International Journal of Molecular Sciences

21 pages, 1090 KiB

Open AccessArticle

Non-Invasive Determination of the Paternal Inheritance in Pregnancies at Risk for β-Thalassaemia by Analyzing Cell-Free Fetal DNA Using Targeted Next-Generation Sequencing

by Stefania Byrou, Rutger W. W. Brouwer, Marios Tomazou, Stella Tamana, Petros Kountouris, Carsten W. Lederer, Miranda Petrou, Zeliha Ozgur, Xander den Dekker, Zakia Azmani, Soteroula Christou, Christiana Makariou, Marina Kleanthous, Wilfred F. J. van IJcken and Thessalia Papasavva

Int. J. Mol. Sci. 2025, 26(2), 570; https://doi.org/10.3390/ijms26020570 (registering DOI) - 10 Jan 2025

Abstract

Non-invasive prenatal testing (NIPT) has been widely adopted for the screening of chromosomal abnormalities; however, its adoption for monogenic disorders, such as β-thalassaemia, has proven challenging. Haemoglobinopathies are the most common monogenic disorders globally, with β-thalassaemia being particularly prevalent in Cyprus. This study [...] Read more.

Non-invasive prenatal testing (NIPT) has been widely adopted for the screening of chromosomal abnormalities; however, its adoption for monogenic disorders, such as β-thalassaemia, has proven challenging. Haemoglobinopathies are the most common monogenic disorders globally, with β-thalassaemia being particularly prevalent in Cyprus. This study introduces a non-invasive prenatal haplotyping (NIPH) assay for β-thalassaemia, utilizing cell-free DNA (cfDNA) from maternal plasma. The assay determines paternal inheritance by analyzing highly heterozygous single-nucleotide variants (SNVs) in the β-globin gene cluster. To identify highly heterozygous SNVs in the population, 96 randomly selected samples were processed using Illumina DNA-prep NGS chemistry. A custom, high-density NGS genotyping panel, named HAPLONID, was designed with 169 SNVs, including 15 common pathogenic ones. The AmpliSeq for Illumina assay was then applied to cfDNA to evaluate the panel’s efficiency in performing NIPT for β-thalassaemia. Analysis revealed 219 highly polymorphic SNVs, and the sequencing of 17 families confirmed successful paternal allele determination. The NIPH assay demonstrated 100% success in diagnostic interpretation. This study achieved the advancement of an integrated NGS-NIPT assay for β-thalassaemia, bringing it one step closer to being a diagnostic assay and thereby enabling a reduction in the number of risky invasive prenatal sampling procedures in Cyprus and elsewhere. Full article

(This article belongs to the Special Issue Molecular Advances in Blood Disorders)

18 pages, 4934 KiB

Open AccessArticle

Cu-Ion Hybrid Porous Carbon with Nanoarchitectonics Derived from Heavy-Metal-Contaminated Biomass as Ultrahigh-Performance Supercapacitor

by Jieni Wang, Xiaobo Han, Shuqin Zhang, Haodong Hou, Chenlin Wei, Chenxiao Liu, Leichang Cao, Jinglai Zhang, Li Wang and Shicheng Zhang

Int. J. Mol. Sci. 2025, 26(2), 569; https://doi.org/10.3390/ijms26020569 - 10 Jan 2025

Abstract

It is challenging to handle heavy-metal-rich plants that grow in contaminated soil. The role of heavy metals in biomass on the physicochemical structure and electrochemical properties of their derived carbon has not been considered in previous research. In this study, Cu-ion hybrid nanoporous [...] Read more.

It is challenging to handle heavy-metal-rich plants that grow in contaminated soil. The role of heavy metals in biomass on the physicochemical structure and electrochemical properties of their derived carbon has not been considered in previous research. In this study, Cu-ion hybrid nanoporous carbon (CHNC) is prepared from Cu content-contaminated biomass through subcritical hydrocharization (HTC) coupling pyrolytic activation processes. The CHNCs are used as advanced electrode material for energy storage applications, exhibiting an impressively ultrahigh capacitance of 562 F g⁻¹ at a current density of 1 A g⁻¹ (CHNC-700-4-25), excellent energy density of 26.15 W h kg⁻¹, and only 7.59% capacitance loss after enduring 10,000 cycles at a current density of 10 A g⁻¹, making CHNCs rank in the forefront of previously known carbon-based supercapacitor materials. These comprehensive characterizations demonstrate that copper ions introduce new electrochemically active sites and enhance the conductivity and charge transport performance of the electrode material, elevating the specific capacitance of CHNC from 463 to 562 F g⁻¹. These findings offer valuable insights into the effective energy storage application of heavy-metal-contaminated biomass wastes. Full article

(This article belongs to the Special Issue Electrochemical Behavior and Application of Advanced Electrode Materials 2.0)

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13 pages, 1225 KiB

Open AccessArticle

Green Synthesis, Formulation and Test Field of Lymantria monacha L. (Lepidoptera: Lymantriidae) Sex Pheromone in East European Region

by Iuliana Vasian, Mihai-Leonard Duduman, Emese Gal, Adrian Pîrnău and Monica Gorgan

Int. J. Mol. Sci. 2025, 26(2), 568; https://doi.org/10.3390/ijms26020568 - 10 Jan 2025

Abstract

The nun moth, Lymantria monacha L. (Linnaeus, 1758), is one of the most important defoliators of coniferous forests in Europe and Asia. In sexual communication, females produce three epoxides and an alkene: (−)-disparlure [(7S,8R)-cis-7,8-epoxy-2-methyloctadecane], (+)-monachalure [(7R [...] Read more.

The nun moth, Lymantria monacha L. (Linnaeus, 1758), is one of the most important defoliators of coniferous forests in Europe and Asia. In sexual communication, females produce three epoxides and an alkene: (−)-disparlure [(7S,8R)-cis-7,8-epoxy-2-methyloctadecane], (+)-monachalure [(7R,8S)-cis-7,8-epoxyoctadecane], (−)-monachalure [(7S,8R)-cis-7,8-epoxyoctadecane], and their corresponding olefins. This study aimed to develop a green synthesis pathway for all pheromonal components, emphasizing the use of common raw materials, a simplified three-step process, lower costs, and an environmentally friendly approach compared to existing methods. The proposed method introduces a novel synthetic route employing an innovative improvement alkylation step catalyzed by lithium iodide in diglyme. The synthesized compounds were characterized using GC-MS, ¹H NMR, and ¹³C NMR spectroscopy. Six synthetic blends were formulated for field testing, with the goal of identifying the most attractive composition. Field trials demonstrated that a blend with a 10:10:1 ratio of (±)-Disparlure, (±)-Monachalure, and (Z)-2-Methyl-7-octadecene exhibited the highest attraction efficiency. Full article

(This article belongs to the Special Issue Animal and Plant Cell–Tissue, Organ Specialization and Function: Investigational, Experimental and Medical Aspects, 4th Edition)

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10 pages, 1363 KiB

Open AccessArticle

Production of an Oncolytic Adeno-Associated Virus Containing the Pro-Apoptotic TRAIL Gene Can Be Improved by shRNA Interference

by Nicholas Donohue, Simeng Li, Stefano Boi, Alana Rainbow-Fletcher and Niall Barron

Int. J. Mol. Sci. 2025, 26(2), 567; https://doi.org/10.3390/ijms26020567 - 10 Jan 2025

Abstract

Recombinant Adeno-associated virus (rAAV) is a popular vector for treating genetic diseases caused by absent or defective genes. rAAVs can be produced that contain a therapeutic transgene, i.e., a correct copy of the affected gene, which is then delivered into target cells. A [...] Read more.

Recombinant Adeno-associated virus (rAAV) is a popular vector for treating genetic diseases caused by absent or defective genes. rAAVs can be produced that contain a therapeutic transgene, i.e., a correct copy of the affected gene, which is then delivered into target cells. A further application of rAAV is to deliver pro-apoptotic genes such as TNF-related apoptosis-inducing ligand (TRAIL) into cancer cells, leading to tumor regression. However, rAAV production is expensive and insufficient yields may hinder wide-spread adoption especially in systemic conditions. During rAAV production, the therapeutic transgene may be expressed in the producer cell line, and in the case of an oncolytic gene, this would likely lead to cell death thus reducing rAAV yields. Here we demonstrate that expression of TRAIL during rAAV production in HEK293F cells negatively impacts rAAV yield. A shRNA-based strategy was developed to suppress the expression of TRAIL in rAAV-producing cells specifically during the production process. Incorporating a TRAIL-targeting shRNA expression cassette within the backbone of the rAAV genome-encoding plasmid during triple-transfection of HEK293F cells reduced transgene expression and led to a 60% increase in the yield of rAAV-TRAIL compared to controls. Full article

(This article belongs to the Section Molecular Microbiology)

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22 pages, 7241 KiB

Open AccessArticle

Enhancing the Solubility and Dissolution of Apigenin: Solid Dispersions Approach

by Natalia Rosiak, Ewa Tykarska, Andrzej Miklaszewski, Robert Pietrzak and Judyta Cielecka-Piontek

Int. J. Mol. Sci. 2025, 26(2), 566; https://doi.org/10.3390/ijms26020566 - 10 Jan 2025

Abstract

Apigenin (APG), a bioactive flavonoid with promising therapeutic potential, suffers from poor water solubility, which limits its bioavailability. To address this, solid dispersions of APG were prepared using ball milling with sodium alginate (SA), Pluronic^® F-68 (PLU68), Pluronic^® F-127 (PLU127), PVP [...] Read more.

Apigenin (APG), a bioactive flavonoid with promising therapeutic potential, suffers from poor water solubility, which limits its bioavailability. To address this, solid dispersions of APG were prepared using ball milling with sodium alginate (SA), Pluronic^® F-68 (PLU68), Pluronic^® F-127 (PLU127), PVP K30, and PVP VA64 as polymeric excipients. These dispersions were screened for apparent solubility in water and buffers with pH 1.2, 5.5, and 6.8. Based on improved solubility after 60 min, APG–PLU68 and APG–PLU127 dispersions were selected for further study. DSC and FT-IR analysis confirmed molecular interactions between APG and the polymer matrices, contributing to enhanced solubility and dissolution rates. Dissolution rate studies showed that APG–PLU127 achieved 100% solubility at pH 6.8, suggesting its potential use in environments such as the small intestine. Additionally, APG–PLU127 exhibited 84.3% solubility at pH 1.2, indicating potential for solid oral dosage forms, where APG could be absorbed in the acidic conditions of the stomach. The stability study confirmed that storage for one year under ambient conditions does not cause chemical degradation but affects the physical state and solubility of the dispersion. Antioxidant activity was assessed using the ABTS assay. Freshly obtained APG–PLU127 showed 68.1% ± 1.94% activity, whereas APG–PLU127 stored for one year under ambient conditions exhibited 66.2% ± 1.62% (significant difference, p < 0.05). The difference was related to a slight decrease in the solubility of APG in the solid dispersion (T0 = 252 ± 1 μg∙mL⁻¹, T1 = 246 ± 1 μg∙mL⁻¹). The findings demonstrate the superior performance of PLU127 as a carrier for enhancing the solubility, release, and antioxidant activity of APG. Full article

(This article belongs to the Special Issue Recent Research in Supramolecular Chemistry)

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25 pages, 5755 KiB

Open AccessArticle

Combined Transcriptomics and Metabolomics Uncover the Potential Mechanism of Plant Growth-Promoting Rhizobacteria on the Regrowth of Leymus chinensis After Mowing

by Ting Yuan, Weibo Ren, Jiatao Zhang, Mohsin Mahmood, Ellen L. Fry and Ru Meng

Int. J. Mol. Sci. 2025, 26(2), 565; https://doi.org/10.3390/ijms26020565 - 10 Jan 2025

Abstract

Mowing significantly influences nutrient cycling and stimulates metabolic adjustments in plants to promote regrowth. Plant growth-promoting rhizobacteria (PGPR) are crucial for enhancing plant growth, nutrient absorption, and stress resilience; however, whether inoculation with PGPR after mowing can enhance plant regrowth capacity further, as [...] Read more.

Mowing significantly influences nutrient cycling and stimulates metabolic adjustments in plants to promote regrowth. Plant growth-promoting rhizobacteria (PGPR) are crucial for enhancing plant growth, nutrient absorption, and stress resilience; however, whether inoculation with PGPR after mowing can enhance plant regrowth capacity further, as well as its specific regulatory mechanisms, remains unexplored. In this study, PGPR Pantoea eucalyptus (B13) was inoculated into mowed Leymus chinensis to evaluate its effects on phenotypic traits, root nutrient contents, and hormone levels during the regrowth process and to further explore its role in the regrowth of L. chinensis after mowing. The results showed that after mowing, root nutrient and sugar contents decreased significantly, while the signal pathways related to stress hormones were activated. This indicates that after mowing, root resources tend to sacrifice a part of growth and prioritize defense. After mowing, B13 inoculation regulated the plant’s internal hormone balance by reducing the levels and signal of JA, SA, and ABA and upregulated the signal transduction of growth hormones in the root, thus optimizing growth and defense in a mowing environment. Transcriptomic and metabolomic analyses indicated that B13 promoted nutrient uptake and transport in L. chinensis root, maintained hormone homeostasis, enhanced metabolic pathways related to carbohydrates, energy, and amino acid metabolism to cope with mowing stress, and promoted root growth and regeneration of shoot. This study reveals the regenerative strategy regulated by B13 in perennial forage grasses, helping optimize resource utilization, increase yield, and enhance grassland stability and resilience. Full article

(This article belongs to the Special Issue Molecular Insights into Microbial Dynamics in Agroforestry for Resilience and Climate Adaptation)

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21 pages, 3729 KiB

Open AccessArticle

Submicron Dispersions of Phytosterols Reverse Liver Steatosis with Higher Efficacy than Phytosterol Esters in a Diet Induced-Fatty Liver Murine Model

by Raimundo Gillet, Tomás G. Cerda-Drago, María C. Brañes and Rodrigo Valenzuela

Int. J. Mol. Sci. 2025, 26(2), 564; https://doi.org/10.3390/ijms26020564 - 10 Jan 2025

Abstract

Consumption of phytosterols is a nutritional strategy employed to reduce cholesterol absorption, but recent research shows that their biological activity might go beyond cholesterol reduction for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD), and novel phytosterol formulations, such as submicron dispersions, [...] Read more.

Consumption of phytosterols is a nutritional strategy employed to reduce cholesterol absorption, but recent research shows that their biological activity might go beyond cholesterol reduction for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD), and novel phytosterol formulations, such as submicron dispersions, could improve these effects. We explored the therapeutic activity of phytosterols, either formulated as submicron dispersions of phytosterols (SDPs) or conventional phytosterol esters (PEs), in a mouse model of MAFLD. MAFLD was induced in mice by atherogenic diet (AD) feeding. The reversion of distorted serum and liver parameter values after a period of AD feeding was investigated after supplementation of the AD with SDPs, PEs, or a placebo (PT). Additionally, the metabolic parameters of fatty acid synthesis, fatty acid oxidation, and inflammation were studied to understand the mechanism of action of phytosterols. AD supplementation with SDPs was shown to reduce liver fat, along with showing a significant improvement in liver triglycerides (TGs), free fatty acids (FFAs), and liver cholesterol levels. These results were reinforced by the analyses of the liver steatosis scores, and liver histologies, where SDP intervention showed a consistent improvement. Treatment with PEs showed slighter effects in the same analyses, and no effects were observed with the PT treatment. Additionally, SDP intervention reversed, with a higher efficacy than PEs, the effect of AD on the serum levels of TGs, total- and LDL-cholesterol levels, and glucose levels. And, exceptionally, while SDP improved HDL-cholesterol serum levels, PEs did not show any effect on this parameter. We provide evidence for the therapeutical activity of phytosterols in MAFLD beyond the regulation of cholesterol levels, which is increased when the phytosterols are formulated as submicron dispersions compared to ester formulations. Full article

(This article belongs to the Special Issue Metabolic Dysfunction-Associated Steatotic Liver Disease: From Basic Science to Therapy)

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14 pages, 3388 KiB

Open AccessArticle

Impact of Larval Sertraline Exposure on Alternative Splicing in Neural Tissue of Adult Drosophila melanogaster

by Luis Felipe Santos-Cruz, Myriam Campos-Aguilar, Laura Castañeda-Partida, Santiago Cristobal Sigrist-Flores, María Eugenia Heres-Pulido, Irma Elena Dueñas-García, Elías Piedra-Ibarra, Rafael Jiménez-Flores and Alberto Ponciano-Gómez

Int. J. Mol. Sci. 2025, 26(2), 563; https://doi.org/10.3390/ijms26020563 - 10 Jan 2025

Abstract

Sertraline, a selective serotonin reuptake inhibitor (SSRI), is commonly used to treat various psychiatric disorders such as depression and anxiety due to its ability to increase serotonin availability in the brain. Recent findings suggest that sertraline may also influence the expression of genes [...] Read more.

Sertraline, a selective serotonin reuptake inhibitor (SSRI), is commonly used to treat various psychiatric disorders such as depression and anxiety due to its ability to increase serotonin availability in the brain. Recent findings suggest that sertraline may also influence the expression of genes related to synaptic plasticity and neuronal signaling pathways. Alternative splicing, a process that allows a single gene to produce multiple protein isoforms, plays a crucial role in the regulation of neuronal functions and plasticity. Dysregulation of alternative splicing events has been linked to various neurodevelopmental and neurodegenerative diseases. This study aims to explore the effects of sertraline on alternative splicing events, including exon inclusion, exon exclusion, and mutually exclusive splicing events, in genes associated with neuronal function in Drosophila melanogaster and to use this model to investigate the molecular impacts of SSRIs on gene regulation in the nervous system. RNA sequencing (RNA-seq) was performed on central nervous system samples from Drosophila melanogaster adults exposed to sertraline for 24 h when they were third instar larvae. Alternative splicing events were analyzed to identify changes in exon inclusion and exclusion, as well as intron retention. Sertraline treatment significantly altered alternative splicing patterns in key genes related to neuronal stability and function. Specifically, sertraline promoted the inclusion of long Ank2 isoforms, suggesting enhanced axonal stability, and favored long ATPalpha isoforms, which support Na⁺/K⁺ ATPase activity essential for ionic balance and neuronal excitability. Intron retention in the yuri gene suggests that cytoskeletal reorganization could impact neuronal morphology. Additionally, splicing alterations in sxc and Atg18a indicate a potential influence of sertraline on epigenetic regulation and autophagy processes, fundamental aspects for neuronal plasticity and cellular homeostasis. These findings suggest that sertraline influences alternative splicing in the central nervous system of Drosophila melanogaster, potentially contributing to its therapeutic effects by modulating neuronal stability and adaptability. Full article

(This article belongs to the Special Issue Cell Pathways Underlying Neuronal Differentiation)

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16 pages, 5329 KiB

Open AccessArticle

Mitochondrial Genome Characteristics Reveal Evolution of Danxiaorchis yangii and Phylogenetic Relationships

by Xuedie Liu, Huolin Luo, Zhong-Jian Liu and Bo-Yun Yang

Int. J. Mol. Sci. 2025, 26(2), 562; https://doi.org/10.3390/ijms26020562 - 10 Jan 2025

Abstract

Danxiaorchis yangii is a fully mycoheterotrophic orchid that lacks both leaves and roots, belonging to the genus Danxiaorchis in the subtribe Calypsoinae. In this study, we assembled and annotated its mitochondrial genome (397,867 bp, GC content: 42.70%), identifying 55 genes, including 37 protein-coding [...] Read more.

Danxiaorchis yangii is a fully mycoheterotrophic orchid that lacks both leaves and roots, belonging to the genus Danxiaorchis in the subtribe Calypsoinae. In this study, we assembled and annotated its mitochondrial genome (397,867 bp, GC content: 42.70%), identifying 55 genes, including 37 protein-coding genes (PCGs), 16 tRNAs, and 2 rRNAs, and conducted analyses of relative synonymous codon usage (RSCU), repeat sequences, horizontal gene transfers (HGTs), and gene selective pressure (dN/dS). Additionally, we sequenced and assembled its plastome, which has a reduced size of 110,364 bp (GC content: 36.60%), comprising 48 PCGs, 26 tRNAs, and 4 rRNAs. We identified 64 potential chloroplast DNA fragments transferred to the mitogenome. Phylogenomic analysis focusing on 33 mitogenomes, with Vitis vinifera as the outgroup, indicated that D. yangii is grouped as follows: D. yangii + ((Dendrobium wilsonii + Dendrobium wilsonii henanense) + Phalaenopsis aphrodite). Phylogenetic analysis based on 83 plastid PCGs from these species showed that D. yangii is grouped as follows: (D. yangii + Pha. aphrodite) + (Den. wilsonii + Den. henanense). Gene selective pressure analysis revealed that most mitochondrial and plastid genes in D. yangii are under purifying selection, ensuring functional stability, and certain genes may have undergone positive selection or adaptive evolution, reflecting the species’ adaptation to specific ecological environments. Our study provides valuable data on the plastomes and mitogenomes of D. yangii and lays the groundwork for future research on genetic variation, evolutionary relationships, and the breeding of orchids. Full article

(This article belongs to the Special Issue Advances in Plant Genomics and Genetics: 2nd Edition)

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21 pages, 8006 KiB

Open AccessArticle

Insights into the Corrosion Inhibition Performance of Plant Extracts of Different Genera in the Asteraceae Family for Q235 Steel in H₂SO₄ Medium

by Tian-Shu Chu, Wen-Jie Mai, Hui-Zhen Li, Bo-Xin Wei, Yu-Qing Xu and Bo-Kai Liao

Int. J. Mol. Sci. 2025, 26(2), 561; https://doi.org/10.3390/ijms26020561 - 10 Jan 2025

Abstract

Nowadays, the development of plant extracts as corrosion inhibitors to protect metals from corrosion is a popular research direction. However, given the vast diversity of plant species in nature, it is imperative to explore effective methods to improve screening efficiency in order to [...] Read more.

Nowadays, the development of plant extracts as corrosion inhibitors to protect metals from corrosion is a popular research direction. However, given the vast diversity of plant species in nature, it is imperative to explore effective methods to improve screening efficiency in order to quickly identify the corrosion inhibition potential of plants. In this work, a new strategy for developing plant-extracted eco-friendly corrosion inhibitors based on the family and genus of plants is proposed. Three plants of different genera in the Asteraceae family, including Artemisia argyi extract (AAE), Chrysanthemum indicum extract (CIE), and Centipeda minima extract (CME), were selected and successfully prepared as novel corrosion inhibitors for Q235 steel in a sulfuric acid solution. The corrosion inhibition behavior and corresponding mechanism were systematically investigated by using some electrochemical tests (open circuit potential, potentiodynamic polarization, and electrochemical impedance spectroscopy) and surface characterizations (Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy). The experimental results illustrated that the main components of the three extracts were similar and that when combined with KI as mixed-type corrosion inhibitors, they could dramatically slow down the metal corrosion rate. The maximum value of the corrosion inhibition efficiency reached 96.29%, 96.50%, and 97.52%, respectively, at 200 mg/L and could increase to 98.64%, 97.65%, and 99.06%, respectively, with a prolonged immersion time. A synergistic effect exists between the three plant extracts and KI, leading to the firm adsorption of the three plant extract molecules onto a Q235 steel surface, thereby forming a robust protective film. This work demonstrated that plants of different genera in the Asteraceae family possessed similar corrosion inhibition capabilities, providing a novel way to select potential corrosion inhibitors from numerous plants based on family and genus classification. Full article

(This article belongs to the Section Physical Chemistry and Chemical Physics)

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18 pages, 871 KiB

Open AccessReview

The Role of Long Non-Coding RNA in Rheumatoid Arthritis

by Kajetan Kiełbowski, Maciej Ćmil, Wojciech Jerzy Biniek, Estera Bakinowska and Andrzej Pawlik

Int. J. Mol. Sci. 2025, 26(2), 560; https://doi.org/10.3390/ijms26020560 - 10 Jan 2025

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint damage and physical dysfunction. The pathogenesis of RA is highly complex, involving genetic, epigenetic, immune, and metabolic factors, among others. Over the years, research has highlighted the importance of non-coding RNAs [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint damage and physical dysfunction. The pathogenesis of RA is highly complex, involving genetic, epigenetic, immune, and metabolic factors, among others. Over the years, research has highlighted the importance of non-coding RNAs (ncRNAs) in regulating gene expression. Given their dysregulation in numerous conditions, ncRNAs are thought to play a role in pathological processes. In RA, aberrant levels of circulating long ncRNAs (lncRNAs) are commonly observed in peripheral blood, along with their dysregulated expression in peripheral blood mononuclear cells and synovial tissue. This review discusses the involvement of lncRNAs in inflammation and the aggressive characteristics of fibroblast-like synoviocytes, a key cellular population driving RA progression. Full article

(This article belongs to the Special Issue RNA Biology and Regulation)

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16 pages, 2936 KiB

Open AccessArticle

The Modulatory Effect of Selol (Se IV) on Pro-Inflammatory Pathways in RAW 264.7 Macrophages

by Gwan Yong Lim, Emilia Grosicka-Maciąg, Maria Szumiło, Daniel Graska, Iwonna Rahden-Staroń and Dagmara Kurpios-Piec

Int. J. Mol. Sci. 2025, 26(2), 559; https://doi.org/10.3390/ijms26020559 - 10 Jan 2025

Abstract

Selol is a semi-synthetic mixture of selenized triglycerides. The results of biological studies revealed that Selol exhibits several anticancer effects. However, studies on its potential anti-inflammatory activity are scarce, and underlying signaling pathways are unknown. The aim of our study was to investigate [...] Read more.

Selol is a semi-synthetic mixture of selenized triglycerides. The results of biological studies revealed that Selol exhibits several anticancer effects. However, studies on its potential anti-inflammatory activity are scarce, and underlying signaling pathways are unknown. The aim of our study was to investigate the ability of Selol to exert anti-inflammatory effects in a RAW 264.7 cell line model of LPS (lipopolysaccharide)-induced inflammation. Cells were treated either with Selol 5% (4 or 8 µg Se/mL) or LPS (1 µg/mL) alone or with Selol given concomitantly with LPS. The parameters studied were reactive oxygen species (ROS) production, glutathione and thioredoxin (Txn) levels, and nuclear factor kappa B (NF-κB) activation, as well as nitric oxide/prostaglandin E₂ (NO/PGE₂) production. The presented research also included the effect of Selol and/or LPS on glucose (Glc) catabolism; for this purpose, the levels of key enzymes of the glycolysis pathway were determined. The results showed that Selol exhibited pro-oxidative properties. It induced ROS generation with a significant increase in the level of Txn; however, it did not affect the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. Selol moderately activated NF-κB but failed to affect NO/PGE₂ production. The effect of Selol on glucose catabolism was not significant. However, the simultaneous administration of Selol with LPS exerted a statistically significant anti-inflammatory effect via a decrease in the production of pro-inflammatory mediators and NF-κB activation. Our study also showed that as a result of LPS action in cells, the anaerobic glycolysis activity was increased, and incubation with Selol caused a partial reprogramming of Glc metabolism towards aerobic metabolism. This may indicate different pharmacological and molecular effects of Selol action in physiological and pathological conditions. Full article

(This article belongs to the Special Issue The Role of Oxidative Stress in Human and Animal Health)

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8 pages, 1383 KiB

Open AccessArticle

Cross-Species Epitope Sequence Analysis for Discovery of Existing Antibodies Useful for Phospho-Specific Protein Detection in Model Species

by Yanhui Hu, Chenxi Gao, William McKenna, Baolong Xia, Majd Ariss, Stephanie E. Mohr and Norbert Perrimon

Int. J. Mol. Sci. 2025, 26(2), 558; https://doi.org/10.3390/ijms26020558 - 10 Jan 2025

Abstract

Signaling pathways play key roles in many important biological processes, such as cell division, differentiation, and migration. Phosphorylation site-specific antibodies specifically target proteins phosphorylated on a given tyrosine, threonine, or serine residue. The use of phospho-specific antibodies facilitates the analysis of signaling pathway [...] Read more.

Signaling pathways play key roles in many important biological processes, such as cell division, differentiation, and migration. Phosphorylation site-specific antibodies specifically target proteins phosphorylated on a given tyrosine, threonine, or serine residue. The use of phospho-specific antibodies facilitates the analysis of signaling pathway regulation and activity. Given the usefulness of phospho-specific antibodies, a number of collections of these antibodies have been generated, typically for the detection of phosphorylated mammalian proteins. Anecdotal evidence shows that some of these are also useful for the detection of phosphorylated forms of orthologous proteins in model organisms. We propose that anti-phospho-mammalian protein antibody collections comprise an untapped resource for research in other species. To systematically analyze the potential utility of anti-phospho-mammalian protein antibodies in other species, we developed the Cross-species Epitope Sequence Analysis software tool (CESA). CESA identifies and aligns orthologous proteins in model species and then analyzes the conservation of antibody target sites. We used CESA to predict what phospho-specific antibodies in a collection from Cell Signaling Technology (CST) might be useful for studies in Drosophila melanogaster and other species. CESA predicts that more than 232 sites on 116 Drosophila proteins can potentially be targeted by the antibodies initially developed at CST to detect human, mouse, or rat phosphoproteins. Full article

(This article belongs to the Special Issue Drosophila: A Model System for Human Disease Research)

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30 pages, 1774 KiB

Open AccessReview

Omics Approaches to Study Perilipins and Their Significant Biological Role in Cardiometabolic Disorders

by Erica Gianazza, Giulia G. Papaianni, Lisa Brocca, Cristina Banfi and Alice Mallia

Int. J. Mol. Sci. 2025, 26(2), 557; https://doi.org/10.3390/ijms26020557 - 10 Jan 2025

Abstract

Lipid droplets (LDs), highly dynamic cellular organelles specialized in lipid storage and maintenance of lipid homeostasis, contain several proteins on their surface, among which the perilipin (Plin) family stands out as the most abundant group of LD-binding proteins. They play a pivotal role [...] Read more.

Lipid droplets (LDs), highly dynamic cellular organelles specialized in lipid storage and maintenance of lipid homeostasis, contain several proteins on their surface, among which the perilipin (Plin) family stands out as the most abundant group of LD-binding proteins. They play a pivotal role in influencing the behavior and functionality of LDs, regulating lipase activity, and preserving a balance between lipid synthesis and degradation, which is crucial in the development of obesity and abnormal accumulation of fat in non-adipose tissues, causing negative adverse biological effects, such as insulin resistance, mitochondrial dysfunction, and inflammation. The expression levels of Plins are often associated with various diseases, such as hepatic steatosis and atherosclerotic plaque formation. Thus, it becomes of interest to investigate the Plin roles by using appropriate “omics” approaches that may provide additional insight into the mechanisms through which these proteins contribute to cellular and tissue homeostasis. This review is intended to give an overview of the most significant omics studies focused on the characterization of Plin proteins and the identification of their potential targets involved in the development and progression of cardiovascular and cardiometabolic complications, as well as their interactors that could be useful for more efficient therapeutic and preventive approaches for patients. Full article

(This article belongs to the Special Issue Proteomics: An Invaluable Tool to Gain Information on Biological Systems and Their Disease Alterations)

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16 pages, 3118 KiB

Open AccessArticle

Comparative Pharmacokinetic Analysis of Aflibercept and Brolucizumab in Human Aqueous Humor Using Nano-Surface and Molecular-Orientation Limited Proteolysis

by Kosuke Nagaoka, Natsuka Kimura, Satoru Inoda, Takuya Takayama, Yusuke Arai, Yasuo Yanagi, Takashi Shimada, Ryozo Nagai, Hidenori Takahashi and Kenichi Aizawa

Int. J. Mol. Sci. 2025, 26(2), 556; https://doi.org/10.3390/ijms26020556 - 10 Jan 2025

Abstract

Aflibercept and brolucizumab, two anti-VEGF agents used as intravitreal injections in ophthalmology, differ significantly in molecular weight (aflibercept—115 kDa and brolucizumab—26 kDa). Using aqueous humor samples collected after drug administration, we measured and performed a comparative analysis of pharmacokinetics and half-lives of these [...] Read more.

Aflibercept and brolucizumab, two anti-VEGF agents used as intravitreal injections in ophthalmology, differ significantly in molecular weight (aflibercept—115 kDa and brolucizumab—26 kDa). Using aqueous humor samples collected after drug administration, we measured and performed a comparative analysis of pharmacokinetics and half-lives of these drugs in the human eye. Since the quantification of monoclonal antibodies (mAbs) using antigen–antibody reactions, such as ELISA, is influenced by endogenous ligands or anti-drug antibodies, we employed nano-surface and molecular-orientation limited proteolysis (nSMOL), combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS), for accurate measurements. Aqueous humor samples were collected from 59 eyes of 59 patients treated with aflibercept and 52 eyes of 52 patients treated with brolucizumab. Samples were obtained with a median post-injection period of 30 (range, 2–49) days for aflibercept and 28 (range, 4–60) days for brolucizumab. A population pharmacokinetic (PPK) analysis revealed that the half-life of aflibercept in human aqueous humor was significantly shorter than that of brolucizumab, 2.88 days versus 9.00 days, respectively (p = 1.16 × 10⁻⁷). Using the same mass spectrometry conditions, we calculated the half-lives of the two drugs. These results may be useful for optimizing the efficacy of these drugs in clinical practice. Full article

(This article belongs to the Special Issue Molecular Application of Mass Spectrometry and Chromatography in Biomedicine)

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15 pages, 599 KiB

Open AccessReview

Jun, an Oncological Foe or Friend?

by Zuhayr Jafri, Yue Li, Jingwen Zhang, Connor H. O’Meara and Levon M. Khachigian

Int. J. Mol. Sci. 2025, 26(2), 555; https://doi.org/10.3390/ijms26020555 - 10 Jan 2025

Abstract

Jun/JUN is a basic leucine zipper (bZIP) protein and a prototypic member of the activator protein-1 (AP-1) family of transcription factors that can act as homo- or heterodimers, interact with DNA elements and co-factors, and regulate gene transcription. Jun is expressed by both [...] Read more.

Jun/JUN is a basic leucine zipper (bZIP) protein and a prototypic member of the activator protein-1 (AP-1) family of transcription factors that can act as homo- or heterodimers, interact with DNA elements and co-factors, and regulate gene transcription. Jun is expressed by both immune and inflammatory cells. Jun is traditionally seen as an oncoprotein that regulates processes involved in transformation and oncogenesis in human tumours. This article examines the traditional view that Jun plays a permissive role in cancer development and progression, whilst exploring emerging evidence supporting Jun’s potential to prevent immune cell exhaustion and promote anti-tumour efficacy. Full article

(This article belongs to the Section Molecular Oncology)

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25 pages, 406 KiB

Open AccessReview

Matters of the Heart: Cardiotoxicity Related to Target Therapy in Oncogene-Addicted Non-Small Cell Lung Cancer

by Sara Torresan, Martina Bortolot, Elisa De Carlo, Elisa Bertoli, Brigida Stanzione, Alessandro Del Conte, Michele Spina and Alessandra Bearz

Int. J. Mol. Sci. 2025, 26(2), 554; https://doi.org/10.3390/ijms26020554 - 10 Jan 2025

Abstract

The treatment of Non Small Cell Lung Cancer (NSCLC) has been revolutionised by the introduction of targeted therapies. With the improvement of response and frequently of overall survival, however, a whole new set of adverse events emerged. In fact, due to the peculiar [...] Read more.

The treatment of Non Small Cell Lung Cancer (NSCLC) has been revolutionised by the introduction of targeted therapies. With the improvement of response and frequently of overall survival, however, a whole new set of adverse events emerged. In fact, due to the peculiar mechanism of action of each one of the tyrosine kinase inhibitors and other targeted therapies, every drug has its own specific safety profile. In addition, this safety profile could not fully emerge from clinical trials data, as patients in clinical practice usually have more comorbidities and frailties. Cardiotoxicity is a well-known and established adverse event of anti-cancer therapies. However, only recently it has become a central topic for targeted therapies in NSCLC, due to the unknown real range and frequency. Management of this toxicity begins with prevention, and must balance the need of continuing an effective anticancer treatment versus low risk of even fatal events and the preservation of long-term quality of life. The aim of this review is to summarise the current knowledge focusing on currently used targeted therapies in NSCLC. Full article

(This article belongs to the Section Molecular Oncology)

18 pages, 4585 KiB

Open AccessArticle

Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment

by Pavel E. Volynsky, Anatoly S. Urban, Konstantin V. Pavlov, Yaroslav V. Bershatsky, Olga V. Bocharova, Anastasia K. Kryuchkova, Veronika V. Zlobina, Alina A. Gavrilenkova, Sofya M. Dolotova, Anna V. Kamynina, Olga T. Zangieva, Amir Taldaev, Oleg V. Batishchev, Ivan S. Okhrimenko, Tatiana V. Rakitina, Roman G. Efremov and Eduard V. Bocharov

Int. J. Mol. Sci. 2025, 26(2), 553; https://doi.org/10.3390/ijms26020553 - 10 Jan 2025

Abstract

Alzheimer’s disease (AD) pathogenesis is correlated with the membrane content of various lipid species, including cholesterol, whose interactions with amyloid precursor protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are products of APP cleavage by secretases, which differ depending on the [...] Read more.

Alzheimer’s disease (AD) pathogenesis is correlated with the membrane content of various lipid species, including cholesterol, whose interactions with amyloid precursor protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are products of APP cleavage by secretases, which differ depending on the APP and secretase location relative to ordered or disordered membrane microdomains. We used high-resolution NMR to probe the interactions of the cholesterol analog with APP transmembrane domain in two membrane-mimicking systems resembling ordered or perturbed lipid environments (bicelles/micelles). In bicelles, spin-labeled sterol interacted with the peptide near the amphiphilic juxtamembrane region and N-terminal part of APP transmembrane helix, as described earlier for cholesterol. Upon transition into micellar environment, another interaction site appeared where sterol polar head was buried in the hydrophobic core near the hinge region. In MD simulations, sterol moved between three interaction sites, sliding along the polar groove formed by glycine residues composing the dimerization interfaces and flexible hinge of the APP transmembrane domain. Because the lipid environment modulates interactions, the role of lipids in the AD pathogenesis is defined by the state of the entire lipid subsystem rather than the effects of individual lipid species. Cholesterol can interplay with other lipids (polyunsaturated, gangliosides, etc.), determining the outcome of amyloid-β production cascades. Full article

(This article belongs to the Special Issue Molecular Insight into Alzheimer’s Disease)

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18 pages, 1314 KiB

Open AccessReview

An Alternative Mode of GPCR Transactivation: Activation of GPCRs by Adhesion GPCRs

by Hsi-Hsien Lin

Int. J. Mol. Sci. 2025, 26(2), 552; https://doi.org/10.3390/ijms26020552 - 10 Jan 2025

Abstract

G protein-coupled receptors (GPCRs), critical for cellular communication and signaling, represent the largest cell surface protein family and play important roles in numerous pathophysiological processes. Consequently, GPCRs have become a primary focus in drug discovery efforts. Beyond their traditional G protein-dependent signaling pathways, [...] Read more.

G protein-coupled receptors (GPCRs), critical for cellular communication and signaling, represent the largest cell surface protein family and play important roles in numerous pathophysiological processes. Consequently, GPCRs have become a primary focus in drug discovery efforts. Beyond their traditional G protein-dependent signaling pathways, GPCRs are also capable of activating alternative signaling mechanisms, including G protein-independent signaling, biased signaling, and signaling crosstalk. A particularly novel signaling mode employed by these receptors is GPCR transactivation, which enables cross-communication between GPCRs and other receptor types. Intriguingly, GPCR transactivation by distinct GPCRs has also been identified. In this review, I provide an overview of the known GPCR transactivation mechanisms and explore recently uncovered GPCR transactivation mediated by adhesion-class GPCRs (aGPCRs). These aGPCR-GPCR transactivation processes regulate unique cell type-specific functions, offering an exciting opportunity to develop therapies that precisely modulate specific GPCR-mediated biological effects. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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