specific transcription factors that regulate organ polarity and reproductive development. As a member of this family, CRABS CLAW (CRC) plays crucial roles, but its molecular mechanism in oilseed rape stigma development remains unclear. In this study, [...] Read more.

The YABBY family consists of plant-specific transcription factors that regulate organ polarity and reproductive development. As a member of this family, CRABS CLAW (CRC) plays crucial roles, but its molecular mechanism in oilseed rape stigma development remains unclear. In this study, we identified YABBY genes in four Brassicaceae species. The results showed that CRC proteins are highly conserved in structure, but their cis-acting elements vary among species. To explore its function, we performed transcriptome sequencing on an oilseed rape CRC-deficient mutant (sd). The transcriptome data revealed multiple changes in the sd mutant. Specifically, brassinosteroid (BR) signaling factors were downregulated. Sugar transporters and auxin-related genes showed abnormal expression. Furthermore, pro-senescence and programmed cell death (PCD) genes were upregulated, whereas the classic senescence pathway remained unchanged. Based on these findings, we propose a potential mechanism. The loss of CRC disrupts BR signaling, sugar transport, and calcium homeostasis. This disruption triggers non-classic death of stigma papilla cells, which hinders pollen tube penetration and reduces seed set. Notably, increasing environmental humidity partially rescued the seed set, likely by delaying cell death. Although these transcriptomic insights warrant further experimental validation, this study provides valuable clues and genetic resources for future research on reproductive development in oilseed rape. Full article

(This article belongs to the Section Molecular Plant Sciences)

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26 pages, 1030 KB

Open AccessArticle

Low-Pass Nanopore Sequencing of Plasma cfDNA Reveals Fragmentomic, Epigenomic, and Age-Associated Signatures Under Ultra-Low-Coverage Conditions

by Andrey Eremin, Alexander Sergeev, Tsimur Hasanau and Maria Zvereva

Int. J. Mol. Sci. 2026, 27(13), 5739; https://doi.org/10.3390/ijms27135739 (registering DOI) - 25 Jun 2026

Abstract

Circulating cell-free DNA (cfDNA) enables minimally invasive assessment of chromatin organization and DNA modifications. Whether such information can be reliably recovered under conditions of limited plasma input (below 1 mL) and ultra-low sequencing depth remains unclear. We performed low-pass whole-genome Oxford Nanopore sequencing [...] Read more.

Circulating cell-free DNA (cfDNA) enables minimally invasive assessment of chromatin organization and DNA modifications. Whether such information can be reliably recovered under conditions of limited plasma input (below 1 mL) and ultra-low sequencing depth remains unclear. We performed low-pass whole-genome Oxford Nanopore sequencing (down to 0.01× coverage) of plasma cfDNA from young and elderly donors and jointly analyzed fragment length distributions and base modifications (5mC, 5hmC, 6mA). In parallel, we analyzed an enzymatically fragmented model DNA system to assess whether controlled in vitro fragmentation can reproduce cfDNA-like nucleosomal profiles and associated modification patterns. Despite shallow coverage, cfDNA samples displayed reproducible mono-, di-, tri-, and tetra-nucleosomal peaks, indicating that major fragmentomic features can be retained under ultra-low-coverage conditions. Modification-aware basecalling enabled exploratory quantification of global modification fractions across nucleosomal size classes and nomination of candidate group-specific modification loci. Overall, these results support the feasibility of low-pass nanopore sequencing as an exploratory framework for simultaneous cfDNA fragmentomic and epigenomic profiling in low-input studies. Full article

(This article belongs to the Special Issue Advances in Next-Generation Sequencing for Aging and Cancer Research)

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12 pages, 2353 KB

Open AccessArticle

Translational Validation of a Novel Multi-Locus ctDNA Methylation Assay for Early Detection and Stratification of Colorectal Cancer: An Exploratory Prospective, Case-Control Study

by Hayoung Lee, Jae Cheol Kang, In Ja Park, Gwang-un Kim, Hwi Hyun, Na Young Min, Sungwon Jeon and Byoung-Chul Kim

Int. J. Mol. Sci. 2026, 27(13), 5738; https://doi.org/10.3390/ijms27135738 (registering DOI) - 25 Jun 2026

Abstract

To evaluate the diagnostic performance and clinicopathologic relevance of a multi-locus circulating tumor DNA methylation assay. In this prospective, single-center, case-control exploratory study, we enrolled 35 patients with colorectal cancer undergoing surgery and 57 healthy controls undergoing screening colonoscopy at the Asan Medical [...] Read more.

To evaluate the diagnostic performance and clinicopathologic relevance of a multi-locus circulating tumor DNA methylation assay. In this prospective, single-center, case-control exploratory study, we enrolled 35 patients with colorectal cancer undergoing surgery and 57 healthy controls undergoing screening colonoscopy at the Asan Medical Center, Seoul, Republic of Korea between July 2024 and January 2025. Peripheral blood was collected before surgery or colonoscopy, and circulating tumor DNA methylation was analyzed using a multi-locus panel targeting Septin9, IKZF1, BCAT1, Septin9-2, BCAN, and VAV3. The main outcomes were test accuracy (sensitivity, specificity, and area under the curve [AUC]) and associations between methylation marker positivity and clinicopathologic features. Circulating tumor DNA was positive in 74.3% of the patients and 12.3% of controls, yielding a sensitivity of 74.3%, specificity of 87.7%, and an AUC of 0.837, whereas serum carcinoembryonic antigen exhibited lower sensitivity (25.7%). Sensitivity in stage I disease was limited (36.4%). Circulating tumor DNA-positive tumors were larger (5.7 cm vs. 2.2 cm, p < 0.001) and had more advanced T and N stages. The number of positive markers increased with pathologic stage (p = 0.003). Individual marker analysis revealed that BCAT1, Septin9-2, and VAV3 were associated with higher T stage, whereas BCAN positivity was linked to nodal metastasis. The six-marker circulating tumor DNA methylation assay demonstrated acceptable diagnostic accuracy, with multi-locus patterns associated with tumor burden and invasive features. However, sensitivity for early-stage disease was limited. The assay may serve as a complementary tool for screening and risk stratification. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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