Current Issues in Molecular Biology

32 pages, 945 KB

Open AccessReview

Advances in Therapies for Mucopolysaccharidoses

by Joanna Szmydtka, Maja Ziemian, Rafał Banaszak, Martyna Ciesielska, Jagoda Ładosz, Urszula Maliszewska, Adrian Nowakowski, Martyna Paszek, Gabriela Suproń, Zuzanna Świętochowska, Agata Tkaczuk, Szymon Wojciechowski and Grzegorz Węgrzyn

Curr. Issues Mol. Biol. 2026, 48(7), 671; https://doi.org/10.3390/cimb48070671 (registering DOI) - 29 Jun 2026

Abstract

Mucopolysaccharidoses (MPS) are severe, inherited metabolic diseases, classified among lysosomal storage diseases (LSDs). The presence of pathological variants of genes coding for enzymes involved in the degradation of glycosaminoglycans (GAGs) is a primary cause of each MPS type, and accumulation of these compounds [...] Read more.

Mucopolysaccharidoses (MPS) are severe, inherited metabolic diseases, classified among lysosomal storage diseases (LSDs). The presence of pathological variants of genes coding for enzymes involved in the degradation of glycosaminoglycans (GAGs) is a primary cause of each MPS type, and accumulation of these compounds is a characteristic feature of MPS. Depending on the kind of defective enzyme and the type of stored GAG(s), 12 classical types are distinguished, and a few other related diseases, whose classification is unclear. Although there is no fully effective cure for MPS, several kinds of therapeutic approaches have been proposed to treat these diseases, and some of them have been introduced into clinical practice. In this review article, we present and discuss very recent advances in developing various therapies for MPS, also indicating problems and limitations. This paper focuses on enzyme replacement therapy (ERT), cell- and gene-based therapies (including hematopoietic stem cell transplantation and gene therapy), inhibition of GAG synthesis, and some other newly developed therapeutic approaches. Perspectives on MPS therapies are also discussed. Full article

(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)

28 pages, 5118 KB

Open AccessArticle

Peel of Pomegranate Fruit (Punica granatum) Improves Glucose Homeostasis in Obese Mice: An Integrated In Vitro, In Vivo, and In Silico Molecular Docking Study

by Prawej Ansari, Alexa D. Reberio, Asif Ali, Md Hamza Naquib, Sandeep Kumar, Dhivya C, Md Abeduzzaman Anon, Hajera Khatun, Md Ferdos Ahamed, Peter R. Flatt and Yasser H. A. Abdel-Wahab

Curr. Issues Mol. Biol. 2026, 48(7), 670; https://doi.org/10.3390/cimb48070670 (registering DOI) - 29 Jun 2026

Abstract

Pomegranate (Punica granatum), a shrub belonging to the Lythraceae family, has long been recognized for its diverse pharmacological benefits, including potential roles in managing inflammation and diabetes. The present study explored the insulin-secretory and β-cell proliferative properties of the ethanol extract of [...] Read more.

Pomegranate (Punica granatum), a shrub belonging to the Lythraceae family, has long been recognized for its diverse pharmacological benefits, including potential roles in managing inflammation and diabetes. The present study explored the insulin-secretory and β-cell proliferative properties of the ethanol extract of P. granatum fruit peel (EEPG) and assessed its influence on glucose regulation in high-fat-fed diet-induced obese mice (HFDi-OM) through in vivo and in silico studies. In vitro, EEPG was found to activate cAMP-dependent pathways and regulate K_ATP channels, thereby enhancing glucose-stimulated insulin secretion from BRIN-BD11 β-cells, with partial reliance on extracellular calcium. EEPG promoted β-cell proliferation, as indicated by an increase in Ki-67 positive cells, and displayed inhibitory effects on glucose diffusion and starch hydrolysis, suggesting a capacity to delay carbohydrate digestion and absorption. Furthermore, EEPG demonstrated antioxidant activity by neutralizing free radicals. In an acute test, EEPG (at doses of 150 and 250 mg/5 mL/kg) improved oral glucose tolerance and elevated plasma insulin levels. Long-term oral treatment for 21 days to HFDi-OM led to a significant reduction in fasting blood glucose, body weight, and food and fluid intake. It also enhanced gastrointestinal motility and improved lipid profiles by increasing HDL and lowering total cholesterol, LDL, and triglycerides. The therapeutic properties of EEPG are likely attributed to its rich bioactive components, including flavonoids (quercetin, kaempferol, catechin, and epicatechin) and phenolic acids (ellagic acid), which exhibited strong multi-target binding affinities in in silico molecular docking studies toward SUR1, PDE4, PI3K, and α-amylase, thereby supporting enhanced insulin secretion, β-cell function and glucose homeostasis. Full article

(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)

22 pages, 1311 KB

Open AccessArticle

α-Iso-Cubebene Alleviates AMD-like Retinal Injury Through Modulation of Oxidative Stress and Inflammatory Response

by Ye Ryeong Kim, Ayun Seol, Su Jin Lee, Ji Eun Kim, Hee Jin Song, Su Jeong Lim, Su Ha Wang, Ye Eun Ryu, Young Whan Choi, Sun Il Choi and Dae Youn Hwang

Curr. Issues Mol. Biol. 2026, 48(7), 669; https://doi.org/10.3390/cimb48070669 (registering DOI) - 29 Jun 2026

Abstract

Although oxidative stress plays a critical role in age-related macular degeneration (AMD) progression, natural product–derived single compounds against AMD remain largely unexplored. We investigated the protective effects and underlying mechanism of α-iso-cubebene against AMD-like retinal injury. Alterations in key phenotypes for AMD were [...] Read more.

Although oxidative stress plays a critical role in age-related macular degeneration (AMD) progression, natural product–derived single compounds against AMD remain largely unexplored. We investigated the protective effects and underlying mechanism of α-iso-cubebene against AMD-like retinal injury. Alterations in key phenotypes for AMD were analyzed in AMD-mimicking models using ARPE-19 cells co-treated with blue light (BL) and N-retinylidene-N-retinylethanolamine (A2E), as well as BL-exposed BALB/c mice. In BL+A2E-treated ARPE-19 cells, α-iso-cubebene reduced intracellular reactive oxygen species (ROS) and nitric oxide (NO) production and restored superoxide dismutase (SOD) activity and nuclear factor erythroid 2–related factor 2 (Nrf2), suggesting enhancement of the antioxidant defense system. Furthermore, α-iso-cubebene improved cell viability, reduced apoptotic cell populations, and regulated apoptosis-related signaling pathways under oxidative stress conditions. It also attenuated cyclooxygenase-2 (COX-2)-mediated inducible nitric oxide synthase (iNOS) signaling and was associated with reduced inflammasome-related signaling. Importantly, these protective effects were consistently observed regarding the protection of histopathological structure and normalization of inflammatory cytokines in the retina of BL-exposed BALB/c mice. Collectively, our results demonstrate that α-iso-cubebene, as a potential therapeutic candidate, alleviates AMD-like retinal injury and was associated with enhanced antioxidant responses and reduced inflammatory and apoptotic signaling markers. Full article

(This article belongs to the Special Issue Therapeutic Effects of Natural Bioactive Compounds in the Management of Human Diseases: 2nd Edition)

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14 pages, 3661 KB

Open AccessArticle

In Silico Identification of Plant-Derived GPX4 Inhibitors as Potential Ferroptosis Inducers: Molecular Docking, Dynamics, and ADMET Studies

by Şerife Efsun Antmen, Hasan Öz, Cem Yalaza and Necmiye Canacankatan

Curr. Issues Mol. Biol. 2026, 48(7), 668; https://doi.org/10.3390/cimb48070668 (registering DOI) - 29 Jun 2026

Abstract

This study aims identify plant-derived compounds that can inhibit glutathione peroxidase 4 (GPX4) enzyme and evaluate them through molecular docking, dynamics simulations, and ADMET analyses. The 3D structure of the GPX4 protein (PDB ID: 2OBI) was obtained from the Protein Data Bank. The [...] Read more.

This study aims identify plant-derived compounds that can inhibit glutathione peroxidase 4 (GPX4) enzyme and evaluate them through molecular docking, dynamics simulations, and ADMET analyses. The 3D structure of the GPX4 protein (PDB ID: 2OBI) was obtained from the Protein Data Bank. The plant-derived ligand library was compiled from the PubChem database and screened for compliance with Lipinski’s rules using ADMETLAB 2.0. Molecular docking simulations were performed using Autodock Vina. Molecular dynamics simulations of 100 nanoseconds were performed for the selected ligand–protein complexes using AMBER Tools and OpenMM software. The ADMET properties of the ligands were evaluated using the pKCSM web server. Compared to the reference inhibitor RSL3 (−7.2 kcal/mol), five plant compounds showed stronger binding affinity: withaferin A (−8.0 kcal/mol), mahanine (−7.9 kcal/mol), pseudobufarenogin (−7.8 kcal/mol), cucurbitacin I (−7.6 kcal/mol), and liquiritin (−7.5 kcal/mol). Molecular dynamics simulations showed that the complexes of withaferin A, mahanine, and liquiritin exhibited superior structural stability. ADMET analysis revealed that the compounds generally possess acceptable pharmacokinetic profiles but require some bioavailability optimization. The identified plant-derived compounds can be considered as potential therapeutic agents in cancer treatment by inducing ferroptosis via GPX4 inhibition. These findings provide an important basis for natural product-derived drug discovery studies. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

24 pages, 108617 KB

Open AccessArticle

αB-Crystallin Protects Against Cisplatin-Induced Nephrotoxicity by Modulating Apoptosis In Vivo and In Vitro

by Sylia Ardache, Shu Tang and Endong Bao

Curr. Issues Mol. Biol. 2026, 48(7), 667; https://doi.org/10.3390/cimb48070667 (registering DOI) - 29 Jun 2026

Abstract

Cisplatin (CP) chemotherapy is limited by nephrotoxicity, primarily involving tubular epithelial cell apoptosis. αB-crystallin (CryAB) is a small heat shock protein that plays a cytoprotective role in stressed kidneys but can also promote tumor progression. Its precise role and molecular mechanisms in CP-induced [...] Read more.

Cisplatin (CP) chemotherapy is limited by nephrotoxicity, primarily involving tubular epithelial cell apoptosis. αB-crystallin (CryAB) is a small heat shock protein that plays a cytoprotective role in stressed kidneys but can also promote tumor progression. Its precise role and molecular mechanisms in CP-induced kidney injury remain largely unclear. This study highlighted the function of CryAB and its regulatory pathways in CP nephrotoxicity by employing in vitro models of rat renal tubular epithelial cells (NRK-52E) with CryAB gene knockdown/overexpression, and in vivo models of CryAB knockout/wild-type mice, followed by CP treatment. Apoptosis and key signaling pathways (NF-κB, MAPK, AKT) were evaluated in this study. The results indicated that CP treatment (20 µM) significantly upregulated CryAB expression in renal cells (p < 0.01) and triggered both apoptosis and MAPK activation. CryAB deficiency sensitized cells and mice to CP, exacerbating renal dysfunction, tubular injury, and apoptosis, as evidenced by increased Bax, cyt c release, and caspase-3 cleavage. Conversely, CryAB overexpression attenuated these effects. Furthermore, our findings suggest that the lack of CryAB favors the cytoplasmic retention of NF-κB, and that CryAB status can influence MAPK signaling, pointing to a potential regulatory loop. Additionally, CP-induced AKT phosphorylation was diminished in CryAB-deficient models. Therefore, CryAB may exert a cytoprotective role in CP nephrotoxicity, potentially mitigating tubular apoptosis by modulating the mitochondrial apoptotic pathway, supporting NF-κB-mediated survival signaling, and cross-talking with MAPK and AKT pathways. Our findings suggest that CryAB serves as an important regulator of renal cell fate and a potential therapeutic target for mitigating CP-induced kidney injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Kidney Diseases)

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17 pages, 6320 KB

Open AccessCommunication

Optimization of the Chemical Monoubiquitination System for Low-Solubility Protein: Achieving Balance Between Specificity and Yield

by Qingyu Cao, Mengyuan Zhang, Dan Wang, Kaixuan He, Yuanyuan Mei and Ning Ning Wang

Curr. Issues Mol. Biol. 2026, 48(7), 666; https://doi.org/10.3390/cimb48070666 (registering DOI) - 29 Jun 2026

Abstract

Monoubiquitination is a significant post-translational modification that plays a pivotal role in various biological processes. Chemical monoubiquitination holds significant value in investigating the functional implications of site-specific ubiquitination on target proteins. Despite all progress made in this area, conventional enzymatic methods so far [...] Read more.

Monoubiquitination is a significant post-translational modification that plays a pivotal role in various biological processes. Chemical monoubiquitination holds significant value in investigating the functional implications of site-specific ubiquitination on target proteins. Despite all progress made in this area, conventional enzymatic methods so far rely largely on high yields of substrate proteins and the removal of tags to prevent non-specific ubiquitin binding, which poses substantial challenges for low-solubility proteins. Here, an optimized chemical monoubiquitination system that facilitates precise, site-specific ubiquitination of low-solubility target protein was developed using SSPP as an example. A cysteine-free GST tag (GST^4CS) was engineered, and a flexible (GGGGS)₃ linker was incorporated to mitigate steric hindrance and enhance the solubility of GST-SSPP fusion protein, resulting in a 2.5-fold increase in purification yield. Successful monoubiquitination of SSPP at the position of lysine 305 was achieved using disulfide-mediated conjugation, as proven via SDS-PAGE and Western blotting. Moreover, the phosphatase assay showed that monoubiquitination at residue C305 of the mutated SSPP significantly decreased its phosphatase activity. This system eliminates tag interference and enhances compatibility with low-solubility targets, providing a robust platform for functional studies of plant protein ubiquitination. Full article

(This article belongs to the Special Issue Autophagy and the Ubiquitin–Proteasome System: Regulators of Protein Homeostasis, Cell Death, and Disease Pathogenesis)

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8 pages, 745 KB

Open AccessArticle

Fully Complementary Interactions Between LmiRNA and mRNA of Human Genes

by Anatoliy Ivashchenko, Anna Pyrkova, Raigul Niyazova and Saltanat Orazova

Curr. Issues Mol. Biol. 2026, 48(7), 665; https://doi.org/10.3390/cimb48070665 (registering DOI) - 29 Jun 2026

Abstract

Londin et al. discovered a novel group of miRNAs, referred to as LmiRNAs, whose properties had been studied little for unknown reasons. In this study, we examine fully complementary interactions between LmiRNAs and mRNAs of human genes. Using the MirTarget program, we identified [...] Read more.

Londin et al. discovered a novel group of miRNAs, referred to as LmiRNAs, whose properties had been studied little for unknown reasons. In this study, we examine fully complementary interactions between LmiRNAs and mRNAs of human genes. Using the MirTarget program, we identified a significant number of target genes showing unique interaction with LmiRNAs. Among the 3707 LmiRNAs, fully complementary binding sites (BSs) were found in the 5′UTR of 75 target genes, with their interactions exhibiting high free energy. Fully complementary LmiRNA binding sites were located within the CDS of 81 target genes, while only seven LmiRNAs were found to bind to the 3′UTR of target genes. The KIFC3, PHF15, RPL15, and SNX11 genes were found to encode both LmiRNA-5p and LmiRNA-3p, which actively bind to their respective mRNAs. While the mRNA of most genes was targeted by only a single LmiRNA, the BMP8B, FGFRL1, and SDC3 genes included mRNAs bound by the specific pair ID00121.5p and ID02992.5p. These results expand our understanding of LmiRNAs and support their potential as diagnostic and therapeutic agents for various diseases. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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16 pages, 10222 KB

Open AccessArticle

Study of the Hypoglycemic Activity of Rhamnolipids Using the In Ovo Model

by Margarida Queirós, Rute S. Moura and Eduardo J. Gudiña

Curr. Issues Mol. Biol. 2026, 48(7), 664; https://doi.org/10.3390/cimb48070664 (registering DOI) - 28 Jun 2026

Abstract

The prevalence of diabetes has increased considerably in recent decades, representing a global health problem. Although several pharmacological approaches for the treatment of diabetes are available, it is pertinent to explore more effective alternatives with reduced adverse effects. In this work, the hypoglycemic [...] Read more.

The prevalence of diabetes has increased considerably in recent decades, representing a global health problem. Although several pharmacological approaches for the treatment of diabetes are available, it is pertinent to explore more effective alternatives with reduced adverse effects. In this work, the hypoglycemic activity of rhamnolipids was studied using the chicken embryo (in ovo) model. The results obtained demonstrated that rhamnolipids produced by Pseudomonas aeruginosa #112 and commercial rhamnolipids (RL-90) significantly reduced blood glucose levels of chicken embryos on embryonic day 11 (from 135 ± 11 mg/dL to 94–107 mg/dL). These values were similar to those achieved with human insulin (104 ± 20 mg/dL) and the rapid-acting human insulin analog FIASP^® (95 ± 18 mg/dL). It was also verified that rhamnolipids did not have a negative effect on chicken embryo development at the concentrations tested. Regarding the molecular mechanisms involved in the decrease in blood glucose levels, for both insulins, a reduction in the expression of genes encoding the glucose transporter 2 (glut2) and the gluconeogenic enzymes phosphoenolpyruvate carboxykinase 2 and fructose-1,6-biphosphatase 1 was observed. However, in the case of rhamnolipids, only a reduction in the expression of glut2 was observed. According to the results obtained, rhamnolipids are potential candidates for further studies on the development of new alternative treatments for diabetes symptoms. Full article

(This article belongs to the Special Issue Molecular Research on Metabolic Disease)

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22 pages, 13494 KB

Open AccessArticle

Centella Asiatica Alleviates Type 2 Diabetes-Related Hepatic Glycolipid Disorders via Regulating UPP1-Mediated Pyrimidine Metabolism

by Yunjiao Shen, Yuanyuan Yao, Zhihui Liu, Yi Li, Shijie Cao and Xinchi Feng

Curr. Issues Mol. Biol. 2026, 48(7), 663; https://doi.org/10.3390/cimb48070663 (registering DOI) - 27 Jun 2026

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by glycolipid dysregulation and hepatic steatosis. Centella asiatica (CA) and its triterpenoid constituents exert metabolic benefits. In addition, previous metabolomics study found that asiatic acid regulated pyrimidine metabolism in obese mice, while the [...] Read more.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by glycolipid dysregulation and hepatic steatosis. Centella asiatica (CA) and its triterpenoid constituents exert metabolic benefits. In addition, previous metabolomics study found that asiatic acid regulated pyrimidine metabolism in obese mice, while the key target and pathway were undefined. This study investigated the regulatory effects of CA and its active constituents on T2DM-related glycolipid disorders, focusing on the pyrimidine metabolism pathway. T2DM mice were established using a high-fat diet combined with streptozotocin (STZ) and treated with Centella asiatica ethanolic extract or asiatic acid (AA), with glibenclamide as a positive control. Then, glycolipid metabolism, hepatic function, pyrimidine metabolites, and related mechanisms were assessed using biochemical assays, LC–MS/MS, cellular experiments, molecular analyses, and molecular docking. CAE and AA significantly reduced FBG (decreased by 51.01% and 53.01%), improved glucose intolerance, corrected dyslipidemia, alleviated hepatic steatosis, and attenuated insulin resistance in T2DM mice. They elevated hepatic uridine, cytidine, and UDP-glucose (UDPG) levels, promoted glycogen synthesis, inhibited uridine phosphorylase 1 (UPP1) activity, upregulated UDPG synthesis genes (PGM1, UGP2), and downregulated lipogenic genes (ACACA, Fasn, SREBP1/2). Molecular docking indicated specific binding of AA and asiaticoside to UPP1. This work distinguishes from our prior research by identifying UPP1 as a functional target and elucidating the detailed molecular mechanism. CA improves T2DM-associated glycolipid disorders and hepatic injury by modulating the pyrimidine metabolism-UDPG-glycogen synthesis pathway and targeting UPP1, highlighting its therapeutic potential for metabolic diseases. Full article

(This article belongs to the Section Molecular Pharmacology)

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17 pages, 1339 KB

Open AccessReview

SnoRNA and SNHG in Bladder Cancer: Molecular Mechanisms and Clinical Significance

by Galiya Gimalova, Irina Gilyazova, Elza Khusnutdinova and Valentin Pavlov

Curr. Issues Mol. Biol. 2026, 48(7), 662; https://doi.org/10.3390/cimb48070662 (registering DOI) - 27 Jun 2026

Abstract

This review summarizes current data on the role of small nucleolar RNAs (snoRNAs) and their host genes (SNHGs) in the development of bladder cancer (BC). It examines snoRNA biogenesis, classical functions (rRNA modification), and non-canonical oncogenic mechanisms, including microRNA sponging, sdRNA [...] Read more.

This review summarizes current data on the role of small nucleolar RNAs (snoRNAs) and their host genes (SNHGs) in the development of bladder cancer (BC). It examines snoRNA biogenesis, classical functions (rRNA modification), and non-canonical oncogenic mechanisms, including microRNA sponging, sdRNA production, and protein interactions (EZH2, DNMT3A, hnRNPK). The factors involved in the deregulation of snoRNA/SNHG expression during tumour transformation are described, such as amplifications, epigenetic changes, and transcriptional control (c-Myc, p53). Studies have shown that in BC, the majority of snoRNAs/SNHGs (SNHG1, SNHG3, SNHG6, SNHG13, SCARNA12) act as oncogenes, activating the PI3K/AKT, Wnt/β-catenin, NF-κB, and c-Myc pathways, thereby enhancing proliferation, EMT, invasion, and metastasis. Suppressor molecules (SNHG2/GAS5) are also discussed. The clinical potential of snoRNAs as prognostic signatures (SNORS), diagnostic biomarkers (SNHG1 in urine), and therapeutic targets (e.g., SNHG3) is analyzed. Thus, snoRNAs and SNHGs represent a promising class of molecules for the development of new diagnostic and therapeutic approaches for BC, although further investigation in prospective studies is required. Full article

(This article belongs to the Special Issue Epigenetics and Chromatin Remodeling in Cancer)

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14 pages, 5428 KB

Open AccessArticle

Nicotinamide Improves Skin Photoaging in Mice by Delaying Cellular Senescence and Suppressing the Senescence-Associated Secretory Phenotype

by Xin-Yue Tang, Ke-Jin Lu, Rui Zhu, Yue Gao, Dong-Yan Wei, Xi-Yu Zhang, Yi-Cheng Ma, Fei-Fei Wang and Cheng-Gang Zou

Curr. Issues Mol. Biol. 2026, 48(7), 661; https://doi.org/10.3390/cimb48070661 (registering DOI) - 27 Jun 2026

Abstract

Nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD⁺), and NAD⁺ are integral to a variety of cellular processes. NAM supplementation has been shown to have benefits for cellular senescence. However, the mechanism by which NAM improves skin photoaging remains [...] Read more.

Nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD⁺), and NAD⁺ are integral to a variety of cellular processes. NAM supplementation has been shown to have benefits for cellular senescence. However, the mechanism by which NAM improves skin photoaging remains unclear. In this study, the multi-omics analysis revealed that insufficient nicotinamide metabolism may be associated with a decrease in NAD⁺ synthesis during skin aging. Importantly, we found that NAM has an ameliorating effect on the skin photoaging in mice. Supplementation with NAM restored the expression of the salvage-pathway enzymes and NAD⁺ consumers. In addition, the supplementation with NAM was shown to restore the expression of skin barrier-related proteins (ZO1 and E-cadherin) and collagen I, while reducing the expression of senescence markers (γ-H2AX, p53, and p21). Furthermore, we found that NAM effectively suppresses the senescence-associated secretory phenotype (SASP) factors’ expression in skin photoaging. Our research reveals the dual role of NAM in attenuating skin photoaging, acting not only to delay cellular senescence but also to suppress the SASP. Full article

(This article belongs to the Special Issue Natural Product in Skin Inflammation and Barrier Function Damage)

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22 pages, 2923 KB

Open AccessArticle

MYD88/TRIF Signaling, Pluripotency and Klotho Regulation in the Intestine, Kidneys, Liver, and Lungs of a Septic Mouse Model

by Maria Erodotou, Alkistis Kapelouzou, Konstantinos S. Mylonas, Ioanna Soukouli, John N. Boletis, Gerasimos Tsourouflis, Theodore Liakakos and Dimitrios Schizas

Curr. Issues Mol. Biol. 2026, 48(7), 660; https://doi.org/10.3390/cimb48070660 (registering DOI) - 26 Jun 2026

Abstract

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to multi-organ dysfunction. Toll-like receptor signaling via MYD88- and TRIF-dependent pathways plays a central role in this process; however, its temporal and tissue-specific dynamics remain incompletely understood. The aim [...] Read more.

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to multi-organ dysfunction. Toll-like receptor signaling via MYD88- and TRIF-dependent pathways plays a central role in this process; however, its temporal and tissue-specific dynamics remain incompletely understood. The aim of this study was to investigate time-dependent transcriptional changes in MYD88- and TRIF-dependent signaling pathways across multiple organs in a murine model of sepsis. mRNA expression of MYD88, IRAK1, IRAK4, NF-kB, CCL4, CCL20, CCR2, IFN-β, IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-18, Klotho, KLF4, HOXA5, NANOG and HIF1α was quantified using qRT-PCR in intestinal, kidney, liver and lung tissues at 24, 48, and 72 h following cecal ligation and puncture-induced sepsis in male C57BL/6J mice. Significant upregulation of innate immune signaling molecules, cytokines, chemokines, and interferon-related genes was observed in all tissues compared with controls. Genes associated with hypoxia and cellular regulation were also increased. These responses were tissue-specific and progressively intensified over time. Sepsis represents a dynamic, time-dependent, and tissue-specific process characterized by sustained activation of immune and hypoxic pathways, providing potential targets for time-stratified therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Insights into Pathogen–Host Interactions and Therapeutic Development)

22 pages, 4156 KB

Open AccessArticle

Molecular Effects of Indocyanine Green-Photodynamic Therapy on Programmed Cell Death Pathways in T98G and U-118MG Glioblastoma Cells—An RT-qPCR Study

by Klaudia Dynarowicz, Joanna Katarzyna Strzelczyk, Dorota Bartusik-Aebisher, Wiktoria Mytych, Alina Pietryszyn-Bilińska, Aleksandra Kawczyk-Krupka, Dorota Hudy, Oliwia Trzaskoś, Jacek Tabarkiewicz and David Aebisher

Curr. Issues Mol. Biol. 2026, 48(7), 659; https://doi.org/10.3390/cimb48070659 (registering DOI) - 26 Jun 2026

Abstract

Glioblastoma multiforme (GBM) remains one of the most aggressive primary brain tumors with poor prognosis despite multimodal therapy. Photodynamic therapy (PDT) using indocyanine green (ICG) is an emerging adjuvant approach aimed at eliminating residual tumor cells after resection. While ICG-PDT exerts cytotoxic effects, [...] Read more.

Glioblastoma multiforme (GBM) remains one of the most aggressive primary brain tumors with poor prognosis despite multimodal therapy. Photodynamic therapy (PDT) using indocyanine green (ICG) is an emerging adjuvant approach aimed at eliminating residual tumor cells after resection. While ICG-PDT exerts cytotoxic effects, its impact on molecular pathways regulating programmed cell death in glioma cells is not fully understood. In this study, T98G and U-118MG glioblastoma cells were divided into four groups: untreated control, light-only (10 min broadband irradiation), ICG-only (15 min incubation), and ICG-PDT (15 min ICG + 10 min broadband irradiation). Relative mRNA expression of apoptosis-related genes (BAX, BCL2, CASP3, FAS) and ferroptosis-related genes (GPX4, ACSL4, SLC7A11, GCH1) was quantified 24 h post-treatment by RT-qPCR using the 2^−ΔΔCt method. ICG-PDT significantly reduced cell viability to 67.79% ± 3.39% (vs. 86.66% ± 4.33% in control), confirming effective phototoxicity. No statistically significant differences in mRNA levels were observed for any of the investigated genes across the groups (one-way ANOVA and Kruskal–Wallis, all p > 0.05). The largest non-significant deviation was a mild decrease in GPX4 (fold change 0.87) in the ICG-PDT group. Fluctuations in GCH1 were accompanied by high variance, likely reflecting technical noise rather than a true biological trend. The mRNA BAX/BCL2 ratio remained stable (~30) across all conditions. In contrast, the U-118MG line showed greater transcriptional sensitivity, with statistically significant decreases in CASP3 (p = 0.012) and ACSL4 (p = 0.031) expression, along with downward trends in BCL2 and GPX4 following ICG-PDT. ICG-PDT does not induce significant transcriptional changes in the analyzed genes T98G at the 24 h time point under the applied experimental conditions. In U-118MG cells, moderate transcriptional engagement of both apoptotic and ferroptotic routes was observed. Further studies at the protein and functional levels, across multiple time points and models, are warranted to fully elucidate the mechanisms of ICG-PDT in glioblastoma. Full article

(This article belongs to the Special Issue Advanced Research in Glioblastoma and Neuroblastoma)

14 pages, 569 KB

Open AccessReview

Stem Cell-Based Strategies for Fibrotic and Neurogenic Bladder Disorders: Current Evidence, Translational Challenges, and Future Directions

by Jae Heon Kim, Miho Song and Yun Seob Song

Curr. Issues Mol. Biol. 2026, 48(7), 658; https://doi.org/10.3390/cimb48070658 (registering DOI) - 26 Jun 2026

Abstract

Progressive bladder fibrosis and impaired detrusor function represent converging pathological endpoints across diverse bladder disorders, including bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia, spinal cord injury (SCI)-induced neurogenic bladder, radiation cystitis, and interstitial cystitis/bladder pain syndrome. Conventional therapies primarily manage symptoms [...] Read more.

Progressive bladder fibrosis and impaired detrusor function represent converging pathological endpoints across diverse bladder disorders, including bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia, spinal cord injury (SCI)-induced neurogenic bladder, radiation cystitis, and interstitial cystitis/bladder pain syndrome. Conventional therapies primarily manage symptoms and rarely reverse established fibrosis or restore durable bladder homeostasis. Mesenchymal stem/stromal cells (MSCs) have attracted considerable interest as therapeutic agents owing to their antifibrotic, immunomodulatory, angiogenic, and trophic paracrine activities. This review synthesises six key studies from our group and places them within the broader international literature on bladder regenerative medicine: (i) feasibility of superparamagnetic iron oxide (SPIO)-based molecular MRI tracking of transplanted human MSCs (hMSCs) in the bladder; (ii) SPIO-hMSC therapy for BOO-associated fibrosis with concurrent MRI monitoring; (iii) hepatocyte growth factor (HGF)-overexpressing engineered hMSC (B10.HGF) therapy in BOO; (iv) hMSC transplantation into the SCI-injured bladder wall monitored by MRI; (v) systematic review and meta-analysis of stem cell therapy effects on urodynamic outcomes in SCI models; and (vi) HGF-overexpressing hMSC therapy for BOO-induced underactive bladder. These six key studies are contextualised within the broader literature addressing cell sources, biomaterial-assisted delivery platforms, mechanistic pathways, emerging clinical evidence, and the evolving regulatory landscape for cell-based advanced therapy medicinal products. Key translational challenges include product standardisation, long-term durability, and mechanism-linked potency assay development. Full article

(This article belongs to the Section Molecular Medicine)

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13 pages, 1993 KB

Open AccessArticle

IgM‒C4d Complex Causes the Inaccurate Measurement of Serum Uric Acid Levels via the Uricase Method

by Yuexinzi Jin, Yuan Mu, Li Wang, Bingfeng Zhang, Suli Ge, Huaguo Xu, Jian Xu and Jiexin Zhang

Curr. Issues Mol. Biol. 2026, 48(7), 657; https://doi.org/10.3390/cimb48070657 (registering DOI) - 25 Jun 2026

Abstract

Accurate measurement of serum uric acid (UA) is critical for disease assessment and therapeutic monitoring; however, numerous factors can compromise the accuracy of UA detection. This study describes a novel circulating immunoglobulin M (IgM)-involved protein complex that interferes with the uricase method and [...] Read more.

Accurate measurement of serum uric acid (UA) is critical for disease assessment and therapeutic monitoring; however, numerous factors can compromise the accuracy of UA detection. This study describes a novel circulating immunoglobulin M (IgM)-involved protein complex that interferes with the uricase method and reduces serum UA measurement accuracy. A total of 24 serum samples were collected from 18 patients, and complete clinical information and laboratory data were obtained. Samples were divided into three groups according to their UA reaction curves. Optical density values were extracted to analyze differential insoluble properties, serum viscosity was measured, coimmunoprecipitation was performed for IgM complex detection, and three additional clinical methodologies were used for UA measurement and comparison. All samples exhibiting unique reaction curves showed simultaneous elevations in IgM and complement component 4 (C4) levels. Circulating IgM formed a protein complex with C4d without significantly increasing serum viscosity. The insolubility of the IgM–C4d complex was attributable to the particular alkaline component of the uricase reagent. Inaccurate UA measurements could only be corrected by mass spectrometry. This study represents the first report of the circulating IgM–C4d protein complex. Given that serum UA serves as a crucial therapeutic indicator for specific patient populations, mass spectrometry is the preferred analytical method for accurate UA quantification in these individuals. Full article

(This article belongs to the Section Molecular Medicine)

18 pages, 699 KB

Open AccessReview

Assessment of Bioavailability and Related Bioactivity of Hydroxycinnamic Acids

by Elica Valkova, Vasil Atanasov, Kiril Kirilov, Kristian Yakimov and Yordan Kutsarov

Curr. Issues Mol. Biol. 2026, 48(7), 656; https://doi.org/10.3390/cimb48070656 (registering DOI) - 25 Jun 2026

Abstract

The aim of the present study was to evaluate the bioavailability and associated bioactivity of p-coumaric (p-COA), caffeic (CA), and ferulic (FA) hydroxycinnamic acids (HCAs) isolated from an aqueous extract of plant material. An aqueous extract is more applicable in practice because this [...] Read more.

The aim of the present study was to evaluate the bioavailability and associated bioactivity of p-coumaric (p-COA), caffeic (CA), and ferulic (FA) hydroxycinnamic acids (HCAs) isolated from an aqueous extract of plant material. An aqueous extract is more applicable in practice because this form is the most commonly used for oral administration. The p-COA, CA, and FA acids were evaluated for their behavior in the processes of absorption, distribution, metabolism, and excretion (ADME) using modern methods for assessing their functional groups according to Lipinski’s Rule of Five and the Rule of Nines. Given the available data on extensive metabolism of hydroxycinnamic acids during the first pass through the liver, it is necessary to consider an alternative route of administration, namely the sublingual route. Sublingual delivery of exogenous molecules obtained from plant material by extraction may represent a preferable alternative to oral administration, as first-pass hepatic metabolism is bypassed when dosage forms are administered sublingually. Full article

(This article belongs to the Special Issue Phytochemical-Based Therapeutics: Emerging Mechanisms and Biomedical Applications)

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16 pages, 25428 KB

Open AccessArticle

L-Menthol Attenuates Acetaminophen-Induced Acute Liver Injury Associated with Reduced Oxidative Stress and Ferroptosis-Related Changes

by Menglong Xu, Yongchao Li, Wenqiang Sun, Haocheng Guan, Tinghui Wu and Shuwei Li

Curr. Issues Mol. Biol. 2026, 48(7), 655; https://doi.org/10.3390/cimb48070655 (registering DOI) - 25 Jun 2026

Abstract

Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury and remains a widely used model of xenobiotic-induced hepatotoxicity. Oxidative stress, mitochondrial dysfunction, and ferroptosis are key events in APAP-mediated liver damage. In this study, we investigated whether L-menthol pretreatment protects against [...] Read more.

Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury and remains a widely used model of xenobiotic-induced hepatotoxicity. Oxidative stress, mitochondrial dysfunction, and ferroptosis are key events in APAP-mediated liver damage. In this study, we investigated whether L-menthol pretreatment protects against APAP-induced acute liver injury and explored the underlying mechanisms in vivo and in vitro. Male C57BL/6 mice were pretreated with L-menthol (100 mg/kg/day) for 7 days before APAP challenge (300 mg/kg). L-menthol markedly attenuated hepatic necrosis, inflammatory infiltration, and hepatocyte injury, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, suppressed IL-1β, IL-6, and TNF-α production, restored hepatic glutathione and superoxide dismutase levels, and decreased malondialdehyde accumulation. Transcriptomic analysis revealed significant enrichment of differentially expressed genes in reactive oxygen species- and ferroptosis-related pathways. In APAP-challenged HepG2 cells, L-menthol improved cell viability, preserved mitochondrial ultrastructure, reduced ferrous iron accumulation, was associated with upregulation of Keap1/Nrf2/HO-1/NQO1 pathway-related proteins, and restored GPX4 expression. Collectively, these findings indicate that L-menthol pretreatment attenuates APAP-induced hepatotoxicity, possibly through enhancement of antioxidant defenses and attenuation of ferroptosis-associated changes, supporting its potential as a preventive hepatoprotective small molecule against xenobiotic-induced liver injury. Full article

(This article belongs to the Section Molecular Medicine)

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19 pages, 7683 KB

Open AccessArticle

Multilocus Identification of Indigenous Trichoderma Isolates and Their Biocontrol Mechanisms Against Macrophomina in Northern Australia

by Dante L. Adorada, Encarnación E. Adorada and Niroshini Gunasinghe

Curr. Issues Mol. Biol. 2026, 48(7), 654; https://doi.org/10.3390/cimb48070654 (registering DOI) - 25 Jun 2026

Abstract

Charcoal rot, caused by the pathogen Macrophomina, is becoming an increasing challenge in Australia’s northern cropping systems, with few effective management options available. The use of non-indigenous biocontrol agents raises ecological and regulatory concerns, which highlights the need to identify locally adapted [...] Read more.

Charcoal rot, caused by the pathogen Macrophomina, is becoming an increasing challenge in Australia’s northern cropping systems, with few effective management options available. The use of non-indigenous biocontrol agents raises ecological and regulatory concerns, which highlights the need to identify locally adapted microbial antagonists. In this study, indigenous Trichoderma isolates were collected from rhizosphere soils across Queensland and northern New South Wales and characterised using multilocus sequencing (ITS, tef-1α, rpb2) coupled with phylogenetic analysis. Twenty-six isolates were resolved into six species, dominated by T. azevedoi and T. afroharzianum. Dual-culture assays revealed substantial variation in antagonistic capacity, with several isolates achieving >70% inhibition of Macrophomina growth and maintaining consistent performance across pathogen genotypes. Functional screening indicated that enzyme-associated antibiosis was widespread, whereas volatile-mediated inhibition was restricted to a small subset of isolates. These findings demonstrate that biocontrol potential in indigenous Trichoderma populations is highly strain-dependent rather than species-driven. By integrating multilocus identification with functional screening, this study provides a practical framework for selecting locally adapted biocontrol candidates. This work establishes a foundation for developing region-specific biological control strategies and supports a shift toward targeted, strain-level selection for effective management of charcoal rot. Full article

(This article belongs to the Special Issue Molecular Biology on Environmental Microorganisms)

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16 pages, 13006 KB

Open AccessArticle

Regulation of Imiquimod-Induced Mouse Psoriasis Development via Apoptosis Signal-Regulating Kinase 1 Potentially by Antagonizing Aryl Hydrocarbon Receptor Expression

by Hideaki Hasegawa, Aruma Watanabe, Yasuhiro Katahira, Izuru Mizoguchi, Tatsuo Maeda, Junya Mizugami, Isao Naguro, Hidenori Ichijo, Kazutoshi Harada, Yukari Okubo and Takayuki Yoshimoto

Curr. Issues Mol. Biol. 2026, 48(7), 653; https://doi.org/10.3390/cimb48070653 (registering DOI) - 25 Jun 2026

Abstract

Imiquimod-induced skin inflammation is the most widely used psoriasis mouse model. Although p38 mitogen-activated protein kinase reportedly plays a role in the pathogenesis of psoriatic inflammation, the purpose of one of its upstream activators, apoptosis signal-regulating kinase 1 (ASK1), remains unclear. This study [...] Read more.

Imiquimod-induced skin inflammation is the most widely used psoriasis mouse model. Although p38 mitogen-activated protein kinase reportedly plays a role in the pathogenesis of psoriatic inflammation, the purpose of one of its upstream activators, apoptosis signal-regulating kinase 1 (ASK1), remains unclear. This study investigated the role of ASK1 and its molecular mechanism in the imiquimod-induced psoriasis model. Compared to wild-type mice, the ASK1 knockout (KO) mouse skin lesion showed a higher clinical score and a thicker epidermis. The mRNA expression of pro-inflammatory cytokines, such as IL-17 and TNF-α, was also higher. Notably, the expression of aryl hydrocarbon receptor (AhR), a sensor for xenobiotic chemicals that is expressed in the skin to strengthen the skin barrier and accelerate terminal differentiation of the epidermis—as well as its downstream molecule CYP1A1, but not NRF2—was increased in the ASK1 KO psoriatic skin lesion. Immunoprecipitation analysis, followed by Western blotting, revealed that ASK1 interacts with AhR in cells transfected with their respective expression vectors, potentially leading to reduced AhR expression. These results suggest that ASK1 negatively regulates the development of the imiquimod-induced mouse psoriasis model by interacting with AhR and presumably antagonizing the AhR-CYP1A1 axis. Full article

(This article belongs to the Special Issue Exploring Molecular Pathways in Skin Health and Diseases)

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